Differential cytotoxicity, uptake and DNA binding of tetraplatin and analogous isomers in sensitive and resistant cancer cell lines.

Abstract

Some platinum complexes contain 1,2-diaminocyclohexane (DACH) as a stable carrier ligand, which can exist as the R,R-, S,S- and cis-isomers. Tetraplatin, for instance, is a mixture of R,R- and S,S-DACH-Cl4-Pt(IV). We have examined each of the three individual isomers of DACH-Cl4-Pt(IV) with respect to cytotoxicity, uptake of platinum and total DNA-platinum in three murine leukemia L1210 (cisplatin-sensitive L1210/0, 50-fold cisplatin-resistant L1210/DDP and 36-fold tetraplatin-resistant L1210/DACH) and human ovarian carcinoma A2780 (cisplatin-sensitive) and A2780cp (8-fold cisplatin-resistant) cell lines. Against A2780, A2780cp and L1210/DDP cell lines, the R,R-isomer was the most potent followed by the S,S-isomer and then the cis-isomer. However, the three isomers demonstrated similar IC50 values against the L1210/0 and L1210/DACH cell lines. The cis-isomer demonstrated cross-resistance (9- to 20-fold) to cisplatin in L1210/DDP and A2780cp cell lines. On the other hand, R,R- and S,S-isomers demonstrated minimal (2- to 4-fold) cross-resistance against these tumor models. Intracellular platinum accumulation over a 2 h period at 40 microM drug concentration was significantly (p < 0.05) greater for the R,R-isomer than the cis-isomer in L1210/0 (122 versus 101 ng Pt/mg protein) and L1210/DDP (73 versus 50) cell lines, while no difference was observed in L1210/DACH cells (55 versus 56). In L1210/DDP cells, total DNA-bound platinum was significantly (p < 0.05) greater for the R,R-isomer compared with the cis-isomer (10.3 versus 7.5 ng Pt/mg DNA).(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: Y Kido, A R Khokhar, Z H Siddik
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 4 Issue 2 Pg. 251-8 (Apr 1993) ISSN: 0959-4973 [Print] England
• PMID: 8490203 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Platinum
• DNA
• Cisplatin
• ormaplatin

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Cell Division (drug effects)
• Cisplatin (metabolism, toxicity)
• Colony-Forming Units Assay
• DNA (metabolism)
• Drug Resistance
• Female
• Humans
• Isomerism
• Leukemia L1210
• Mice
• Organoplatinum Compounds (chemistry, metabolism, pharmacology)
• Ovarian Neoplasms
• Platinum (metabolism)
• Tumor Cells, Cultured