Platinum antitumor compounds resistance

Antitumor drugs cisplatin as, history, 37 175-179 platinum compounds future studies, 37 206-208 resistance to, 37 192-193 second-generation, 37 178 Antiviral agents, 36 37-38 AOR, see Aldehyde oxidoreductase Aphanothece sacrum, ferredoxins, amino acid sequence, 38 225-227 Apo-calcylin, 46 455 Apo-caldodulin, 46 449-450 Apoenzyme, 22 424 Apoferritin biosynthesis, 36 457 cystalline iron core, 36 423 Fe(III)distribution, 36 458-459 Fe(II) sequestration, 36 463-464 ferroxidase centers, 36 457-458 iron core reconstruction in shell, 36 457 mineralization, 36 25 Mdssbauer spectra, 36 459-460 optical absorbance spectra, 36 418-419 subunit conformation and quaternary structure, 36 470-471... 

At the preclinical level, oral antitumor activity has been observed with two other classes of platinum compound, the PtIV monocarboxylate, C(5)-OHP-C1, and the first Ptn complex to exhibit oral activity, the sterically hindered AMD473. Now licenced to Zeneca, AMD473 exhibited promising circumvention of acquired cisplatin resistance against both in vitro and in vivo preclinical models. Together with the drug s favourable pharmacokinetic and toxicology profile in rodents (myelosuppression was dose-limit-... 

The success of cisplatin and carboplatin in treating cancer, combined with the intrinsic and acquired resistance of many tumors to traditional platinum chemotherapy, has generated considerable interest in developing next-generation platinum drugs. Since the discovery of the antitumor activity of cisplatin, researchers have reported the synthesis, characterization, and antitumor activity of thousands of platinum compounds [1] [2]. The previous two chapters in this section describe the promising activity of novel multi-nuclear Ptn and orally active PtIV complexes [3] [4],... 

Dinuclear and trinuclear compounds represent a new class of platinum anticancer complexes and are among the most studied platinum compounds in antitumor chemistry. Many of these complexes circumvent cisplatin-resistance mechanisms. In contrast to cisplatin, the polynuclear complexes predominantly form interstrand cross-links. The dinuclear complex [ tranx-PtCl(NH3)2 2 /u.-(H2N(CH2) NH2) ]2+ (l,l/t,t) (17, Figure 9) is antitumor-active and shows no cross-resistance in cisplatin-resistant cell fines. Binding studies sfiowed tfiat DNA binding for this compound is different from that for cisplatin, as illustrated by the increased interstrand cross-linking. However, clinical testing was abandoned because of severe neurotoxicity. 

Trivalent gold complexes were potentially attractive as anticancer agents because of their cytotoxic effects on established human tumor cell lines. All tested Au+ complexes substantially retained their antitumor potency against platinum-resistant tumor cell lines for leukemia and ovarian cancer. Cytotoxicity of these compounds in vitro is attributed to binding with DNA and modification and subsequent impairment of replication and transcription processes. The paucity of data on Au+ complexes probably derives from their high redox potential and relatively poor stability, which makes their use problematical under physiological conditions. 

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