| Using Saccharomyces cerevisiae (S. cerevisiae ) DNA damage processing-compromised strains, nucleotide excision repair (NER), recombination repair (RR) and translesion synthesis (TLS) were identified as the pathways responsible for the processing of DNA lesions induced by the DNA-crosslinking anticancer drugs, cisplatin, nitrogen mustard, mitomycine, and carmustine. Processing of these lesions, however, requires substantially different contributions of NER, RR, and TLS. In contrast to the previously held belief, TLS and RR contribute to survival to a greater extent than NER in the processing of cisplatin-DNA lesions. Such knowledge can be used to design effective combinations of therapeutics. For example, nitrogen mustard and carmustine saturate capacity of the pathways even at relatively low concentrations, and act synergistically in the RR-compromised strain.;Using denaturing and non-denaturing gel electrophoresis, carrier-ligand size and chirality were found to influence resulting form of the self-complementary dodecamer, d(ApTpGpGpGpTpApCpCpCpApT). Bulky carrier-ligands with alkyl groups covalently linked to the nitrogen atoms were found to favor coil and duplex DNA forms, whereas less bulky ligands, favored coil and hairpin forms. Only chirality of nitrogen atoms was found to play a role in determining DNA form, whereas chirality of carbon atoms was found not to have an influence on the resulting DNA form.;Slight to moderate influences of carrier ligand chirality and bulkiness in various platinum compounds on DNA damage-processing were found using the same set of yeast strains. On the other hand, high overall toxicity was found to be determined by the chirality of both nitrogen and carbon atoms from carrier ligands. These data indicate that the chirality of carrier ligands is one of the major determinants of biological activity of platinum-based chemotherapeutics. |
