Mechanisms exist and by the return of the usual

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mechanisms exist, and by the return of the usual cisplatin side effects, most notably kidney toxicity and neurotoxicity. In order to combat toxic effects to the kidneys, chemoprotector drugs have been introduced. Based on the known affinity of platinum(II) complexes for sulfur-donor ligands, sodium diethyldi- thiocarbamate (DDTC) has been given both to experimental animals and to hu- mans by i. v. infusion over about an hour following cisplatin administration. 53 DDTC inhibits many of the toxic side effects, particularly to the kidneys and bone marrow, without itself producing long-term side effects or apparently in- hibiting the antitumor properties of cis-DDP. Similar efforts have been made to reduce the toxic effects of cisplatin with other sulfur-containing compounds in- cluding thiosulfate and the naturally occurring biomolecules glutathione, cys- teine, and methionine. The relative amounts of the latter three molecules can be controlled by drugs that affect their normal cellular concentrations. Another approach to reducing cisplatin toxicity is to develop new classes of platinum drugs or different routes of their administration. Carboplatin (Figure 9.4) is one result of these efforts. The bidentate chelating dicarboxylate leaving group in carboplatin presumably retards the rates of reactions leading to toxicity, but does not adversely interfere with the chemistry required for antitumor activ- ity. Recently, promising platinum compounds for oral administration have been developed. 54 In Pt(IV) complexes of the kind cis, trans, cis-[Pt(NH 3 )(C 6 H lI NH 2 ) . (02CCH3hCh], where C 6 H ll NH 2 is cyclohexylamine, have been found to be effective in preclinical screens. The greater kinetic inertness of these complexes apparently renders them sufficiently stable to the chemically harsh environment of the gastrointestinal tract. Once absorbed into the bloodstream, these com- pounds are metabolized to the Pt(II) analogues, cis-[Pt(NH 3 )(C 6 H ll NH 2 )Ch], which are presumed to be the active form of the drug. The Pt(IV) compound has recently entered clinical trials. Although impressive inroads have been made in the management of human tumors by platinum chemotherapy, the fact remains that, apart from testicular and to a lesser extent ovarian cancer, the median survival times are measured in months. Clearly, there is much room for improvement. 3. Pharmacology49,52 Solutions of cisplatin are usually given in physiological saline (NaCl), since hydrolysis reactions occur that can modify the nature of the compound and its reactions in vivo (see below). Cisplatin is rapidly cleared from the plasma after injection, 70-90 percent of the platinum being removed within the first 15 min- utes. It has been found that more than half the platinum binds to serum proteins and is excreted. Most of the platinum exits the body via the urine within a few days. These results account for the use of multiple-dose chemotherapy at inter-
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V. PLATINUM ANTICANCER DRUGS: A CASE STUDY 529 vals of several weeks. Animal studies employing cis-DDP labeled with 195mpt, a 99 keV y-emitter with a 4. I-day half-life, reveal retention half-times in var-
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