Differential antitumor activity and toxicity of isomeric 1,2-diaminocyclohexane platinum (II) complexes.
Acquired resistance is a main drawback of using cisplatin in cancer chemotherapy; however, analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. Because DACH can exist as the trans-1R,2R, trans-1S,2S or cis isomer, the antitumor activity and toxicity of individual isomers of both DACH(sulfato)Pt(II) and DACH(1,1-cyclobutanedicarboxylato)Pt(II) complexes have been examined. At optimal doses, differences in antitumor activities among the three isomers were moderately dependent on the in vivo tumor models (L1210/0, L1210/DDP, B16 and M5076). However, differences in efficacy among these isomers were greatly modulated by the sulfate or 1,1-cyclobutanedicarboxylate (CBDCA) leaving ligands. Thus, the trans isomers (R,R and/or S,S) of the sulfate complex generally had greater activities than the corresponding cis form, while the cis configuration appeared to be superior in the complex containing the CBDCA ligand. The isomers were also compared for their potential to elicit myelosuppression and kidney toxicity. Of the six isomers investigated, cis-DACH(CBDCA)Pt(II) was myelosuppressive, and the corresponding R,R and S,S isomers were mildly nephrotoxic. No such toxicities were apparent with any of the sulfate complexes. From these studies, particularly with the cisplatin-resistant L1210/DDP cell line, the R,R isomers are evidently the most interesting. However, it is possible that other leaving ligands or tumor models may indicate either S,S- or cis-DACH as the isomer worthy of greater interest.
Siddik
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ZH
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030.
al-Baker
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S
Burditt
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TL
Khokhar
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AR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000633:toxicity; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C024236:1,2-diaminocyclohexyl platinum sulfate