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Carboplatin has a mechanism of action identical to that of cisplatin, forming cross-links with guanine in DNA. At effective doses, carboplatin produces substantially reduced nephrotoxicity because of the dicarboxylate ligands which facilitate its excretion. Oxaliplatin has shown in vitro and in vivo efficacy against many tumor cell lines, including some that are resistant to cisplatin and carbopla-tin. The presence of the bulky diaminocyclohexane ring is thought to result in the formation of Pt-DNA adducts more effective at blocking DNA replication than in the case of cisplatin.

Oxaliplatin has a spectrum of activity different from that of either cisplatin or carboplatin and lacks cross-resistance with them, suggesting that it has different molecular targets and/or mechanisms of resistance.62 Unlike other platinum complexes, oxaliplatinum is useful in the treatment of colorectal cancer, the fourth largest cause for cancer deaths.63

Other Pt (II) compounds under clinical trials include nedaplatin, which is less toxic than cisplatin, but only moderately successful in overcoming cisplatin resistance, ZD-0473, which is able to overcome the thiol-dependent resistance with very little nephrotoxicity and neurotoxicity,64 and SKI-2053R, with considerably less toxicity than the parent molecule.65

Pt (IV) complexes appear to act by different mechanism, and evidence suggests that reduction to the corresponding Pt (II) derivatives is necessary for activity. For instance, the active species for JM 216 is believed to be JM 118 (Fig. 5.38).66

During the 1990s, it was reported that some trans-platinum complexes had activity against tumors resistant to cisplatin, implying differences in the DNA binding of both types of complexes. The trans isomer of cisplatin, called TDDP, is unable to form 1,2-intrastrand adducts due to its stereochemistry, but it forms interstrand cross-links between complementary guanine and cytosine and 1,3-intrastrand adducts, causing a different type of conformational distortion of the double helix.67 Another type of trans-platinum antitumor compounds are dinuclear and trinuclear Pt (II) complexes (containing two or three reactive platinum centers), designed to form long-range interstrand and intrastrand DNA cross-links. Two examples are compound 5.67 and the triplatinum complex BBR 3464, which has a broad spectrum of antitumor activity and is currently undergoing clinical trials.68 BBR 3464 forms DNA interstrand cross-links as well as 1,4-and 1,5-intrastrand cross-links, showing preference for the guanine-guanine

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