Identifying biomarkers for resistance to novel cisplatin analogues in human lung, breast and prostate cancers

Identifying Biomarkers for Resistance to Novel Cisplatin Analogues in Human Lung, Breast and Prostate Cancers by Becky Michelle Hess Dr. Bryan L. Spangelo, Examination Committee Chair Professor of Chemistry University of Nevada, Las Vegas Cisplatin is a common therapeutic agent used in cancer treatment. Unfortunately, resistance to cisplatin in addition to severe side effects limits its use in cancer treatment. Two novel cisplatin analogues, 4DB and 4TB were shown to have varying cytotoxicity in lung, breast and prostate cancer cells. The hypothesis for this study states that the differences in 4DB and 4TB cytotoxicity among different tissue types is due to the type and efficiency of DNA repair mechanisms involved in response to these drugs. To test the hypothesis, proteins involved in the rate limiting step of nucleotide excision repair (NER) and mismatch repair (MMR) mechanisms were disrupted using stable shRNA transfectants. Survival assays using these cell lines revealed that suppression of MMR enhanced survival in breast and lung cancer cells with respect to cisplatin treatment. Suppression of NER enhanced sensitivity of prostate cancer cells to 4TB.