Biological Effects not Involving DNA

The emphasis on the primary role of DNA in cisplatin-induced cytotoxicity is reflected in the smaller number of studies on other aspects, although it should be stressed that any alternative explanation must account for the differing biological effects of the cis- and trans-isomers. 

The induction of giant nuclei in P. polycephalum occurs at concentrations which do not inhibit synthesis [73], and the authors compare these results with previous suggestions that perturbation of the mitotic machinery, rather than gross inhibition of DNA synthesis, could cause cell death [76, 77]. The translation of these results to a mammalian situation is, however, problematic. The preferential inhibition of the activity of a stimulatory protein of eukaryotic transcription has been reported [78]. 

Consideration of membrane as a target for chemotherapeutic drugs has been reviewed and relevant studies with cisplatin summarized [79]. The amino acid uptake mechanism in LI 210 cells is affected by cisplatin [80] and platinum complexes inhibit plasma membrane phosphatase activity in ascites cells [81]. Microtubule protein polymerization is also affected adversely [82]. Effects on mitochondrial functions and properties have been examined [83—86], along with studies on inhibition of sulfhydryl-containing enzymes [87—90]. 

The platinum complexes cisplatin, d5-[PtCl2(NH3)2], and its 1,1-cyclo-butanedicarboxylato analogue, [Pt(CBDCA) 113)2] have good clinical utility in the treatment of certain cancers. Initial studies on the antibacterial effects of platinum complexes led to the discovery of their antitumour potential. Toxic side effects may now in general be overcome by suitable clinical manipulation. The early dose-limiting nephrotoxicity is now circumvented routinely and sulfur nucleophiles are particularly effective in obviating this toxicity. 

A number of further second-generation analogues are undergoing evaluation for their clinical utility. Alteration of the amine may lead to complexes that are non-cross-resistant with cisplatin and the introduction into the clinic of such a complex is a high priority. A large quantity of biological and biochemical data indicates that the mechanism of action of cytotoxicity involves DNA binding with subsequent effects on the ability of the cell to replicate. 

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