Antitumor activity of isomeric 1,2-diaminocyclohexane platinum(IV) complexes.
Acquired drug resistance is a major drawback of using cisplatin in the treatment of cancer; however, analogs containing the 1,2-diaminocyclohexane (DACH) ligand can overcome this resistance. DACH can exist as the trans-1R,2R, trans-1S,2S or cis isomer, and we have examined whether specific isomers coordinated to a platinum(IV) center can modulate antitumor activities in murine tumor models in vivo. Ten isomeric series of DACH-Pt(IV) complexes were synthesized, each series containing a different combination of axial and equatorial ligands and varying only by the isomeric form of the DACH ligand. Among the ten series, seven clearly indicated superiority of the (R,R)-DACH-Pt(IV) complex against leukemia L1210/0 cells, while in three the R,R and S,S configurations gave similar efficacies which were better than that of the corresponding cis analog. In three out of the ten series, the antitumor activities of the S,S and cis complexes were similar, in six the cis analogs were the least effective, and in the remaining one the cis analog was superior to S,S. One series of complexes with axial chloro ligands and an equatorial 1,1-cyclobutanedicarboxylato group, which had produced the efficacy ranking R,R > cis > S,S in the L1210/0 model, gave S,S > R,R > cis against cisplatin-resistant L1210/DDP cells, R,R = S,S > cis against B16 melanoma cells, and R,R = S,S = cis against M5076 reticulosarcoma cells. The results demonstrate that profound variation can occur in antitumor activities among isomeric forms of the DACH-Pt(IV) complex. However, the (R,R)-DACH-Pt(IV) complexes appear to be of greater interest overall.
Siddik
Z H
ZH
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston 77030.
al-Baker
S
S
Thai
G
G
Khokhar
A R
AR
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003514:Cyclohexylamines / Q000627:therapeutic use*; D007536:Isomerism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D009944:Organoplatinum Compounds; C030435:1,2-cyclohexanediamine