The goal of the proposed work is to translate our recent experimental findings on the mechanisms of antitumor responses to cisplatin into the development of novel compounds to treat cisplatin-resistant tumors. Earlier work on this grant discovered three novel prospective mechanisms of toxicity for cisplatin: (1) its DNA adducts attract proteins, some of which are expressed in cancer cells, that block DNA repair;(2) its DNA adducts """"""""hijack"""""""" specific HMG-domain transcription factors away from their promoters, resulting in diminished expression of certain genes;and (3) mismatch repair proteins bind cisplatin adducts and sensitize cells to the drug. Based on the aforementioned discoveries, in the current grant period, we have developed several novel anticancer candidates with potentially novel mechanisms of action - mechanisms inspired by cisplatin. The lead candidate among these compounds, E27a, was designed to act by mechanisms that may be relevant for the treatment of cisplatin-resistant ovarian cancers. E27a is a bifunctional DNA damaging agent that can create damaged sites in DNA that have high affinity for the estrogen receptor. Principles incorporated into the design of E27a that were uncovered by our investigations of cisplatin include the ability of cisplatin DNA adducts to bind and sequester proteins important to tumor growth and survival. This proposal has two parallel objectives. One is to delineate further the molecular mechanisms responsible for the cytotoxic and antitumor effects of our new agent, E27a. The second is to compare its efficacy against ovarian cancers with that of cisplatin and related compounds that are in clinical use or are clinical candidates. The specific objectives of the proposed research are: (1) to synthesize molecular variants and radiolabeled analogs of platinum and E27a that are tools for structure-activity studies;(2) to perform comparative cytotoxicity studies against cisplatin and cisplatin homologues in sensitive and resistant ovarian cancer cells;(3) to determine the relationship between estrogen receptor expression and sensitivity of ovarian cancers to E27a and the resistance of those cancer cells to cisplatin;and (4) to compare the efficacy of E27a to that of cisplatin in animal models of human ovarian cancer. Using conventional and genetic animal models for ovarian cancer, and relevant cell lines, we plan to determine to what extent the molecules we have recently made work the mechanisms that we intended and to determine their relevance to cancer treatment. A combination of traditional (immunochemical, genetic) and recent (RNAi, accelerator mass spectrometry) methods will be used.
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