Platinum resistance mechanisms

Wiltshaw and B. Carr, in Platinum, Coordination Complexes in Cancer Chemotherapy, ed. T.A. Connors and J.J. Roberts, Springer-Verlag, Heidelberg, 1974, p. 178. 

Williams, L.Stewart, M. Parmar and D. Guthrie, Semin. Oncol., 1992,19 (Suppl 2), 120. 

Eisenhauer, K. Swerton, J. Sturgeon, S. Fine, S. O Reilly and R. Canetta, in Carboplatin Current Perspectives and Future Directions, ed. P. Bunn, R. Canetta, R. Ozols and M. Rozencweig, W.B. Saunders Company, Philadelphia, 1990, p. 133. 

Alberts, R. Canetta and N. Mason-Liddil., Semin. Oncol. 1990,17,54. 

Foster, B.J. Harding, M.K. Wolpert-DeFilippes, L.Y. Rubinstein, K. Clagett-Carr and B. Leyland-Jones, Cancer Chemother. Pharmacol., 1990, 25, 395. 

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As understanding of the mechanisms of platinum resistance has increased, more rationally designed platinum derivatives have been synthesized. One approach has been to insert steric... 

Cositecan (Karenitecin , BNP 1350) 54 (BioNumerik and ASKA Pharmaceutical) is currently being evaluated in a Phase III trial for the treatment of patients with advanced ovarian cancer who have become resistant to platinum and taxane drugs.110 Cositecan 54,111 114 which is also being evaluated against solid tumours in a Phase I trial, is an orally bioavailable, lipophilic 7-[2-(tri-methylsilyl)ethyl] derivative of camptothecin 55 which is less sensitive to both common and camptothecin-specific resistance mechanisms. Camptothecin 55 was first isolated in 1958 from Camptotheca acuminata (Nyssaceae) and its structure was reported in 1966.115 117 Camptothecin 55 was later shown to be a topoisomerase I inhibitor two camptothecin derivatives, topotecan and iri-notecan, are approved for chemotherapy use. 

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. 

Reactions between the sulfur-containing amino acids cysteine and methionine (Fig. 2.18) and rufhenium(II) arene anticancer complexes are of much interest in view of the strong influence of sulfur amino acids on the intracellular chemistry of platinum drugs, their involvement in detoxification and resistance mechanisms [100]. We found [101] that [(ri -biphenyl)Ru(en)Cl][PF 5] reacts slowly with the thiol amino add L-cysteine in aqueous solution at 310 K, pH 2-5, and only to about 50% completion at a 1 2 mM ratio. Reactions appeared to involve aquation as the first step followed by initial formation of 1 1 adducts via substitution of water by S-bound or O-bound cysteine. Two dinuclear complexes were also detected as products from the reaction. In these reactions half or all of the chelated ethylene-diamine had been displaced and one or two bridging cysteines were present The unusual cluster species (biphenyl) Ru g was also formed espedaUy at higher cysteine concentrations. The reaction was suppressed in 50 mM triethylammo-nium acetate solution at pH > 5 or in 100 mM NaCl suggesting that thiols may not readily inactivate Ru(II)-en arene complexes in blood plasma or in cells. Similarly, reactions with the thioether sulfur of methionine appeared to be relatively weak. Only 27% of [(r -biphenyl)Ru(en)Cl][PF5] reacted with L-methionine (L-MetH) at an initial pH of 5.7 after 48 h at 310 K, and gave rise to only one adduct [(ri -biphenyl) Ru(en) (i-MetH -S)]. ... 

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