Platinum coordination complex drugs play important roles in the chemotherapy of many tumor types. The frequent emergence of tumor cell resistance to drugs like Cisplatin (CP) is a principal reason why potentially curable tumors fail treatment. The working hypothesis of this project is that the development of cellular resistance by initially sensitive cells may require the """"""""activation"""""""" of specific Cisplatin resistance (CPR) genes. If so, identification and cloning of CPR genes may facilitate elucidating the mechanisms of CP resistance, predicting clinical tumor response to CP, and, in the long run, circumventing or overcoming CPR. The long-term objectives of this project are: 1) to help elucidate the molecular mechanisms by which mammalian cells cope with damage by platinum coordination complexes and 2) to use this information to improve our ability to predict clinical CPR and, eventually, to help circumvent it. The first step in this process must be identification of genes capable of conferring CPR. Using gene transfer techniques, a novel gene that significantly increases CPR in mammalian cells has been obtained from a CPR ovarian carcinoma cell line.
The specific aims of this proposal are: 1) to molecularly clone and sequence this """"""""novel"""""""" CPR gene (CPR-1); to molecularly clone its normal homolog; and 2) to determine the sequence changes that confer the CPR phenotype; and 3) to determine the frequency of activation of this gene in CPR human ovarian cell lines and ovarian tumors which failed CP therapy by using probes specific for the """"""""activated"""""""" CPR gene. Identification and cloning of CPR genes should eventually lead to understanding their mechanisms of action and perhaps the mechanisms by which cancer cells become resistant to platinum coordination complexes.
