Circumvention of platinum resistance: structure-activity relationship for homologous series of ammine/amine platinum(II) complexes in L1210 cell lines.
Ammine/amine dichloroplatinum(II) complexes have been evaluated for structure-activity relationship in wild-type L1210/0, 185-fold cisplatin-resistant L1210/DDP and 39-fold tetraplatin-resistant L1210/DACH murine leukemia cells. The mechanism of resistance in these cell lines is multifactorial, with DNA repair playing a dominant role. The amines incorporated in the complexes were selected from the alicyclic, heterocyclic and isoaliphatic class, and contained 3, 4, 5 or 6 carbon atoms. The studies demonstrated that ascending each of the homologous series increased cytotoxic potency against sensitive and cisplatin-resistant cell lines and, more importantly, reduced the cross-resistance of cisplatin-resistant cells. Resistance factors (IC50 in resistant cells/IC50 in wild-type cells) were substantially lower than those for cisplatin, but greater than those seen for tetraplatin. In L1210/DACH cells, the potency remained similar across the alicyclic and isoaliphatic series, while there was a consistent decrease in activity in the heterocyclic series for each stepwise increase in amine size. Furthermore, the relationship between structure and resistance factor in L1210/DACH cells was in direct contrast to that seen in the L1210/DDP model in that the factors increased on ascending the homologous series stepwise. The lower members of the alicyclic and heterocyclic series and cisplatin had comparable resistance factors in the L1210/DACH line; higher members displayed resistance factors that were comparable to or greater than that of tetraplatin. These results provide evidence for amine class and size as factors that can modulate the potency and capacity of ammine/amine platinum complexes to circumvent cisplatin or tetraplatin resistance.
Yoshida
M
M
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Khokhar
A R
AR
Siddik
Z H
ZH
D000588:Amines / Q000138:chemical synthesis* / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000588:Amines; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D002945:Cisplatin; C049777:ormaplatin