Evaluation of novel ammine/amine platinum (IV) dicarboxylates in L1210 murine leukaemia cells sensitive and resistant to cisplatin, tetraplatin or carboplatin.
Seventeen alkylamine ammine dicarboxylatodichloroplatinum(IV) complexes of general structure c,t,c-[PtCl2(OCOR1)2NH3(RNH2)], where R = aliphatic or alicyclic and R1 = aliphatic or aromatic, have been evaluated against L1210 cell lines with acquired resistance to cisplatin (10-fold), tetraplatin (34-fold) or carboplatin (14-fold) using an in vitro growth-delay assay. All of these compounds overcame cisplatin, tetraplatin and carboplatin resistance. Potency increased as the number of carbon atoms in the axial aliphatic ligands (R1) increased, for example comparing JM216 (R = cyclohexyl, R1 = CH3, IC50 = 1.2 microM) with JM274 (R = cyclohexyl, R1 = n-C4H9, IC50 = 0.05 microM) against the parent sensitive line (L1210/S). The most active compounds were those possessing aromatic ligands at R1, regardless of whether R = aliphatic or alicyclic, for example JM244 (R = n-C3H7, R1 = C6H5, IC50 = 0.028 microM) and JM2644 (R = c-C6H11, R1 = C6H5, IC50 = 0.031 microM) against L1210/S. For an alicyclic alkylamine series in which R is varied from c-C3H7 to C-C7H13, with R1 = n-C3H7 for each compound, cytotoxic potency was maximised at c-C6H11 (JM221, IC50 = 0.06 microM against L1210/S). Preliminary biochemical studies, at equitoxic doses, comparing JM221 (0.1 microM) with cisplatin (0.6 microM) identified five times more platinum associated with JM221 treated cells and 1.5 times more platinum bound to the DNA of JM221-treated cells. The lipophilic properties of some of these platinum(IV) dicarboxylates may contribute to both the potency and circumvention of resistance by these compounds.
Orr
R M
RM
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
O'Neill
C F
CF
Nicolson
M C
MC
Barnard
C F
CF
Murrer
B A
BA
Giandomenico
C M
CM
Vollano
J F
JF
Harrap
K R
KR
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016190:Carboplatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; C075438:JM 221; D016190:Carboplatin; D002945:Cisplatin; C049777:ormaplatin