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 by stimulating more rapid hematopoietic recovery between drug treatment courses with hematopoietic growth factors; also, selected agents with potential for sparing, or for stimulating more rapid recovery in drug-damaged intestinal epithelium will be evaluated. 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 basis of the biochemical information that prompted that manipulation, will be confirmed on a biochemical level (Project 2) to insure that the chemotherapeutic results are related to the predicted biochemical changes. Biochemical analysis of human tumors, before and after treatment, determine (and establish) that the employed clinical dose is reproducing the same biochemical changes that were responsible for the successful preclinical results. Thus, the preclinical combined in vivo biological and biochemical findings, Projects 1 and 2, lead to guidelines for Project 3's very specific clinical trials.
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