The combination of cisplatin-based chemotherapy with interleukin-2 (IL-2) and interferon-alpha (IFN), a novel therapeutic modality referred to as biochemotherapy, produces overall response rates of approximately 60% in advanced melanoma, with complete remission rates of 15 to 20%, half of which are durable. Biochemotherapy regimens are said to be relatively toxic and expensive, and as such, it would be of significant benefit to have available reliable predictors of clinical response that will allow the selection of patients who are likely to benefit from this therapy. To date, these have not been well defined. Preliminary data from the applicant's laboratory, however, suggest that the enhanced antitumor effect may involve the biotherapy component inhibiting the repair of DNA damage induced by the cytotoxic agents. Based on these data, he conducted a pilot study using an optimized quantitative DNA-PCR assay of DNA damage and showed that in melanoma patients receiving biochemotherapy, the extent of DNA damage in pretreatment peripheral blood mononuclear cells (PBMC) exposed to cisplatin in vitro correlated with patient response. He used PBMC as surrogates for tumor cells in these studies because several prior studies have shown that the level of DNA cisplatin adducts in PBMCs correlates with response to cisplatin-based chemotherapy in individual patients. These preliminary data led him to propose the hypothesis that the extent of gene-specific DNA damage induced in pretreatment PBMC by in vitro cisplatin exposure will predict clinical response to both chemotherapy and biochemotherapy in melanoma patients. In the proposed study, pretreatment blood samples will be obtained from patients enrolled in a randomized intergroup (ECOG/SWOG) trial comparing chemotherapy alone (cisplatin, vinblastine and DTIC, CVD) with CVD combined with IL-2 and IFN (biochemotherapy). Using the DNA-PCR assay described earlier, the extent of DNA damage induced in exon 6 of the GST-p gene in the PBMCs will be determined, following in vitro cisplatin exposure. He will then correlate the extent of DNA damage with response to both chemotherapy and biochemotherapy. Finally, the applicant will determine the optimum cisplatin concentration with which to treat PBMC in vitro to yield the highest positive and negative predictive values of response to both chemotherapy and biochemotherapy. The applicant suggests the results of this project will establish the value of the DNA-PCR assay in optimizing therapy for melanoma patients, and provide a means of improving therapeutic efficacy. He will also facilitate the rational extension of biochemotherapy regimens to other more common solid tumors which traditionally are not treated with this modality.
