The focus of the program is to study the modulation of chemosensitivity by biotherapy in human malignant melanoma. The 3 projects are focused around a randomized clinical trial in which a promising (greater than 50% response rate) sequential biochemotherapy regimen is being tested. The mechanisms by which biotherapy increase drug response in melanoma are unclear. The goal of the present project is to use experimental models of human melanoma to better understand the time and dose response relationships for the modulation of cellular drug resistance by IL-2 and IFNalpha and the role of tumor macrophages in these responses. Our working hypothesis is that macrophage derived oxidants modulate the sensitivity of human melanoma cells to cisPlatin. Implicit in this hypothesis is that such oxidants may either increase or decrease drug sensitivity depending on the sequence, dose and schedule of agents. In vivo studies with xenograft models of human melanoma to identify the temporal aspects of cytokine biotherapy induced chemosensitization and chemoprotection will be complemented by in vitro studies to determine the role of resident tumor macrophage derived oxidants (H2O2, O2-,NO) in the modulation of cisPlatin sensitivity in clonogenic melanoma cells. We will also identify relevant cytokine and anti-oxidant pathways which may affect cytokine mediated changes in cellular chemosensitivity. Since the working hypothesis for our IRPG is that oxidant stress can alter the ability of tumor cells to repair cisPlatin induce DNA injury, we will use atomic absorption spectroscopy to determine the effect of oxidant stress on the accumulation and retention of cisPlatin in tumor cell DNA. Our studies will complement and interdigitate with Dr. Grimm's R0-1 project to investigate the effects of biotherapy on macrophage functions and plasma lipid peroxidation and with Dr. Ali-Osman's project to investigate the effects of oxidant stress on drug sensitivity in clinical material and the repair of cis-Platin-DNA interstrand crosslinks. Our studies will lead to a better understanding of the interaction of biotherapy and chemotherapy and will provide insights for the design of new more efficacious approaches for the treatment of malignant melanoma, and other more prevalent cancers.
