The ultimate goal of the proposed research program is the development of both safer and more effective combination therapy for cancer. Based on principles of biochemical modulation, drug combinations, or drug-metabolite combinations, selected on the basis of known or potential biochemical interaction, will be utilized to manipulate relevant biochemical pathways in a therapeutically beneficial manner to either potentiate selective cytotoxicity in tumor cells, and/or to selectively diminish toxicity in normal host cells. The control of serious host toxicity is viewed as essential to the achievement of chemotherapeutic cure, because the resulting operational increase in drug selectivity will allow both a quantitative and a qualitative intensification of chemotherapy. In addition to the specific """"""""rescue"""""""" approach for antimetabolite toxicity with the corresponding normal metabolite, attempts will be made to prevent drug-induced toxicity through temporary slowing of hematopoietic proliferation with IFN, TNF or TGF-B, and to stimulate more rapid recovery with hematopoietic cytokines with and without EGF to stimulate recovery of drug damaged intestinal epithelium. Finally, immunotherapy with IL-2 and IFN will be integrated into the therapeutic regimen with the aim of restoring and enhancing immune function at a time when the tumor burden has been reduced by chemotherapy. The goal is to increase both the power and selectivity of the therapeutic attack, hopefully to the level of cure of advanced, spontaneous solid cancer, first in a murine model and then ultimately in patients. This approach requires the integration of 3 projects: Project 1, Experimental Therapy; Project 2, Biochemical Studies; Project 3, Clinical Studies. Preclinical therapy studies (Project 1) will be performed entirely in vivo murine tumor models. Therapeutic results from a particular drug manipulation, obtained as expected on the basis of the biochemical information that prompted that manipulation, will be confirmed on a biochemical level (Project 2) to insure that the biological results are related to the predicted biochemical changes. Unexpected therapeutic results will be explored at the biochemical level to provide guidelines for comparative pharmacological and biochemical studies in the clinic (Project 3) which will be used to adjust promising therapeutic drug regimens for translation from the animal tumor model to cancer patients. The combined in vivo biological and biochemical findings, Projects 1, 2, lead to guidelines for specific clinical trials, and feedback from the clinical studies may suggest new experimental studies and refinements.
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