Kleinsmith_treatment_Ch2

Kleinsmith_treatment_Ch2 - r.r r {it High-risk group...

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Unformatted text preview: r.r r {it High-risk group intermediate‘ risk group Lowerisk group Percent of patients with metastases at ten years i 0 10 20 3G 40 50 RECurrence score Figure 11-6 Ability at a Gene Expression Test to Predict Future Cancer Metastases. The data presented here are for the ()ncotype UK gene expression test, which measures the expression ofll key genes in breast cancer tissue and converts the data into a recurrence score. Higher recurrence scores indicate a higher likelihood of future metastases after the original breast cancer has been removed surgically. The breast cancers in this study had estrogen receptors, had not spread to lymph nodes at the time of initial diagnosis, and were treated with tamoxifen after surgery, ID'ala front 8. Pull: et a!” New England l', Merl. 35] {200-1}: it“? {Figure 11].] cancer whose tumors have a high recurrence score are more likely to develop metastases than are women whose tumors exhibit a low recurrence score. Such information is useful in guiding treatment strategies because patients with higher recurrence scores derive more benefit from subsequent chemotherapy. SURGERY, RADIATION, AND CHEMOTHERAPY People diagnosed with cancer have. a variety of treatment options available that depend both on the type of cancer they have and how far it has spread. The ultimate goal of traditional cancer treatments is the complete removal or destruction of cancer cells accompanied by minimal damage to normal tissues. This goal is usually pursued through a combination of surgery (when possible} to remove the primary tumor, followed {if necessary} by radiation, chemotherapy, or both to destroy any remaining cancer cells. Surgery Can Cure Cancers When They Have Not Yet Metastasized Surgical techniques for removing tumors were first described more than three thousand years ago, making surgery the oldest approach for treating cancer. lts early use, however, was severely limited by the excruciating pain caused in the absence of anesthetics and by the 208 Chapter 11 extremely high death rate from infections. The modern era of surgery was ushered in by the discovery of ether anesthesia in the 18405 and by the introduction of carbolic acid to inhibit bacterial infections in the [8605. By H590, these innovations had made it possible to perform the first mastectomy—«that is, complete removal of the breast in women with breast cancer. This milestone was followed in the early 1900:; by the development of surgical techniques for removing tumors from virtually every organ of the body. When people think of cancer surgery, they usually picture a doctor using a scalpel to cut out the tumor and perhaps surrounding tissues. Although that is certainly the most common surgical technique, a variety of newer procedures using different types of instruments have broadened the concept of what surgery is. For example, laser surgery utilizes a highly focused beam of laser light to cut through tissue or to vaporize certain cancers. such as those occurring in the cervix, larynx (voice box), liver. rectum, or skin. Electrosm‘gerJ-J, which involves high- frequency electrical current, is sometimes used to destroy cancer cells in the skin and mouth. (.‘r‘yosnrgery involves the use of a liquid nitrogen spray or a very cold probe to freeze and kill cancer cells. This technique is utilized for the treatment of certain prostate cancers and for precancerous conditions of the cervix such as dysplasia. Finally, high—intensity focused ultrasound {HlFUJ is a technique that focuses acoustic energy at a selected location within the body, where the absorbed energy beats and destroys cancer cells with minimum damage to surrounding tissues. When cancer is diagnosed before a primary tumor has spread to other sites, surgical removal of a tumor can usually cure the disease. In fact, most cancer cures are achieved in this way. But cancers arising in internal organs are difficult to detect in their early stages and have often metastasixed by the time they are diagnosed. Sometimes the metastatic tumors formed at distant sites are large enough to also be detected and surgically removed: in other cases, the body has simply been seeded with tiny clumps of cancer cells, known as mirromcrnstoses, that are too small to be detected. Because roughly half of all cancers (excluding skin cancers) have started to metasta- size by the time they are diagnosed, surgical removal of the primary tumor is frequently followed by radiation, chemotherapy, or both to attack any disseminated cells that were not removed during surgery. The growing use of follow-up radiation and chemotherapy has allowed surgeons to decrease the amount of surgery they need to perform on the average cancer patient. For example, the standard treatment for breast cancer between 1900 and IQFO was the radical mastectomy, a drastic and disfiguring operation that involves complete surgical removal of the breast along with the underlying chest muscles and lymph nodes of the armpit. However, radical mastectomies are rarely performed today because such extensive tissue removal has not been found to improve survival compared to less Cancer Screening. Diagnosis, and Treatment drastic procedures. From 1970 to I990 the most common procedure was the modified radical mastectomy, which involves removal of the breast and lymph nodes but not the chest muscles. Today more than half of all breast cancer patients are treated by partial mastectomy {itiiiipet‘toiin-'l, which removes just the tumor and a small amount of surrounding normal tissue. Surgery is usually followed by radiation therapy to the breast to destroy any cancer cells that may remain in the area. Radiation Therapy Kills Cancer Cells by Triggering Apoptosis or Mitotic Death If a tumor has invaded into surrounding tissues and pos- sibly metastasized to distant sites, surgery may not be able to remove all cancer cells from the body. In some cases, surgery is not even practical. For example, the location of a brain tumor may make it impossible to remove the tumor without causing unacceptable brain damage, and leukemias cannot be treated surgically because the cancer cells reside mainly in the bloodstream. When surgery is insufficient by itself or impractical, other treatments are used {often after surgery} to destroy any cancer cells that may still reside in the body. One type of treatment is radiation therapy, which uses high—energy X—rays or other forms of ionizing radiation to kill cancer cells. Ionizing radiation removes electrons from water and other intracellular molecules, thereby generating highly reactive free radicals that attack DNA. In Chapter 6 we saw that the resulting DNA damage can actually cause cancer to arise. Ironically, the same type of radiation is used in higher doses to kill cancer cells in people who already have the disease. Radiation treatments do create a small risk that a second cancer will develop in the future, but the risk is far outweighed by the potential benefit of curing a cancer that already exists. High doses of radiation kill cancer cells in two dif- ferent ways. First, DNA damage caused by the radiation treatment activates the pSB signaling pathway, which triggers cell death by apoptosis. Lymphomas and cancers arising in reproductive tissues are particularly sensitive to this type of radiation-induced apoptosis. However. more than half of all human cancers have mutations that disable the pS3 protein or other components of the p53 signaling pathway. As a consequence, p53-induced apoptosis plays only a modest role in the response of most cancers to radiation treatment. Radiation also kills cells by causing chromosomal damage that is so severe that it prevents cells from progressing through mitosis, and the cells die while trying to divide. Because this process of mitotic death only occurs at the time of cell division, cells that divide more frequently are more susceptible to mitotic death than cells that divide less frequently (or are not dividing at all). This difference in susceptibility makes rapidly growing cancers more sensitive to the killing effects of radiation than slower—growing cancers and also helps protect nondividing or slowly dividing normal cells in the surrounding tissue from being killed by the radiation. Radiation Treatments Are Designed to Minimize Damage to Normal Tissues To minimize damage to normal tissues, radiation treat— ments must be accurately focused on those regions ofthe body that contain tumor cells. This goal, called radiation planning, is accomplished by taking X—ray pictures that define the three—dimensional boundaries of the tumor and then using that information to guide a moving beam of high—energy radiation that is directed toward the target region from a number of different angles. Such an approach allows maximum radiation to be directed at the tumor area with minimal exposure to surrounding tissues. The effectiveness of radiation therapy is determined to a large extent by differences in the survival rates of normal versus cancer cells after irradiation. If the difference in survival rates is small and the entire radiation dose is administered as a single treatment, the survival curves will closely track one another and there will be little difference in the numbers of cancer cells and normal cells killed {Figure 11—7, left). It might be possible to destroy a tumor this way, but it would be at the expense ofa large amount of damage to normal tissue. If the same total amount of radiation is administered as a series of lower doses, however, small differences in the survival rates of normal and cancer cells after each treatment become magnified as the treatments are repeated multiple times (see Figure I 1—7, right). By the end of the series of treatments, all cancer cells could be destroyed while maintaining enough normal cells One large dose | Normal cells Multiple smaller closes 100 Cancer cells Survival (%}I —I- Radiation close —I- Radiation dose Figure 11 -? Effectiveness of Single Versus Multiple Radiation Doses in Cancer Treatment. {Left} If the difference in survival rates of normal and cancer cells after intense radiation exposure is small, there will be little difference in the percentage of cancer cells killed compared to normal cells following a single dose of radiation. {Right} If the radiation is administered as a series of smaller doses. thereby providing time for cells to repair radiation damage between exposures. small differences in the survival rates after each treatment become magnified as treatments are repeated multiple titties. [Adapted from A. S. lichter in Clinical ('Jncolagy EM. [1 Abelolf, ed, New York: Churchill Livingstone, ltllltii. Chapter 18 (Figure lei-29].! Surgery, Radiation, and Chemotherapy 209 to avoid serious tissue damage. For this reason, radiation therapy is usually divided into multiple treatments admin- istered over several weeks or months. An alternative approach for minimizing damage to normal tissues, called brachytherapy, uses a radiation source that can be inserted directly within (or close to) the tumor. For example, early stage prostate cancer is sometimes treated by implanting small radioactive pellets, about the size of a grain of rice, directly into the prostate gland. The pellets emit low doses of radiation for weeks or months and are simply left in place after the radiation has all been emitted. The advantage of this approach is that most of the radiation is concentrated in the prostate gland itself, sparing surrounding tissues such as the bladder and rectum. Another technique for improving the effectiveness of radiation therapy involves agents that sensitize tumor cells to the killing effects of radiation. One group of drugs, known as hypoxic rodiosensitizers, mimic oxygen and are taken up by cancer cells, which frequently tend to be hypoxic (deficient in oxygen). Radiation creates tnore cellular damage in the presence of adequate oxygen, so the uptake of these drugs by cancer cells increases the effectiveness of radiation therapy. Combining radiation treatments with certain anticancer drugs, such as fliiorouracil and platinum compounds, can likewise enhance the effectiveness of radiation treatments. The properties of these and related anticancer drugs will be described shortly, when we discuss the topic of cancer chemotherapy. Raising the temperature of tumor tissue by a few degrees—a technique known as hyperthermia—also sensitizes cells to the killing effects of radiation. Hyperthermia even works when it is administered rtjier radiation treatment, suggesting that the heat may be interfering with cellular repair pathways. The combination of radiation and hyperthermia is most effective for tumors that are located in relatively accessible regions of the body, where the applied heat can thoroughly penetrate the tumor tissue. The main difficulty with this approach is finding ways of applying heat to hard—to—reach tumors located deep inside the body. Radiation therapy is associated with various side effects that limit the dose of radiation that can be safely administered. The most serious problems arise in tissues containing large numbers of normal dividing cells, which are also susceptible to radiation—induced killing. For example, radiation damage to the dividing cells that line the gastrointestinal tract causes nausea, vomiting, and diarrhea. And damage to dividing cells in the bone marrow reduces the production of one or more types of blood cells, which can lead to anemia, defective blood clotting, and immune deficiencies that increase the sus- ceptibility to infections. The likelihood that such side effects will be severe depends to a great extent on the loca— tion of the tumor and its sensitivity to radiation—induced killing. Some cancers are very sensitive to radiation and can be destroyed with modest doses that elicit minimal 210 Chapter 11 Table 11-1 Radiation Sensitivity of Selected Cancers Sensitivity to Radiation Treatment Type of Cancer Very responsive to radiation Hodgkin‘s disease Non—Hodgkin’s lymphomas Seminoma (testicles) Neuroblastoma Retinoblastolna Moderately responsive to radiation Head and neck cancer Breast cancer Prostate cancer (Iervical cancer Esophageal cancer Rectal cancer Lung cancer Poorly responsive to radiation Melanoma (ilioblastoma Kidney cancer Pancreatic cancer 5a rcomas _,—__—_—.——— Data from A. S. Lichter in Clinical Ontology (M. I). Abelofl', eel. New York: (Ihurchill Livingstone, 2t]0lJ,Chapter IR}. side effects, whereas other cancers require high radiation doses and are more difficult to control using radiation (Table 11—1). Chemotherapy Involves the Use of Drugs That Circulate in the Bloodstream to Reach Cancer Cells Wherever They May Reside The third main approach for treating cancer (in addition to surgery and radiation) is chemotherapy, which involves the use of drugs that either kill cancer cells or interfere with the ability of cancer cells to proliferate. Chemotherapy is especially well suited for treating cancers that have already metastasized because drugs circulate through the bloodstream to reach cancer cells wherever they may have spread, even if the metastasizing cells have not yet formed visible tumors. This also means, however, that the toxic side effects commonly associated with chemotherapy can occur anywhere in the body because most anticancer drugs, like radiation, are toxic to dividing cells in general. Despite its various side effects, chemotherapy has been successfully applied to a wide range of cancers. In some cases, as with certain forms of leukemia, chemotherapy may cure cancer by itself. More com— monly, chemotherapy is employed in conjunction with surgery, radiation, or both. Dozens of anticancer drugs are currently available and the best choice will vary, depending on the type and stage of the cancer being treated. Based on differences in the way they work, the various drugs can be grouped into several distinct categories (Table 11-2). 1n the following sections, each category will be discussed in turn. Cancer Screening, Diagnosis, and Treatment Table 11-2 Examples of Some Drugs Used in Cancer Chemotherapy Class Examples Mechanism 0! Action _ Antinietabolites Metholresate l'lttofinlracil Cylarabitte (Iapecitabine (lemcitahine .\lercaptopurine 'l‘hioguanine 2. _-\ll\'_\'lating and platinatiiig agents tfyclopl‘iospliamidt‘ t Tlilorainbucil Melphalan lit INL' |_ bischloroethyl nilrosoureai (Lisplatin [l’latinol] fi. Antibiotics lloxorubicin lJaunorubit‘in Mitoinycin lileonti'cin -1. Plant- deriyed drugs litopositle Ilt‘ttiptisitle 'l'opolet'an lrinolecan \'inl1lastine \'int'ristine Tamil 3. Hormonetherapy Tamoxifen .-\rintidex l.euprollde lilutamide l’rednisone Mechloretliamine [nitrogen mustard}I Folic acid antagonist l’yriniidine analog Pyriniidine analog l’yrimidlne analog l’yrimidine analog l’urine analog l’urine analog l).\'t\ crosslinking agent DNA crosslinking agent l).\'.-\ crosslinking agent 1).\'.-\ crosslinking agent DNA crosslinking agent DNA crosslinking agent 'litpoisoliierase ll inliilil1or' 'l'opoisoiiierase ll inhibitor DNA crosslinking agent 1J.\'.-\ strand breaks 'l'opoisot‘ttel'dse ll inhibitor 'l'opoisoi‘ttel'ase ll inhibitor 'l'opolsoli‘lel'ase I inhibitor '{opoisomerase | inhibitor Antimicrol ubule agent Antimicrotulnile agent Antimln'otubule agent l‘llocks estrogen receptors [in lii'easti .»\roliiatase inhibitor Inhibitor of androgen production llloclss androgen receptors (ilucocorticoid _—_—,—__—.—-—-——— "l'here are two tot-ms ol' Itilttilstillk‘rau'. called topoisomerase [ and topoisornerase ll. Antimetabolites Disrupt DNA Synthesis by Substituting for Molecules Involved in Normal Metabolic Pathways Antimetabolites, the first group of chemotherapeutic drugs that we will consider, are molecules tltat resemble substances involved in normal cellular metabolism. This resemblance causes enzymes to bind to antimetabolites in place of the normal molecules, thereby disrupting essen- tial metabolic pathways and poisoning the cell. Most ot' the antimetabolites used in cancer chemotherapy disrupt pathways required For normal DNA synthesis and repair. The use of this approach for treating cancer was pioneered in the 1940s by Sidney Farber, who had been studying the nutritional needs of children with leukemia. Farber initially believed that vitamin therapy might help children fight off the disease, so he provided them with supplements of various vitamins, including the B vitamin, falir arid. Unexpectedly, the added folic acid made the leukemias grow even faster. While that was certainly not the desired result, it raised an intriguing possibility: II“ cancer growth is stimulated by excess folic acid, blocking the action of folic acid might have the opposite effect and restrain the disease. Earber therefore decided to treat some of his patients with i‘olic acid analogs, which are chemical derivatives of folic acid that can substitute for the natural molecule and thereby disrupt any pathways in which folic acid is normally involved. When one analog, called ritttiitopteriii, was given to several children who were very sick with leukemia, the children quickly regained their health and returned to virtually normal lives. Unfortunately, the improvement turned out to be only temporary, but these transient remissions caused a stir of excitement and stim- ulated the hunt for other antimetalmlites whose effects might be more permanent than those of aminopterin. The resulting search led to the discovery of metliotrexnte, a derivative of t‘olic acid that efficiently binds to and inhibits the enzyme u’iliytt’roiiii’ote rednctose [Figure ll—S). Dihydrol'olate reduclase catalyxes the Surgery. Radiation, and Chemotherapy 211 ' O J‘ c'H / \N/ (CH2): H ’ | COOH 0H T coon O | 1 “VA NR fi/ KN/CIH I I Xxx l H3C..\ {Clelz . H N” “H N” ; 2 N N H T”? COOH N I I Dihydrofolate N/ I “x. . k / E HzN N N I Methotrexate i I | i | | Dihydrofolate reductase O CIOOH N (CH2); H H 0" l H N COOH N l N/ I HZN/ “N N H H 5 1‘1 Tetra hyd rofolate 1 Required for the Shortly after its discovery, methotrexate was shown to be an effective treatment for choriocnrrinoma, a cancer arising from cells of the placental membranes that are sometimes left behind after childbirth. Choriocarcinoma was fatal for most women who developed the disease prior to the introduction of methottexate chemotherapy in the mid—1950s. After methotrexate began to be used, cure rates improved to almost 90%. Although its effects are not always this dramatic, methotrexate is currently used to treat a diverse spectrum of cancers, including acute leukemias and tumors of the breast, bladder, and bone. in addition to analogs of folic acid such as methotrexate, analogs of the nitrogenous bases found in DNA are also useful for cancer chemotherapy. DNA contains two types of bases: single-ring compounds called pyrimidines, which include the bases cytosine (C) and thymine (T); and double-ring compounds called purines, which include the bases adenine (A) and guanine (C). Figure 11-8 Mechanism oi Action at Methotrexa’re. Methotrexaie resembles folic acid in structure and can therefore bind to and inhibit dihydrofolate red uctase. an enzyme that normally “g; smmofmafll catalyzes the formation ofa reduced form g-ir DNA m of folic acid that is needed for I synthesizing bases found in DNA. ,_ "i If: 31* 'l . . . . . , . . . . . . a; production ofa reduced form of folic acrd that is required Several analogs of pyrimidines and purines are routinely if; for the synthesis of several bases found in DNA; inhibition used as anticancer drugs. Examples include the pyrimidine it: '1' of dih tdrofolate reductase b methotrexate therefore dis— analo s uomumcil and c rarribirre {also called c resins ._ -- l _ y Y _ v _g _)’ y rifl ' rupts pathways involved in DNA synthesis and repair. arubmoside) and the purine analogs mercuptopnrine and .: J thinguanine. As shown in Figure 11-9, the close resemblance of these substances to normal bases found in DNA causes the analogs to bind to and thereby disrupt the activity of enzymes involved in DNA synthesis and repair. Pyrimidine and purine analogs are used mainly for treating leukemias and lymphomas, although fluorouracil is effective against a broad spectrum of other cancers as well. Alkylating and Platinating Drugs Act by Crosslinking DNA Alkylating agents are highly reactive organic molecules that trigger DNA damage by linking themselves directly to DNA. As we saw in Chapter 5, this ability to attack DNA molecules makes alkylating agents mutagenic as well as carcinogenic. However, alkylating agents are also employed as anticancer drugs because they kill cancer cells at higher doses, and the risk that they may cause cancer in 212 Chapter 11 Cancer Screening, Diagnosis, and Treatment Normal bases Analogs I Pyrimidines I O 0 xx ,CH3 ,Lc F HN’ “if HN” “I ’ 4‘“ f/l I K“ I, J 0/ N 0/ 'N H H Thymlne Fluorouracil “I” N/ ,L' .- N O EArahinose Cytarabine Cytosine I Purines NH2 5 N W?“ ,N~-- xhe-sNH :J'W’ fr 5'" </ t l J \ _.-I ._ (,1 \‘ _.--- R,“ /I: N-’ 's. N N Adenine Mercaptopurine o .s N ' N <” </ | ”” N N c N NH: N NH2 Guanine Thioguanine Figure 11—9 Pyrimidine and Purine Analogs. In DNA, the bases thymine ['1‘] and cytosine [til are pyrimidines, and adenine {A} and guanine [(3) are purines. 'l'he pyrimidine analogs Ilttorouracil and cytarabine [cytosine arabinosidel. and the purine analogs mercaptopurine and thioguanine, are shown to illustrate lheir close resemblance to normal bases. Red is used to highlight the chemical groups that differ between the normal bases and their corresponding analogs. such cases is outweighed by the potential benefit of curing a cancer that already exists. The first alkylating agent to be employed for cancer chemotherapy has an interesting history. During World War I, the (ierman military used an oily alkylating agent called sulfur mustard as a chemical weapon because it vaporizes easily and cattses severe blistering injuries to the skin and lungs. A more toxic version, called nitrogen mustard, was produced and stockpiled by both Germany and the United States during World War II. Nitrogen mustard was never employed on the battlefield, but German bombers attacked an Italian seaport in 1943 and sank a US. supply ship loaded with 100 tons of weapons containing the toxic chemical. Survivors pulled from the water, which had become heavily contaminated with nitrogen mustard, exhibited severe skin bttrns and quickly developed a variety of internal symptoms, including a dramatic drop in the number of blood lymphocytes. (liven this toxic effect on lymphocytes, scientists at Yale University decided to investigate whether nitrogen mustard would have a similar effect on cancers arising from lymphocytes. Shortly after the end of\=\-"or|d War II, they reported that nitrogen mustard injections cause lymphocytic cancers to regress in animals and humans—— the first demonstration of the potential usefulness of alkylating agents as anticancer drugs. Better alkylating agents have subsequently been developed, but nitrogen mustard {now called niecltlorelltomrue) is still occasionally used to treat Hodgkin‘s lymphoma. Medical staff who handle the drttg take precautions to avoid inhaling the vapors of this one-time chemical weapon and mttst be certain that it is injected cleanly into a patient‘s vein without contacting the skirt. llased on the initial promising results with nitrogen ntustard, hundreds of other alkylating agents have been synthesized in the laboratory and tested in animals for anticancer activity. This effort has produced several drugs related to nitrogen mustard, including cyclopltosplmmidc, chlorttmhttcil, and melpltrrlrm, that are routinely used to treat cancer patients. In addition to substances related to nitrogen mustard, other alkylating agents have been developed for use as anticancer drugs, including tftiorepri and ititt-osotrrett compounds, such as BCNU [liiscltlot‘octltyl ttiti’osom‘c‘nl. In general, the various alkylating agents disrupt normal DNA function by crosslinking the two strands of the DNA double helix [Figure Il—lt), top}. As a result, the two strands are unable to separate and DNA replication cannot take place. thereby preventing cell division. Another group of li).\lA-crosslinking agents used in cancer chemotherapy contain the element plurimuu {see Figure ll—ltl, bottom}. The ability of these substances, called platinating agents, to act as anticancer drugs was discovered in a roundabottt manner. In some experiments performed during the 1960s that were totally unrelated to cancer biology, platinum electrodes were used to pass an electric current through a culture of bacterial cells to see how the cells react to electricity. The bacteria stopped dividing. but it was soon discovered that this response was caused not by the electricity but by art unexpected reaction involving the platinum electrodes. In essence, ammonium chloride present in the culture nteditttn had reacted with platinum iii the electrodes to form a nitrogen—containing platinum compound called risplttrin, which in turn inhibited bacterial cell division. The ability of cisplatin to block cell division led to successful tests on cancer cells, and the drug was approved for trials in human cancer patients in 19?2. Cisplatin (trade name Platinoli is now one of the most effective agents in our arsenal of anticancer drugs, and efforts are being made to synthesize derivatives of cisplatin that might work even better. Surgery. Radiation. and Chemotherapy 213 COOH (CH2); N H c/ \CH 2 2 / \ H2C CH2 \ / Cl Cl Cyclophosphamide \Cl C Chlorambucil ..-‘_ 'l.l« e'u i .i ii-i't‘ l'ku.‘ -' '- Cisplatin tPIarinol} Figure 11-10 DNA Grosslinking by Aikylaling and Platinating Drugs. The top ofthe diagram shows how nitrogen mustard and related drugs crosslink the two strands ofthe DNA double helix. The bottom of the diagram illustrates the comparable reaction for platinating drugs such as cisplatin (Platinol). Antibiotics and Plant-Derived Drugs Are Two Classes of Natural Substances Used in Cancer Chemotherapy Most of the antimetabolites and alkylating agents being I used as anticancer drugs are synthetic molecules that were created in the laboratory for the purpose of treating cancer. Over the centuries, humans have also found ways of treating disease by drawing on natural substances produced by living organisms. An especially dramatic twentieth—century example was the discovery of penicillin, a substance produced by a fungus that turned out to be one of the first effective drugs against bacterial infections. Penicillin is an antibiotic, a term that refers to any substance produced by a microorganism, or a synthetic derivative. that kills or inhibits the growth of other microorganisms or cells. Antibiotics are generally thought of as being antibacterial drugs, but some of them exhibit anticancer properties as well. One of the most fruitful sources of antibiotics for cancer chemotherapy has been a group of bacteria called Streptomyres. Besides producing streptomycin, which is an antibiotic used for treating tuberculosis and other serious bacterial infections, members of the Streptmnyres group synthesize several antibiotics that have found their way into our arsenal of anticancer drugs, including doxorulticin, (intriioritbicin, miromycin, and bleamycin. All these antibiotics target the DNA molecule, although their mechanisms of action are somewhat different. Doxorubicin and daunorubicin insert themselves into the DNA double helix and inhibit the action of topoisomerase, an enzyme that normally breaks and rejoins DNA strands during DNA replication to prevent excessive twisting of the double helix. In contrast. mitomycin is a DNA crosslinking agent and bleomycin triggers DNA strand breaks. Plants are another natural source of anticancer drugs. Several of the drugs obtained from plants act as topo- isomerase inhibitors; included in this category are etoposide and tertiposide, derived from a substance present in the mayapple (mandrake) plant, and topolecnit and irinotemn, derived from a substance present in the bark of the Chinese camptotheca tree. Another group of plant- derived drugs attack the microtubules that make up the mitotic spindle. This class of drugs includes vinblastine and vincrisrine, obtained from the Madagascar periwinkle plant, and Taxoi (generic name pnclitnxel), discovered in the bark of the Pacific yew tree. Vinblastine and vincristine block the process of tnicrotubule assembly, whereas Taxol stabilizes microtubules and promotes the formation of abnormal microtubule bundles. In either case, the mitotic spindle is disrupted and cells cannot divide. Hormones and Differentiating Agents Are Relatively Nontoxic Tools for Halting the Growth of Certain Cancers One of the main problems with the drugs described thus far is that their toxic effects on DNA replication and cell division are harmful to normal cells as well as to cancer cells. When cancers arise in hormone—dependent tissues, an alternative and considerably less toxic approach can sometimes be used. This approach, known as hormone therapy, was pioneered in the 1940s by Charles Huggins in studies involving prostate cancer patients. Based on earlier observations in animals, Huggins believed that the proliferation of prostate cells is dependent on steroid hor- mones known as androgens {testosterone is one example}. 214 Chapter 11 Cancer Screening, Diagnosis, and Treatment In an effort to eliminate the source of androgens in men with advanced prostate cancer, he surgically removed their testicles, which produce most of the testosterone, and also treated them with the female steroid hormone, estrogen. More than half of his prostate cancer patients improved and saw their tumor growth reduced. These early observations eventually led to the develop- ment of drugs that block the production or the actions of androgens as an alternative to removing the testicles. Androgen production is normally controlled by peptide hormones called gonndorropins. which are synthesized in the pituitary gland. One drug used to treat prostate cancer, named lenprolide, is an analog of the gonadotropin—relensing hormone that controls the release of these gonadotropins. By suppressing the release of gonadotropins, leuprolide inhibits androgen production by the testicles. Another group of drugs inhibit the activity of androgen receptors, which are receptor proteins located in prostate epithelial cells that bind incoming androgens and transmit the signal that stimulates cell division. Flurnmide and bicnlutnmide are examples of anticancer drugs that act by blocking androgen receptors. Similar considerations apply to breast cancers, which arise from cells whose normal proliferation is driven by steroid hormones of the estrogen family. For breast cancers that retain this estrogen requirement, drugs that block estrogen action may be effective cancer treatments. One widely used drug that works in this way is tamoxifen, a molecule that exhibits some similarities to estrogen in chemical structure (Figure 11—1 1). Estrogens normally exert their effects on target cells by binding to intracellular proteins called estrogen receptors. When tamoxifen is administered to breast cancer patients whose tumors require estrogen, it binds to estrogen receptors in place of estrogen and prevents the receptors from being activated. Another group of drugs, called aromntnse inhibitors, inhibit one ofthe enzymes required for estrogen synthesis. Generally these drugs are only recommended for treating OH HO' Tamoxifen Estradiol Flgure 11-11 Chemical Structures of Estradiol and Tamoxifen. Tamoxifen exhibits some similarities to estrogens in its chemical structure, which is enough to allow it to bind to estrogen receptors in place of normal estrogens. such as estradiol. The binding of tamoxifen to estrogen receptors in breast cells prevents the receptors from being activated. In some other tissues, such as the uterus. tamoxifen activates estrogen receptors instead of blocking them. Color shading is used to highlight the similarities between the two molecules. breast cancer in postmenopausal women, where they inhibit the synthesis of the small amounts of estrogen that are being produced. A somewhat different rationale is used when applying the principle of hormone therapy to lymphocytic cancers. The adrenal cortex produces a family of steroid hormones called glucocorticoids, whose properties include the ability to inhibit lymphocyte proliferation. Consequently prednisone, a synthetic glucocorticoid that slows down the proliferation of lymphocytes, is sometimes used in treating lymphomas and lymphocytic leukemias. One advantage of hormone therapies is that their side effects tend to be mild because they do not destroy normal cells and because they only affect a selected group of target cells whose proliferation is controlled by the hormone in question. On the other hand, this latter property also imparts a significant limitation: Hormone-based treatments are only useful for cancers that arise in hormone—dependent tissues. And even in these tissues, cancers do not always exhibit the hormone—dependence seen in the corresponding normal cells. For example, some breast cancers lack the estrogen receptors found in normal breast cells, and some prostate cancers lack the androgen receptors found in normal prostate cells. In such cases, hormone therapies are of little value. Another relatively nontoxic approach to cancer chemotherapy involves the use of substances called differentiating agents. Whereas hormone therapies are designed to restrain cell proliferation, differentiating agents promote the process by which cells acquire the spe— cialized structural and functional traits of differentiated cells. When cells undergo differentiation, they also lose the capacity to divide (p. 5). Agents that promote cell differentiation therefore tend to decrease the overall level of cell proliferation. An example of a differentiating agent used in cancer therapy is rerinoir acid, a form of vitamin A employed in the treatment of acute promyelocytic leukemia. Toxic Side Effects and Drug Resistance Can Limit the Effectiveness of Chemotherapy The ultimate goal of chemotherapy is to destroy or restrain the proliferation of cancer Cells without harming normal cells. However, with the exception of hormones and differentiating agents, which are useful for only a few selected types of cancer, most chemotherapeutic drugs act by inhibiting DNA replication. damaging DNA, or blocking cell division—actions that are detrimental to normal dividing cells as well as to cancer cells. Moreover, because chemotherapeutic drugs circulate throughout the body, they encounter normal dividing cells no matter where the cells reside. For example, the hair loss that commonly accompanies chemotherapy is a toxic side effect that is triggered when circulating drugs encounter the dividing cells that line the hair follicles. The most serious side effects of chemotherapy involve the gastrointestinal tract and the bone marrow. As with Surgery. Radiation. and Chemotherapy 215 .- «n: ‘e —£ ( _, fang. !-'-J .. it-LJ -' '-' radiation therapy, damage to normal dividing cells in these tissues can lead to nausea, vomiting, diarrhea, anemia, defective blood clotting, and immune deficiency. Such side effects usually tend to be more severe with chemotherapy than with radiation because drugs cannot be easily focused on a particular region of the body to minimize toxicity to the gastrointestinal tract and bone marrow. Fortunately, some cancer cells are particularly sensitive to chemotherapy and can be destroyed without excessive toxicity to normal cells; for many cancers, however, chemotherapy may fail because the drug dosage required to kill all cancer cells would trigger overwhelm- ingly toxic side effects. Another problem that can reduce the effectiveness of chemotherapy is the tendency for tumors to become resis- tant to the killing effects of anticancer drugs, especially after a prolonged series oftreatments. Even if most of the cancer cells in a person's body are destroyed by a partic- ular drug, a few drug-resistant cells present in the initial population could proliferate and form a new tumor that would then be completely resistant to the drug. And if drug-resistant cells are initially absent, cancers tend to be genetically unstable and may acquire mutations that impart drug resistance during the course of treatment. An illustration of this problem is provided by methotrexate, an anticancer drug that inhibits the enzyme dihydrojolate reductase (see Figure 11—8). In cancers that are being treated with methotrexate, the gene for dihydrofolate reductase sometimes undergoes mutation or amplifica— tion. The mutations create altered forms of dihydrofolate reductase that are no longer inhibited by methotrexate, and gene amplification leads to increased production of dihydrofolate reductase, thereby diminishing the effectiveness of methotrexate treatment. Such genetic changes, which alter the target of a drug to make it less susceptible to the drug’s effects, are commonly observed in individuals receiving chemotherapy. Given the large number of anticancer drugs available, it might seem that a simple solution would be to just switch drugs when resistance arises. Unfortunately, the situation is complicated by the fact that tumors often develop resistance to several drugs at the same time, even though only a single drug is administered. One way in which cancer cells become resistant to tnultiple drugs is by producing plasma membrane proteins that actively pump drugs out of the cells. These drug-pumping proteins, called multidrug resistance transport proteins, have a remarkably broad specificity: They export a wide range of chemically dissimilar molecules, thereby imparting resistance to a broad spectrum of drugs. Another factor that can contribute to multidrug resistance is related to the mechanism by which anticancer drugs kill cells. Although multiple killing mechanisms appear to be involved, chemotherapeutic drugs sometime act by damaging DNA to such an extent that apoptosis is invoked to destroy the damaged cell. In such cases, the effectiveness of chemotherapy may be reduced by mutations that disable apoptosis. Mutations of this type are often present at the time of initial diagnosis, or they may arise during chemotherapy. In either case, mutations that disable apoptosis would be expected to decrease the effectiveness of any drug that kills a particular type of cancer cell primarily by triggering apoptosis. Another possible source of drug resistance is related to the heterogeneity of tumor cell populations. A growing body of evidence suggests that in any given tumor, only a small population of cells, called cancer stem cells, are able to proliferate indefinitely. The existence of these cancer stem cells, which have been postulated to give rise to all the other cells found in a tumor, could help explain why treatments that cause tumors to shrink until they are undetectable may still not cure the disease. While the treatment may eliminate the bulk of the cancer cells, a few remaining cancer stem cells may be all that is needed to replenish the tumor cell population. According to this theory, existing anticancer drugs may be more effective at killing the majority of a person‘s tumor cells than they are at killing the rare cancer stem cells, which then regenerate the tumor after treatment is stopped. Researchers are currently exploring this idea by searching for cancer stem cells in various tumor types and testing to see whether they exhibit any unique properties that could be targeted by future anticancer drugs. Combination Chemotherapy and Stem Cell Transplants Are Two Strategies for Improving the Effectiveness of Chemotherapy For certain kinds of cancer, chemotherapy is successful in restoring normal life expectancies to many patients. Sometimes the chemotherapy by itself is responsible for the improved prognosis, but it is more common for chemotherapy to be used in conjunction with surgery or radiation. Despite these successes, the effectiveness of chemotherapy is often hindered by the emergence of drug resistance and by the toxic side effects that restrict the dose that can be safely administered. Additional chal- lenges are raised by the need for delivery techniques that convey drugs to tumor sites at the proper concentration for an appropriate period of time and by the existence of heterogeneous tumor populations containing mixtures of cells that respond differently to the same drug. One strategy for trying to improve the effectiveness of chemotherapy is to administer several drugs in combina- tion rather than a single agent alone. Drug combinations are often named using an acronym that is derived from the initials of the drugs being used. For example, BEP chemotherapy (bleomycin, etoposide, and Platinol) is the name of a treatment for testicular cancer, and CMF chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) is the name ofa treatment for breast cancer. This general approach, known as combination chemotherapy, is most effective with drugs that differ in their mechanisms of action. For example, consider three drugs exhibiting different side effects that limit the dose of each that can be safely administered. Combining the three 216 Chapter 11 Cancer Screening, Diagnosis. and Treatment drugs at their maximum tolerated doses will increase the overall tumor—killing effectiveness compared with each drug by itself, and yet the overall toxicity may remain at an acceptable level because each drug works in a different way. Another advantage of drug combinations is that cancer cells are less likely to become resistant to chemotherapy when several drugs are administered simultaneously, especially if the drugs differ in their chemical properties, cellular targets, and mechanisms of action. The enormous challenge of combination therapy is finding the most effective drug mixtures for each type of cancer, especially given the dozens of drugs that could in theory be administered in thousands of different combinations. Another approach for improving the effectiveness of chemotherapy deals with the potential problem of bone marrow damage. Many anticancer drugs are capable of killing all cancer cells if the dose is raised high enough. The dose that can be realistically administered, however, is limited by toxicity to the bone marrow, which contains the hematopoietic stem cells whose proliferation gives rise to blood cells. If too many of these stem cells are destroyed during high-dose chemotherapy, blood cells will not be produced and a person cannot survive. One approach for addressing this problem is to use high—dose chemotherapy to destroy all cancer cells and then follow the treatment with stem cell transplantation (also called bone marrow transplantation) to replenish the person’s hematopoietic stem cells. Under such conditions, higher drug doses can be used because the blood-forming stem cells destroyed by the chemotherapy are subsequently being replaced. The stem cells used for transplantation can be obtained either from a cancer patient’s own bone marrow or blood prior to administration of high—dose chemotherapy, or from the bone marrow or blood of a genetically compatible individual who is willing to serve as a stem cell donor. Unfortunately, each approach has its complications. Using a cancer patient's own stem cells for subsequent transplantation creates the risk of either rein- troducing cancer cells or relying on stem cells that have been damaged during earlier cancer treatments. On the other hand, finding an appropriately matched donor can be difficult, and immune cells present in the donor’s blood or bone marrow sometimes attack the tissues of the cancer patient, thereby creating a potentially life-threatening condition known as graft-versus-host disease. An alternative is to use umbilical cord blood rather than bone marrow or peripheral blood as a source of stem cells for transplantation. The umbilical cord, which is normally discarded at birth, contains blood with a large number of hematopoietic stem cells. These cells elicit a lower incidence of graft-versus-host disease, do not require as close a genetic match as do adult stem cells, and are readily obtained from blood banks that store frozen umbilical cord blood taken from healthy newborns. The possible usefulness of cord blood as a source of stem cells for cancer patients is currently under investigation. Molecular and Genetic Testing Is Beginning to Allow Cancer Treatments to Be Tailored to individual Patients A final approach for enhancing the effectiveness of chemotherapy involves the possibility of designing drug treatments that are personalized for each individual patient. it has been known for many years that cancer patients with tumors that are indistinguishable from one another by traditional criteria often exhibit different outcomes after receiving the same treatment. Experiments using DNA microarray technology to analyze gene activity have provided a likely explanation: Cancers of the same type exhibit different patterns of gene expression that cause them to behave differently. We saw earlier in the chapter that the Oncotype DX gene expression test, which measures the activity of2l key genes in breast cancer cells, is able to predict which patients are most likely to have their cancers recur after surgery. In the absence of such information, doctors would usually recommend that most patients receive chemotherapy. The value of gene expres— sion testing is that it can help identify those patients who really need chemotherapy and are likely to benefit from it. Taking this approach one step further, analyzing cancer specimens for gene expression patterns and the presence of specific mutations may provide information about the exact type of cancer treatment that is most appropriate for each person. A striking example is provided by lressa, a member of a new class of drugs that will be described later in the chapter when we cover the concept of molecular targeting. lressa. which acts by inhibiting the receptor for epidermal growth factor (EGF), has been approved for use in the treatment of lung cancer. Tumor shrinkage occurs in only about 10% of the patients treated with Iressa, but when the drug does work, it works extremely well. The reason lressa is more effective in some individ- uals than others has been traced to the presence of a mutant form of the EGF receptor gene in the cancers of those patients who respond well to the drug. When lung cancer cells containing the mutant form of the EGF receptor are grown in laboratory Culture, they are found to be much more sensitive to the gr0wth-inhibiting effects of lressa than are cancer cells that contain the normal form of the EGF receptor (Figure 11—12). This discovery opens the door to a personalized type of cancer therapy in which genetic testing of cancer cells is used to identify those particular patients who are most likely to benefit from treatment with Iressa. A patient’s hereditary background can also affect how he or she responds to different types of treatment. For example, inherited genes that influence steps in drug metabolism have been found to influence how well a person responds to different kinds of drugs. It is therefore hoped that a better understanding of patient-specific and tumor—specific differences in genetic makeup will eventu— ally allow treatments to be tailor-made for each individual cancer patient. Surgery, Radiation, and Chemotherapy 217 l 100 Normal EGF receptor 80 60 40 Cell viability 1% of control} Mutant EGF receptor 20 0.00] 0.01 0.1 1 1C- Iressa concentration mm Figure 11-12 Sensitivity at Lung Cancer Cells to Iressa. Lung cancer cells with or without a mutant EGF receptor were exposed to various concentrations oflressa in cell culture. After 72 hours oftreatment, the rate of cell proliferation was measured and expressed relative to the rate in cells that had not been treated with lressa. The data show that the presence of the mutant form of the EGF receptor makes lung cancer cells more susceptible to the growth~inhibiting effects of lressa. [Data from I. (i. Paez et al.. Science fill-'1 12004): I49? {Figure 3AM EMERGING TREATMENTS: IMMUNOTHERAPY AND MOLECULAR TAHGETING The use of surgery, radiation, or chemotherapy either alone or in various combinations—can cure or signifi- cantly prolong survival times for many types of cancer, especially when the disease is diagnosed early. However, some of the more aggressive cancers, including those involving the lung, pancreas, or liver, are difficult to control in these ways, nor are current approaches very successful with cancers diagnosed in their advanced stages. In trying to find more effective ways of treating such cancers, scientists have been working to develop “magic bullets” that will selectively seek out and destroy cancer cells without damaging normal cells in the process. Although this goal presents a formidable challenge, several approaches for achieving better selectivity in targeting cancer cells are beginning to show signs of success. lmmunotherapies Exploit the Ability of the Immune System to Recognize Cancer Cells One way of introducing better selectivity into cancer treatments is to exploit the ability of the immune system to recognize cancer cells. This general approach, called immunotherapy, was first proposed in the 1800s after doctors noticed that tumors occasionally regress in people who develop bacterial infections. Since infections stimulate the immune system, it was postulated that the stimulated immune cells might be attacking cancer cells as well as the 21 8 Chapter 11 invading bacteria. Efforts were therefore made to build on this idea by using live or dead bacteria to provoke the immune system of cancer patients. Some success was eventually seen with Bacillus Calmette-Guérin iBCG), a bacterial strain that does not cause disease but elicits a strong immune response at the site where it is introduced into the body. One use of BCG is in the treatment of early stage bladder cancers that are localized to the bladder wall. After the cancer is surgically removed, inserting BCG into the bladder elicits a prolonged activation of immune cells that leads to lower rates of cancer recurrence. Although this example demonstrates the potential value of stimulating the immune system, BCG must be administered directly into the bladder to provoke an immune response at the primary tumor site. With other types of cancer, especially when they have metastasized to unknown locations, it becomes necessary to stimulate an immune response against cancer cells wherever they may have traveled. For this purpose scientists have turned to molecules called cytokines, which are proteins produced by the body to stimulate immune responses against infectious agents. The first cytokine found to be helpful in treating cancer was interferon alpha, a protein produced in response to viral infections. Interferon alpha is used in the treatment of several kinds of cancer, including hairy cell leukemia and Kaposi‘s sarcoma. interleukin—2 (hi—2) and tumor necrosisfnctor [TNFJ are two other cytokines that are being evaluated for possible use as immune stimulators in cancer patients. lL—2 and TNF both elicit a strong antitumor response in laboratory animals, but they are extremely toxic when administered to humans. At present, TNF is still under active investigation and lL~2 is an approved treatment for advanced kidney cancer and melanoma. As we will see shortly, lL—2 is also being used experimentally to stimulate antitumor lymphocytes that are isolated from a patient’s tumor site and grown in the laboratory prior to being injected back into the bloodstream. Large Quantities of Identical Antibody Molecules Can Be Produced Using the Monoclonal Antibody Technique BCG and cytokines are relatively nonspecific approaches to immunotherapy because they strengthen the overall activity of the immune system rather than preferentially directing an attack against cancer cells. Devising immunotherapies that act more selectively requires approaches for distinguishing cancer cells from normal cells. The immune system sometimes recognizes cancer cells through the presence of specific antigens that cancer cells carry (see p. 38 for a discussion of tumor-specific and tumor-associated antigens). One way in which the immune system responds to antigens is by producing antibodies. which are soluble proteins manufactured by immune cells known as B lymphocytes. Antibodies circulate in the bloodstream and penetrate into extracellular fluids, where they specifically bind to the antigens that triggered the Cancer Screening. Diagnosis, and Treatment immune response. Antibody molecules recognize and bind to their corresponding antigens with extraordinary preci— sion, making antibodies ideally suited to serving as “magic bullets” that selectively target antigens that are unique to {or preferentially concentrated in) cancer cells. For many years, the use of antibodies for treating cancer was hampered by the lack ofa reproducible method for producing large quantities of pure antibody molecules directed against the same antigen. Then in 1975, Georges Kohler and César Milstein solved the problem by devising the procedure illustrated in Figure 11— 13. In this technique, animals are injected with material containing an antigen of interest, and antibody aproducing lymphocytes are isolated from the animal a few weeks later. Within Such a heteroge- neous lymphocyte population, each lymphocyte produces a single type of antibody directed against one particular antigen. To facilitate the selection and growth of individual lymphocytes, the lymphocytes are fused with cells that divide rapidly and have an unlimited lifespan in culture. The resulting hybrid cells are then individually selected and grown to form a series of clones called hybridomas. The antibodies produced by hybridomas are referred to as monoclonal antibodies because each one is a pure anti— body produced by a cloned population of lymphocytes. Hybridomas can be maintained in culture indefinitely and represent inexhaustible sources of individual antibody molecules, each directed against a different antigen. Monoclonal Antibodies Can Be Used to Trigger Cancer Cell Destruction Either by Themselves or Linked to Radioactive Substances The ability to obtain monoclonal antibodies in large quantities gave rise to high expectations regarding their usefulness for selectively targeting cancer cells. The basic strategy is to immunize animals with human cancer tissue 0 inject sample containing .intatp‘ns of interest into mouse to stimulate antibody formation. ._ __ / _ _ e Isolate antibody producing lymphocytes from -,]lillil:lll‘s spleen. @555). o Isointo single hybrid cells and cine-5.: a series of t Iona. 4, cell populations I.|iybz'ic|or“-asi -. t‘mt mt l] nuikiirs a single type of antibody. ‘\ % \Lymp©hoc ytes © © efi Cells that grow well in culture MAJ @ tag?) I 6 Fuse antibody gz-itirltitinc; I _ --| lymrjhoLytEs u.-'it:'irei|\1lir'i1 6' grow well :ai t llllLJll'. (a? l l C?) Hybrid cells l L. 5% Hybridorna A Hybridoma B Hybridoma C Monoclonal Monoclonal Monoclonal antibodyA antibody B antibodyC Figure 11-13 The Monoclonal Antibody Technique. This technique makes it possible to produce large amounts of pure populations of antibody molecules, each directed against a single anligcn. Many ofthe monoclonal antibodies isolated in any given experiment will be directed against antigens to which the animal has been exposed prior to the experiment, so extensive screening is required to find a hybridoma that makes an antibody directed against the antigen of interest. Emerging Treatments: lmmmunotherapy and Molecular Targeting 219 -1 l l l if Q _.—.—-—bv - against cancer cell antigen | Canceroull Toxin or Figure 11-14 Two Ways of Using Monoclonal Antibodies tor Cancer Treatment. target cancer cells by binding to tumor—specific antigens located on the outer cell surface. { Top] After monoclonal antibodies become selectively bound to cancer cells, the antibody‘s presence triggers an attack by other cells or proteins ot‘thc immune system. [_ Bottom} Antibodies can also he used as delivery vehicles for radioactive groups or other toxic substances. Linking them to monoclonal antibodies allows such subsl accumulating to toxic levels elsewhere in the body. and then select those monoclonal antibodies that bind to antigens on the cancer cell surface. When they are injected into individuals with cancer, these antibody molecules would be expected to circulate throughout the body until they encounter cancer cells. The antibodies then bind to the cancer cell surface, where their presence triggers an immune attack that destroys only those cells to which the antibody is attached [Figure 11—14, top). Antibodies can also be used as delivery vehicles for toxic molecules by linking them to radioactive substances, chemotherapeutic drugs, or other kinds of toxic substances that are too lethal to administer alone (Figure 11—14, bottom). Attaching these substances to monoclonal antibodies allows the toxins or radioactivity to be selectively concentrated at tumor sites by the antibody without accumulating to toxic levels elsewhere in the body. Although this strategy sounds simple in theory, several obstacles have slowed its application to cancer patients. One problem is that monoclonal antibodies are usually produced in mice by injecting them with human cancer tissue. The resulting antibodies are therefore recognized as foreign proteins when administered to cancer patients, who mount an immune response that 220 Chapter 11 \_23 WW Monoclonal antibody directed / radioactive group ' C) ances to be concentrated at tumor sites without \ '\.. _. at. - Bound antibody attracts ‘1 "4-2.; l} immune system proteins or c ” cells that destroy cancer cell n W . _ _ '\ 't . .s. - Toxrn 0r radroactivrty ‘2) "sag-23: 'f' bound to antibody '\__ r destroys cancer cell fl v’e/ Monoclonal antibodies can selectively inactivates the mouse antibody molecules, especially if the antibody is administered more than once. For this reason, monoclonal antibodies cannot be used for repeated treatments unless they are first made more human-like by replacing large parts of the mouse antibody molecule with corresponding sequences derived from human antibodies. A second complication encountered with monoclonal antibodies is that the cancer cell antigens they recognize may be present on certain normal cells as well. Each newly developed antibody must therefore be tested by linking it to a radioisotope and injecting it into patients to see whether the radioactivity becomes preferentially localized to sites where tumor cells are present. The preceding issues have complicated the develop- ment of antibody-based therapies, but several successes have already been achieved. For example, the monoclonal antibodies Ritirxmi, Zevaiin, and Bexxrtr are now among the approved treatments for non—Hodgkin's B cell lymphoma. All three antibodies target B lymphocytes for destruction by binding to the CD20 antigen, which is present on the surface of malignant as well as normal B lymphocytes. Although antibodies that target CD20 are toxic to normal B lymphocytes, C020 is not present Cancer Screening. Diagnosis. and Treatment (bl Treatment with antibody that targets CD20. when antibodies directed against C020 are injected into cancer patients with non—Hodgkin's B cell lymphoma, the (a) Before treatment. The CD20 antigen is present on the surface of both normal and malignant B lymphocytes, but not on the precursor cells that give rise to normal B lymphocytes. antibody binds to and promotes the destruction of normal and malignant B lymphocytes. Because C020 is not present on the precursor cells that give rise to B lymphocytes. these precursor cells remain unharmed. {c} After treatment. The unharmed precursor cells replenish the normal B lymphocyte population that had been destroyed by the antibody treatment. flannel cells B lymphocytes Precursor cells 0 @\ R 0 C020 antige I! Non—Hodgkin‘s B cell lymphoma cells B lymphocytes Figure 11-15 Use of Monoclonal Antibodies Directed Against CD20. When monoclonal antibodies directed against CD20 are injected into cancer patients with non-Hodgkin's B cell lymphoma. the antibody promotes the destruction of normal and malignant B lymphocytes. Unharmed precursor cells then replenish the normal B lymphocyte population. on the precursor cells whose proliferation gives rise to B lymphocytes. These precursor cells therefore replenish the normal B lymphocyte population that is inadvertently destroyed along with malignant B lymphocytes during antibody treatment (Figure 11-15). Besides being admin— istered by themselves. monoclonal antibodies directed against CD20 have been linked to radioactive chemicals and used to direct high doses of radiation to tumor sites, which may be more effective in killing cancer cells than the use of antibodies alone. Radioactive antibodies are also useful for determining where cancer cells are localized and for monitoring changes in tumor cell numbers in response to treatment. The value of monoclonal antibodies is not restricted to their ability to target cancer cells for destruction. Monoclonal antibodies have also been developed that target signaling pathway components required by cancer cells for their proliferation. For example. some breast cancer patients are being treated with Herceptin, a mono— clonal antibody that binds to and blocks a growth factor receptor. Because monoclonal antibodies are not the only tools used for targeting signaling pathway components, we will delay a discussion of this type of cancer therapy until the section on molecular targeting. Several Types of Cancer Vaccines Are Currently Under Development Antibodies are one of two basic mechanisms used by the immune system for attacking foreign antigens. The second mechanism, known as cell-mediated immunity, utilizes cytotoxic T lymphocytes that bind to the surface of cells exhibiting foreign antigens and kill the targeted cells by causing them to burst. This tactic is normally used to ——___.-, Emerging Treatments: lmmmunotherapy and Molecular Targeting 221 I .«..=-- -— .Kfl‘tZ'Dut ‘ "Til... 4—5.; r-._-=-u - ;—1er as s I... ii: A' . destroy cells harboring infectious agents such as viruses, bacteria, and fungi, and it also plays a role in the destruc- tion of foreign tissue grafts and organ transplants. The realization that cytotoxic T lymphocytes might be able to mount an attack against cancer cells first emerged in the 19405 from studies in which cancer was induced in mice by exposing them to carcinogenic chemicals or viruses. The resulting tumors were found to contain antigens whose administration to other mice immunized the animals against transplants of the same tumor. When T lymphocytes were isolated from the immunized animals, these T lymphocytes could kill tumor cells in culture and transfer tumor immunity when injected into other animals. In contrast, antibodies produced by the tumor—bearing animals were relatively ineffective at killing cancer cells or transferring immunity. These observations have stimulated interest in the idea of developing vaccines that will stimulate a cancer patient’s own T lymphocytes to attack cancer cells. The underlying rationale is that tumor antigens tend to be weak antigens that do not elicit a strong immune response, but an appro— priate vaccine might be able to present the antigens in a way that would stimulate the immune system to become more aware of their existence. Among the candidates for vaccine antigens are the abnormal proteins that cancer cells produce as a result of genetic mutations. Since these proteins are not produced by normal cells, putting them into vaccines should stimulate an immune response that is selectively directed against cancer cells. Other proteins that are overproduced by tumors might also be useful candi- dates for incorporation into cancer vaccines. it is possible to vaccinate cancer patients by simply injecting them with tumor antigens, but attempts are being made to improve vaccination efficiency by first introducing the antigens into dendritic cells for antigen processing. (Recall from Chapter 2 that triggering an effi- cient immune response requires that antigens be broken into fragments and presented to the immune system by antigen—presenting cells such as dendritic cells.) When dendritic cells obtained from cancer patients are grown in the laboratory together with tumor antigens, the dendritic cells take up the antigens, chop them into pieces, and present the resulting fragments on their cell surface in a way that activates an immune response. Experiments are currently under way to determine whether the injection of such antigennloaded dendritic cells into patients is a feasible tactic for treating cancer. Adoptive-Cell-Transfer Therapy Uses a Person’s Own Antiturnor Lymphocytes That Have Been Selected and Grown in the Laboratory Adoptive-cell-transfer (ACT) therapy is an alternative to vaccination in which a patient’s own lymphocytes are first isolated, selected, and grown in the laboratory to enhance their cancer—fighting properties prior to injecting the cells back into the body. The underlying reasoning is that individuals with cancer often possess 222 Chapter 11 lymphocytes that are capable of attacking tumor cells, but these lymphocytes are not produced in sufficient quantities to keep the tumor under control. ACT therapy attempts to solve this problem by removing some of these lymphocytes from the body and increasing their numbers by growing them in culture prior to reintro- ducing the cells into the patient. If a person with cancer has any lymphocytes that are capable of attacking tumor cells, the most likely place to find them would be within the tumor itself. Lymphocytes that are located at the tumor site, called rumor-infiltrating lymphocytes (TILs), have therefore been used as a source of cells for ACT therapy. In one set of studies, illustrated in Figure 11—16, multiple samples of TILs were isolated from the tumors of advanced stage melanoma patients and tested for their ability to attack tumor cells. TIL samples exhibiting the greatest anti-tumor activity were then selected and grown in culture in the presence of interleukin-2 (IL—2), a cytokine that stimulates the proliferation and cancer—destroying properties of the lymphocytes. Before introducing the tumor-killing lymphocytes back into the body, each cancer patient was treated with high-dose chemotherapy to destroy a large fraction of their existing lymphocytes. The tumor-killing lymphocytes were then injected back into the bloodstream and the patients were treated with IL—2 to further stimu~ late the proliferation of the injected cells. The net result was that tumor-killing lymphocytes became a large portion of each person’s immune system, and a significant number of patients experienced tumor regressions. ACT therapy is still an experimental procedure and will be difficult to apply to large numbers of patients, but these results suggest that cancer therapies may eventually be able to exploit the ability of lymphocytes to recognize and kill cancer cells. Several problems remain to be solved, however. First, the possibility exists that lymphocytes targeted against cancer cell antigens will mistakenly attack healthy cells possessing similar antigens. Another problem is that cancer cells can devise ways of evading immune attack (p. 39). For example, sometimes cancer cells acquire mutations that cause them to stop making the antigens being targeted by the immune system. in other cases, cancer cells become resistant to immune attack by pro— ducing molecules that either kill lymphocytes or disrupt their ability to function. Of course, the possibility that resistance will develop is not unique to immunotherapy; we have already seen that resistance arises with chemo- therapy as well. For this reason, a combination of different therapeutic approaches may end up being the best approach for treating cancer. Herceptin and Gleevec Are Anticancer Drugs That Illustrate the Concept of Molecular Targeting Until the early 1980s, research into new cancer treatments focused largely on the development of drugs that disrupt DNA synthesis and interfere with cell division. Although Cancer Screening, Diagnosis, and Treatment "" / 0 Remove lymphocytes from tumor site. © © ___. ———* Tumor—infiltrating © © ———“' © lymphocytes tTth) © © ———I~ .-. .r’ a Test TlLs for abitity to attack tumor cells and select TlLs with greatest antittlmor 0 Treat patient with high-dose chemotherapy to destroy most existing lymphocytes and thereby make room for the incoming antitumor lymphocytes. '6 Inject antiturnOr / lymphocytes back i into patient. .r' -'— 9 Grow best antitumor lymphocytes in the presence of interleukin 2 to expand their numbers rtr‘icl enhance their acu‘my' cancerdestroying properties. Figure 11-16 Adoptive-CeII-Transter Therapy. ACT therapy is an alternative to vaccination in which a patient’s own lymphocytes are isolated and grown in the laboratory to enhance their cancer—fighting properties prior to injecting them back into the body. Before reintroducing the antitumor lymphocytes. the patient is treated with high-dose chemotherapy to destroy most existing lymphocytes and thereby make room for the incoming antitumor lymphocytes, which become a large portion ofthe person‘s immune system. some of the resulting drugs have turned out to be useful in treating cancer. their effectiveness is often limited by toxic effects on normal dividing cells. In the past two decades, the identification of specific genes whose mutation or altered expression can lead to cancer has opened up a new possibility—molecular targeting—in which drugs are designed to target those proteins that are critical to the cancerous state. One way to pursue the goal of molecular targeting is to take advantage of the specificity of antibodies. Substantial efforts are currently being made to develop monoclonal antibodies that bind to and inactivate key proteins involved in the signaling pathways required for cancer cell proliferation. The first such antibody to be approved for use in treating cancer patients, called Herceptin, binds to and inactivates a cell surface growth factor receptor called the ErbBZ receptor, which is produced by the ERBB2 gene (also called HER2). About 25% of all breast and ovarian cancers have amplified ERBBZ genes, which produce excessive amounts of ErbB2 receptor that in turn causes hyperactive signaling. When individuals whose cancers overexpress the ErbBZ receptor are treated with Herceptin, the Herceptin antibody binds to the ErbBZ receptor and the ability of the receptor to stimulate cell proliferation is blocked, thereby slowing or stopping tumor growth. Monoclonal antibodies are not the only way to target specific molecules for inactivation. Another approach, called rational drug design, involves the laboratory synthesis of small molecule inhibitors that are designed to bind to and inactivate specific target molecules. Unlike antibodies, these inhibitors are small enough to enter cells and affect intracellular proteins. One of the first such drugs to be developed, called Gleevec (generic name imminib}, is a small molecule that binds to and inhibits the abnormal tyrosine kinase produced by the BCR—ABL oncogene present in chronic myelogenous leukemias. As described in Chapter 9, BCR—ABL is a fusion gene generated during the chromosomal translocation that creates the Philadelphia chromosome. Because it arises from the fusion of DNA sequences derived from two different genes, BCR—ABL produces a structurally abnormal protein—the Bcr—Abl tyrosine kinase——that represents an ideal drug target because it is produced only by cancer cells. Initial studies of the effectiveness of Gleevec as a treatment for chronic myelogenous leukemia were extremely encouraging. In patients with early stage disease, more than 50% had no signs of cancer six months Emerging Treatmentsr Immmunotherapy and Molecular Targeting 223 -q if- , . after treatment (a response rate ten times better than had been seen before). Unfortunately, patients with late stage disease frequently develop mutations that alter the structure of the Bcr—Abl tyrosine kinase, thereby making it resistant to Gleevec. Additional small molecule inhibitors that overcome this resistance to Gleevec have been devel— oped, but it takes many years to take each new compound through the necessary testing before it can be approved for routine medical use. A Diverse Group of Potential Targets for Anticancer Drugs Are Currently Being Investigated The drugs Herceptin and Gleevec illustrate two different approaches—monoclonal antibodies and small mole- cule inhibitors—for targeting specific proteins found in cancer cells. These two drugs are relatively recent accomplishments in the long history of cancer drug research; Herceptin was introduced in 1998 and Gleevec in 2001. As might be expected, their success has stimu- lated interest in developing other drugs that target molecules important to cancer cells. For example, the introduction of Gleevec in 2001 was followed in 2003 by another small molecule inhibitor called Iressa (generic name gefitinib). As mentioned earlier in the chapter, lressa targets the receptor for epidermal growth factor and is effective in a subset of lung cancer patients whose cancer cells possess a mutant form of the EGF receptor (see Figure 11—12). Dozens of other drugs based on the principle of molecular targeting are currently under investigation. Tyrosine kinases and growth factor receptors (the targets for Gleevec and Herceptin, respectively) are just two of many potential targets. As we saw in Chapters 9 and 10, the uncontrolled proliferation of cancer cells can be traced to disruptions in a variety of growth signaling pathways, including the Ras—MAPK, Jak—STAT, Wnt, and Pl3K—Akt pathways. Any of the proteins involved in these pathways could represent a potential target for an anticancer drug. Other proteins whose activities contribute to the six hall- mark traits of cancer cells (p. 195) might likewise be good candidates. Table 1 1-3 lists some examples of proteins in these various categories that are now being investigated as potential targets for anticancer drugs. Despite the attractiveness of molecular targeting, many of the drugs developed after the initial successes with Herceptin and Gleevec have failed to work well when tested in cancer patients. While such disappointments may simply mean that these particular drugs are ineffec— tive, several factors complicate the testing of anticancer drugs that could have contributed to the failures. First. targeted therapies would only be expected to work in those individuals whose cancer cells exhibit the appro- priate molecular target. Since cancers of the same type often differ in their molecular properties from person to person, obtaining a molecular profile of each person’s tumor might assist in identifying patients most likely to benefit from a given type of treatment. Second. testing of new drugs is generally done in patients who also receive standard chemotherapy, which might obscure the benefits of an experimental drug. For example, in the case of tamoxifen, which targets the estrogen receptor, inferior results are obtained when tamoxifen is combined with standard chemotherapy compared with giving tamoxifen either alone or after ii" if" P n Examples of Possible Targets for Anticancer Drugs é Target protein Pathway or Function Drugs APPVOVed' E ErbBl receptor Growth factor receptor Herceptin 3 '1 EGF receptor Growth faclor receptor lressa, Erbitux,Tarceva FGF receptor Growth factor receptor PIX“? receptor Growth factor receptor Vhtil“ Angiogenesis signaling Avastin Ber—Abl kinase Apoptosis signaling (ileevec Src kinase Ras—MAPK pathway Raf kinase Ras-MAI’K pathway .I Has Ras—MAPK pathway i (lyclin—dependent kinases Cell cycle progression 1’] 3-kinase PlfiK-Akt pathway Hsp90 Stabilizes growth signaling proteins Mdml Apoptosis inhibitor 8ch Apoptosis inhibitor I Matrix metalloproleinases lnvasionlmetastasislangiogenesis I Proteasome Targeted protein degradation Velcade Telomerase Limitless replicative potential ___________________—————————-——- 'lJrugs listed in this column have already been approved for treating cancer patients. 224 Chapter 11 Cancer Screening, Diagnosis. and Treatment chemotherapy. In theory, the most reliable results would be obtained by comparing a new drug given to one group of patients versus standard chemotherapy given to another group of patients. However, ethical considera- tions make it inappropriate to withhold standard treatment from the first group of patients if the standard treatment is known to be beneficial. A third type of problem is related to the need for better drug delivery methods that reliably convey drugs to tumor sites at the proper concentration for an appropriate period of time. In many cases, drugs are simply degraded too quickly after entering the body and do not accumulate in tumor tissues. One way to improve drug delivery is through the use of water-soluble polymers such as polyethylene glycol or N-(Z-ltydroxypropyl)methacryinmide. Binding drugs to these polymers prolongs a drug’s lifetime in the body and alters its pattern of distribution. The reason for the altered behavior is that the large size of drug—polymer complexes prevents them from passing out ofthe bloodstream and into cells as rapidly as the free drug itself. In addition, tumor blood vessels tend to be “leaky,” causing drug-polymer complexes to leave the bloodstream and enter tumor tissues more readily than normal tissues. A final problem that complicates drug testing is that clinical trials are usually carried out in late-stage cancer patients after all other treatments have failed. At this advanced stage, targeted molecular therapy may no longer be useful. For example, consider the behavior of drugs that inhibit matrix metniloproteinoses (MMPS), which are attractive targets because they play important roles in angiogenesis, tissue invasion, and metastasis (see Chapter 3). Animal studies have shown that MMP inhibitors are effective antitumor agents during the early stages of cancer progression, when tumor invasion and metastasis are just beginning. Human testing, however, has been performed mainly in patients with late stage disease, when MMP inhibitors appear to be largely ineffective. This is just one of many examples of experi- mental anticancer drugs that have been tested in late stages of cancer progression rather than early in the disease, when they are more likely to work. Such prob- lems are difficult to avoid for the simple reason that experimental new treatments are not likely to be tried on patients until other treatments have failed, at which point the disease may have reached an advanced stage that makes it unresponsive to targeted therapies. Anti-angiogenic Therapy Illustrates the Difficulties Involved in Translating Laboratory Research into Human Cancer Treatments We saw in Chapter 3 that tumor growth and metastasis depend on angiogenesis—that is, the growth of blood vessels that supply nutrients and oxygen to tumor cells and remove waste products. It is therefore logical to expect that angiogenesis inhibitors might be useful for treating cancer patients. Initial support for this concept of anti-angiogenic therapy came from the studies of Judah Folkman, who reported that treating tumor-bearing mice with the angiogenesis—inhibiting proteins angiosmtin and endosmtin makes tumors shrink and disappear (see Figure 3~6). When these experiments were first described in 1998 in a front page story appearing in the New York Times, a distinguished scientist was quoted as saying, “Judah is going to cure cancer in two years.” Needless to say, such sensational news coverage led to unrealistic expectations concerning the prospects for an immediate cancer cure. Applying the results of animal studies to human patients takes many years of testing, and humans do not always respond in the same way as animals. Dozens of angiogenesis-inhibiting drugs are therefore being evaluated in cancer patients to see if the promising results observed in animals will apply to humans. On the positive side, the early human studies showed that anti-angiogenic therapy elicits few of the harsh side effects seen with chemotherapy, and in a few cancer patients, tumors seemed to stop growing. However, some disappointment was expressed with the early results because they failed to show the quick cure for cancer that people had been led to expect. Of course, expectations for a quick cancer cure were unrealistic, and there are many reasons why it would be premature to come to any definitive conclusions at this point regarding the effectiveness of anti—angiogenic therapy. First, the early human trials were carried out mainly on cancer patients with late stage disease, and anti-angiogenic therapy may work better at earlier stages. Second, the optimal dose for angiogenesis-inhibiting drugs may need to be tailored to each individual patient based on the concentration of angiogenesis—stimulating molecules their tumors produce. Third, angiogenesis inhibitors may work best when their concentration within the body is maintained at a relatively constant level, which is quite different from the way in which standard chemotherapy is typically administered using large intermittent doses. Finally, the effectiveness of anticancer drugs is usually tneasured by assessing their ability to make tumors shrink or disappear. This outcome might be an appropriate expectation for a drug that kills cancer cells, but inhibiting blood vessel growth may simply stop tumors from becoming any larger. Such a state, called stable disease, could represent an acceptable outcome for an anti—angiogenic drug if it allowed patients to live with cancer as a chronic but manageable disease condition, especially in view of the minimal side effects associated with the use of angiogenesis inhibitors. The complexities raised by the preceding issues mean that it will take many years to assess the effectiveness of angiogenesis—inhibiting drugs and determine how best to use them. Nonetheless, signs of progress are already evident. In 2004, Avastin became the rst anti~angiogenic drug to be approved for routine medical use in cancer patients. Avastin is a monoclonal antibody that binds to and inactivates the angiogenesis—stimulating growth factor, VEGF (p. 48). In tumors that depend on VEGF to stimulate angiogenesis, blocking VEGF with Avastin Emerging Treatments: lmmmunotherapy and Molecular Targeting 225 _____4 a _.... .4” it} FR would be expected to inhibit angiogenesis and thereby inhibit tumor growth. Human clinical trials have shown that patients with metastatic colon cancer who received standard chemotherapy plus Avastin lived longer than patients who received standard chemotherapy without Avastin. These results were one of the first signs that anti-angiogenic therapy may one day become an integral component of human cancer treatment. Engineered Viruses Are Potential Tools for Repairing or Killing Cancer Cells Over the past two decades, the roles played by oncogenes and tumor suppressor genes in the development of cancer have become increasingly apparent. This discovery raises the possibility of attacking the disease at its root cause: defective genes. In other words, rather than trying to kill or restrain the proliferation of cancer cells, it might be possible to repair the defective genes that are responsible for the cancerous state. The process of replacing defective genes with normal versions is called gene therapy. Gene therapy was initially envisioned as a treatment for genetic diseases in which a person inherits a single defective gene, such as a gene responsible for cystic fibrosis. hemophilia, or certain immune deficiencies. Curing illnesses of this type would simply require that a normal copy of the single defective gene be inserted into a person’s cells under conditions that allow the inserted gene to be actively expressed. While the concept sounds simple in theory, it is difficult to transfer genes into cells efficiently under conditions that permit the transferred genes to become permanently incorpo- rated and expressed. As a result, gene therapy had been of limited usefulness in treating genetic diseases thus far. Applying gene therapy to cancer is even more compli- cated than treating an inherited genetic disease because it may be necessary to repair the defect in all cancer cells, not just some of them. Moreover, cancer cells usually exhibit defects in several genes rather than just one, although it may not be necessary to repair them all. As mentioned in Chapter 10. human cancers often exhibit defects in the p53 pathway that prevent cells from undergoing apoptosis. If this single pathway could be restored, the other abnormali- ties exhibited by cancer cells might trigger the p53 pathway and cause the cells to self-destruct by apoptosis. Attempts have therefore been made to repair the p53 gene in cancers in which this gene is defective (Figure 11-17). Support for this approach has come from animal studies showing that tumor regression can be induced by injecting animals with a virus whose DNA contains a normal copy of the p53 gene. In early human testing, a similar virus injected into the tumors of lung cancer patients has been found to restore p53 production and induce disease stabilization in some patients. An alternative to using viruses for gene therapy is to engineer them to kill cancer cells selectively. It has been known for many years that some viruses cause infected cells to rupture and die, a process called lysis. Attempts are 226 Chapter 11 Genetically engineered virus Normal copy of p53 gene / Viral DNA Cancer cell Figure 11-1? Strategy for Using Gene Therapy to Repair a Detective Cancer Cell Gene. Many human cancers exhibit defects in the p53 gene. If these defects could be corrected, restoration of the p53 pathway might cause cancer cells to self—destruct by apoptosis. Viruses engineered to contain a normal copy of the p53 gene have therefore been used in gene therapy experiments to infect tumors and insert the normal p53 gene into the DNA ofcancer cells. therefore being made to create viruses that selectively infect and cause the lysis of cancer cells. One ofthe first of these viruses to be tested in humans was ONYX—015, an adenovirus containing a mutation designed to permit the virus to replicate only in cells with a defective p53 pathway. Since the p53 pathway is defective in a majority of human cancers, it was predicted that ONYX—Oi 5 might be a broadly useful tool for killing cancer cells. Early investigations appeared to verify the ability of ONYX-015 to replicate preferentially in cancer cells, but follow-up studies failed to confirm the dependence of viral replica- tion on the presence ofa defective p53 pathway and future development ofthis particular virus is uncertain. ONYX—015, however, represents just one of many engineered viruses that are being developed to kill cancer cells without harming normal cells. Like ONYX-015, these viruses have been genetically altered to make their replica- tion dependent either on the absence of genes that are inactive only in cancer cells or on the presence of genes that are active only in cancer cells (Figure 11-18. left]. Another potential strategy is to modify viruses in ways that cause them to interact preferentially with cancer cells, Cancer Screening, Diagnosis. and Treatment H“ Outer coat protein Viral DNA Cancer cell Virus cannut genes all 1.; replicate in vir normal cell ' fl Cell bursts 3 and dies Figure 11 -18 Designing Viruses to Kill Cancer Cells. Modified outer coat protein \ Receptor made only by cancer cells Virus does not bind to cell surface receptor fit Q Cell bursts and dies Two experimental strategies are being pursued for creating viruses that might selectively kill cancer cells. {Left} One approach uses viruses that infect normal cells as well as cancer cells. The viruses are modified, however. to make their replication dependent either on the absence of genes that are inactive only in cancer cells or on the presence ofgenes that are active only in cancer cells. In either case, such viruses would be expected to replicate preferentially in (and therefore kill) cancer cells. (Right) Alternatively. the coat proteins of some viruses have been modified so that they bind to receptors that are only present on cancer cells. These viruses would be expected to infect cancer cells but not normal cells. perhaps by altering viral coat proteins so that they bind to receptors present on the surface of cancer cells (see Figure 11-18, right). Such approaches are currently under active investigation to see whether they might be of any use in the treatment of cancer. CLlNICAL TRIALS AND OTHER APPROACHES Before any new treatment can be incorporated into standard medical practice, it must first undergo a lengthy and painstaking evaluation process. In the early days of cancer research, identifying and evaluating new treatments was especially time consuming because anticancer drugs were often discovered through a largely random approach. For example, the National Cancer Institute established a massive screening program in the mid—19605 that system- atically tested thousands of chemical compounds for possible anticancer activity. Those substances that exhib— ited the most promise in killing cancer cells in laboratory culture or in animal studies were eventually tested in humans, and a number of drugs now used in cancer chemotherapy were discovered in this way. In recent years, our growing understanding of the molecular abnormalities exhibited by cancer cells has permitted more selective approaches for developing drugs that target cancer cells. Nonetheless, such drugs still require extensive testing before they can be incorporated into standard medical practice. The testing process, which is regulated in the United States by the Food and Drug Administration (FDA), requires that any drug proposed for human use first undergo preclinical testing in animals to demonstrate that the treatment is safe and effective. If successful, animal testing is followed by an extensive series of human tests to determine whether the drug works in humans and whether it compares favorably to existing methods oftreatment. Clinical Trials and Other Approaches 227 ...
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