Relationships between the aqueous chemistry and the in vitro cytotoxic activities of mixed-amine cisplatin analogues.
The possibility that variations in the cytotoxic activities of cisplatin analogues could be a result of differences in the aqueous chemistry of the compounds was investigated. A series of structurally related mixed-amine dichloroplatinum complexes (cis-coordinated with amine and various diphenylmethylamines and 1,2-diphenylethylamines) was prepared and selected physicochemical properties of the new compounds were characterized. Cytotoxicity was determined in two human breast cancer cell lines (MDA-MB-231 and MCF-7) and one human ovarian cancer cell line (SK-OV-3) by means of a microtiter assay. There is no apparent relationship between the hydrophobicities of the compounds and their cytotoxic potencies. There is no evidence for an inverse relationship between the aqueous stability of the dichloroplatinum complexes and cytotoxic potency, as has been reported for nitrogen mustards and some nitrosoureas. The differences in cytotoxic activity cannot be explained by inter-compound variations in the area under the concentration-time curves (AUC) of the dichloroplatinum complexes in culture medium. Thus, it appears that the differences in the cytotoxic potencies of this series of cisplatin analogues are related to factors other than dissimilarities in these physiochemical properties. Nevertheless, a relationship was found between the AUC of a dichloroplatinum complex in medium and the efficacy of the compound in the MCF-7 cell line. However, the AUC-efficacy relationship does not always hold in the MDA-MB-231 and SK-OV-3 cell lines. In these cells, treatment with a "high" bolus dose of platinum complex over finite exposure times is often less cytotoxic than treatment with lower doses of the same compound but over a continuous exposure time, although the cells are subjected to the same AUC of dichloroplatinum complex.
Bednarski
P J
PJ
Institut für pharmazeutische Chemie II, Fakultät Chemie-Pharmazie, Universität Regensburg, Germany.
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry; D003470:Culture Media / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006868:Hydrolysis; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D013810:Therapeutic Equivalency; D013997:Time Factors
D003470:Culture Media; D002945:Cisplatin