We hypothesize that the antitumor effect(s) od chemotherapy are enhanced by responses to IL-2 and IFNalpha in human melanoma patients receiving biochemotherapy. This proposal is centered around the analysis of a randomized clinical trial which compares the efficacy of systemic biochemotherapy vs. chemotherapy alone for advanced malignant melanoma. Previous studies have suggested a >50% response from the biochemotherapy group, therefore, we expect to elucidate changes that are relevant to a successful therapeutic maneuver and which will provide insight into response mechanism(s). This R01 is complemented by two others, one which incorporates analysis of specific effects on the DNA of the patients during therapy, and the other studying human melanoma models for direct testing of agents. The working hypothesis of this proposal is that biotherapy stimulates tumor infiltrating macrophages and/or endothelia to produce oxidants which interfere with DNA repair in the tumor cells, thereby augmenting the effect of chemotherapy.
Aim 1 will determine whether systemic measurements of macrophage activation relate to pro-oxidant effects, and if either of these parameters correlate with DNA interstrand crosslinks and/or patient response to therapy. This will be accomplished by measuring neopterin (by RIA), measurements of monocyte activation, immunostaining for macrophages in the tumor, and plasma lipid peroxidation as an indicator of pro-oxidant production during the clinical trial. We further hypothesize that IL-1s are critical local mediators inducing the production of oxygen radicals, and that in some patients IL-1 may already be expressed by the tumor, while in others the biochemotherapy or chemotherapy induces production.
Aim 2 will test whether those patients whose tumors are producing Il-1alpha or IL-1beta are those patients most responsive to biochemotherapy or chemotherapy. Finally, using ELISA and immunohistology evaluation of the systemic and local presence of TNFalpha, IL-6, IFNlambda, and IL-8 will be performed. The final hypothesis is that an explanation for the variability of patient response to biochemotherapy or chemotherapy is due, in part, to the heterogeneity of multiple cytokine expression from the tumor itself.
