Biochemical pharmacology of homologous alicyclic mixed amine platinum(II) complexes in sensitive and resistant tumor cell lines.
Three homologous alicyclic mixed amine cis-(NH3)(R-NH2)Cl2Pt(II) complexes, in which R = C3H5, C6H11, and C8H15 (complexes abbreviated C3, C6, and C8, respectively), were evaluated with reference compounds cisplatin and tetraplatin for antitumor activities and biochemical pharmacology in wild-type (murine leukemia L1210/0 and human ovarian A2780) and corresponding variant cell lines resistant to cisplatin (L1210/DDP and 2780CP) and tetraplatin (L1210/DACH and 2780TP). Cytotoxicities, measured by either a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or a clonogenic assay, were maximal for the C6 complex, which was up to 12-, 40-, and 6-fold more potent than C3 against wild-type, cisplatin-resistant, and tetraplatin-resistant models, respectively, and up to 2-fold more potent than C8 against these cell lines. In general, cross-resistance to mixed amine analogues was partial in cisplatin- and tetraplatin-resistant cells and decreased (in L1210/DDP and 2780CP) or increased (in L1210/DACH and 2780TP) with increase in the alicyclic ring size. The increase in ring size resulted in a corresponding increase in partition coefficient, which correlated directly with intracellular accumulations of mixed amine analogues in all cell lines. However, the intracellular DNA-platinum adducts, and not cellular platinum content, was the pharmacological entity that corresponded closely to potencies of the molecules. DNA adduct formation was disproportionate to the level of cellular drug accumulation. For instance, complex C8, which accumulated to the greatest extent in any given cell line, produced adduct levels that were similar to or lower than those produced by C6. A partial explanation for this observation was the demonstrated reduced rate of binding of C8 to DNA. This study has highlighted the significance of alicyclic ring size in modulating the potency, cross-resistance profile, and biochemical pharmacology of mixed amine platinum(II) complexes in sensitive and cisplatin- or tetraplatin-resistant tumor cells.
Department of Clinical Investigation, University of Texas M. D. Anderson Cancer Center, Houston 77030.
M
M
Yoshida
A R
AR
Khokhar
Z H
ZH
Siddik
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D003514:Cyclohexylamines / Q000378:metabolism* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007939:Leukemia L1210 / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; C030435:1,2-cyclohexanediamine; D002945:Cisplatin; C049777:ormaplatin