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Modulation of Cytotoxicity and Cellular Pharmacology of 1,2-Diaminocyclohexane Platinum(IV) Complexes Mediated by Axial and Equatorial Ligands¹

Department of Clinical Investigations. The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

² To whom requests for reprints should be addressed, at Department of Clinical Investigations (Box 52), The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

Isomers (R,R-, S,S-, and cis-) of 1,2-diaminocyclohexane (DACH) platinum(IV) complexes with selected axial and equatorial ligands were synthesized and evaluated for in vitro antitumor activity, cellular uptake, and total DNA-Pt adducts. L1210 cells, sensitive to cis-diamminedichloroplatinum(II) (CDDF) and tetraplatin (L1210/0), 160-fold resistant to CDDP [L1210/diamminedichloroplatinum (DDP)], or 70-foid resistant to tetraplatin (L1210/DACH), were used in conjunction with compounds having the general structure DACH-Pt(IV)-X₂Y₂, where X and Y are axial and equatorial ligands and X₂Y₂ are specifically CI₂CI₂, Ac₂CI₂, (TFA)₂CI₂, (OH)₂CI₂, and CI₂CBDCA (CI, chloro; Ac, acetato; TFA, trifluoroacetato; OH, hydroxo; CBDCA, 1,1-cyclobutanedicarboxylato). Comparison of cytotoxicities between isomers of CI₂CI₂, Ac₂CI₂, or CI₂CBDCA indicated that R,R-isomers were the most effective against all three cell lines. The relatively lower activity of the S,S- and cis-isomers was cell line dependent: against L1210/DACH, both isomers of CI₂CI₂ were only 2- to 3-fold less effective, and this contrasted with 7- and 26-fold lower cytotoxicities, respectively, against L1210/DDP. Cross-resistance factors in the L1210/ DDP and L1210/DACH lines depended on both isomeric form and the nature of axial or equatorial ligand. The L1210/DDP cells were 6- to 9-fold cross-resistant to the R,R-isomer, 8- to 15-fold to S,S-isomer, and 13- to 38-fold to cis-isomer. The L1210/DACH line was only 4- to 7-fold cross-resistant to the three isomers of Ac₂CI₂, but cross-resistance to the isomers was 47- to 79-fold for CI²CI² and 22- to 56-fold for CI²CBDCA complexes. Compared with CDDP, accumulation (2 h at 100 µM drug concentration) of Ac₂CI₂ in the three L1210 cell lines was 26–50%, while uptake of CI₂CI₂ and (TFA)₂CI₂ was 100–170% and 320–570%, respectively. The greatest DNA binding was seen with CI₂CI₂ in all cell lines, followed by (TFA)²CI², CDDP, and Ac²CI². DNA binding correlated directly with potency (1/ concentration producing 50% inhibition) in the L1210/0 model (r = 0.973, P < 0.016) but not in the L1210/DDP and L1210/DACH models. Accumulation and DNA-binding studies indicated that binding efficiency to DNA was: CI₂CI₂ > Ac₂CI₂ > CDDP > (TFA)₂CI₂. In a nonreducing environment, the Pt(IV) complexes (20 µM) did not react with salmon sperm DNA. Reduced glutathione (100 µM), as a reducing agent, rendered full binding capacity to CI₂CI₂; binding was 25–30% of the expected maximum for (TFA)₂CI₂, while Ac₂CI₂ remained inert. These data indicate profound effects of axial and equatorial ligands in Pt(IV) complexes on the antitumor activity and cellular pharmacology of the compounds. The investigations also identified Ac₂CI₂ as of particular interest because of its low cross-resistance in the L1210/DDP and L1210/DACH cells.

¹ This work was supported in part by grants R01 CA-41581 and R01 CA-50380 from the National Institutes of Health.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 1/93. Accepted 7/28/93.

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