The long-term objective of our laboratory is to understand the molecular mechanisms of cisplatin drug resistance and to identify biological and pharmacological agents that may reverse drug resistance to cisplatin in human ovarian cancer. Although the mechanism of cisplatin resistance in vivo is not clearly defined, laboratory studies on tumor tissues and cell lines suggest that enhanced nucleotide excision repair (NER) of cisplatin-caused DNA damage may play a crucial role in the development of cisplatin-resistance phenotype. SU5416 is a selective inhibitor of the vascular endothelial growth factor (VEGF)/Flk-1 signal transduction pathway, a critical pathway implicated in angiogenesis, and it is currently on phase III clinical trial for use in the treatment of human cancers. However, the effect of SU5416 on cisplatin sensitivity in human tumors is not known. Recently, we have found that SU5416 increases sensitivity to cisplatin and decreases proficiency of DNA repair in resistant human ovarian cancer cells. Furthermore, SU5416 was found to inhibit cisplatin-induced increases in Raf-1 protein and c-jun mRNA levels as well as JNKI activity in these cells. These novel findings suggest that SU5416 may exert another action in cisplatin resistant tumors. Therefore, based on our observations, we hypothesize that the sensitivity to cisplatin is enhanced by SU5416 through regulating, directly or indirectly, on Ras/JNK/AP-1 pathway leading to nucleotide excision repair gene expression in human ovarian cancer. Understanding the mechanism of SU5416 action in cisplatin toxicity could lead not only to a better understanding the mechanisms of molecular pathways regulating NER activity, but also to the definition of new therapeutic applications in resistant ovarian cancer. To further explore the potential therapeutic application of SU5416 in sensitizing ovarian cancer cells to cisplatin and the underlying mechanisms, we will (1) establish a model system for studying the effect of SU5416 on the modulation of cellular sensitivity to cisplatin in human ovarian cancer; (2) assess the effect of SU5416 on the levels of expression of known NER DNA repair genes in human ovarian cancer cells; 3) determine the mechanisms underlying the effect of SU5416 on the altered cisplatin cytotoxicity and DNA repair activity in human ovarian cancer cells; 4) demonstrate that the Ras/JNK/AP-1 signaling pathway plays a critical role in the control of NER activity and the regulation of NER gene expression by SU5416 in human ovarian cancer cells; and 5) identify markers that will be used in the future to predict which cells are likely to respond favorably to cisplatin following SU5416 treatment.
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