Ammine/amine platinum(IV) dicarboxylates: a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin-resistant human ovarian carcinoma cell lines.
Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c,t,c-[PtCl2(OCOR1)2NH3(RNH2)]. A clear relationship existed between increasing the number of carbons in the R1 substituent and increasing cytotoxicity up to R1 = C5H11. In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains (e.g., JM300, R = cyclohexyl, R1 = C6H13) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines (e.g., for HX/62, cisplatin 50% inhibitory concentration, 12.6 microM; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 microM and 41 M; cisplatin 50% inhibitory concentration, 0.23 microM; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 (R = cyclohexyl, R1 = C3H7) and JM244 (R = n-propyl, R1 = C6H5) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a "third-generation" agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.
Kelland
L R
LR
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Murrer
B A
BA
Abel
G
G
Giandomenico
C M
CM
Mistry
P
P
Harrap
K R
KR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D015394:Molecular Structure; D010051:Ovarian Neoplasms; D010984:Platinum / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D003998:Dicarboxylic Acids; D010984:Platinum; D002945:Cisplatin