The incidence of melanoma in the United States has continued to rise at the steady rate of 4 percent. The outcome of therapy in this malignancy, however, remains disappointing. An urgent need therefore exists for the development of new strategies in the treatment of malignant melanoma. This proposal is one of three R01 projects developed as an IRPG that will address this problem by performing coordinated laboratory investigations and a clinical trial of sequential biochemotherapy versus chemotherapy alone in advanced melanoma. The proposed studies are based on the results of recent biochemotherapy trials (for the most part developed empirically) suggesting superiority of sequential biochemotherapy over chemotherapy alone in metastatic melanoma. Despite the encouraging results of these trials, little information was obtained on the mechanisms involved in the action of biochemotherapy. Preliminary data from their laboratory indicate that impaired DNA interstrand crosslink repair in circulating lymphocytes of melanoma patients undergoing biochemotherapy may correlate with patient response. Additional data generated by their group from the same biochemotherapy trial suggest that patient response is associated with macrophage activation. These data and those of others showing that interleukin-1a enhances the anti-tumor action of cisplatin through the activation of macrophages to release reactive oxygen intermediates provide the background to the proposal. They hypothesize that the therapeutic efficacy of biochemotherapy results from enhancement of the action of chemotherapy by the biotherapy component of the therapy, and that this enhancement is the consequence of impaired repair of drug-induced DNA damage in the tumor cells. To test this hypothesis, they will perform experiments designed to determine (1) whether the efficacy of biochemotherapy results from impaired DNA repair, (2) whether reactive oxygen intermediates (H202) impairs DNA repair and enhances the anti-tumor action of chemotherapy and, (3) whether the levels of cellular systems for protection against oxidative injury (GSH, GSH-peroxidase and catalase) will protect cells against the action of biochemotherapy and chemotherapy. The results of these studies will be correlated with patient response to therapy and with the results from the other projects, in particular those on cytokine expression, monocyte/macrophage activation, and lipid peroxidation in patients. They believe that these studies will provide a better understanding of the mechanism(s) underlying the antitumor action of biochemotherapy, and will offer, potentially, the rationale upon which biochemotherapy regimens may be further modified to enhance their clinical efficacy. Furthermore, the insights gained into the mechanisms of action of the agents and/or combinations would facilitate the development of strategies to overcome subsequent tumor resistance to biochemotherapy. These studies of biochemotherapy in malignant melanoma could also lead to the design of similar trials in other more prevalent human malignancies.
