The objective of Project 1, Experimental Chemotherapy, is to develop clinical guidelines at the preclinical level for the optimization of anticancer drug combinations based on principles of biochemcail modulation. The rationale is to combine certain modulating and effector agents, so that the modulating agents can manipulate the existing quantitative differences among the metabolic determinants of drug action in tumor cells versus normal host cells so as to favor the antitumor action of the effector agent. Therefore, one modulating agent may be selected for combination with an effector, or cytotoxic, agent in order to increase cyctotoxicity specifically in tumor cells as opposed to normal cells, and another modulating agent (e.g., normal metabolite) may be selected for ability to protect normal cells specifically from the cytotoxic action of an effector agent ( e.g., an antimetabolite). Agents will be selected on the basis of a specific biochemical rationale and drug combinations will be assembled in a stepwise approach. In an increased antitumor effect is accompained by untoward host toxicity, the next step is the addition of an agent to selectively protect the host. This procedure continues with the addition of another drug to yield further augmentation of tumor toxicity, and so on, until the ultimate objective of cure is attained. Specific drug combinations are proposed. This approach seeks the control of serious host toxicity as essential to the achievement of chemotherapeutic cure, because the resulting operational increase in drug selectively will allow both a quantitative and a qualitative increase in the chemotherapeutic drug combination. Chemotherapy studies will be performed entirely in in vivo murine tumor models. Tumors will be advanced at initiation of treatment, and therapeutic activity will be assessed in terms of tumor growth inhibition, number of partial and complete tumor regressions, and ultimately, the most promising drug combinations will be evaluated for activity against metastatic tumor and on lifespan. Potential toxic side effects (e.g., damage to the intestinal epithelium and leukopenia) will be monitored in the same experiments. In vivo biochemical and pharmacological studies (Project 2, Biochemical Studies) in the same animal tumor models will provide guidelines for comparative pharmacological and biochemical studies in the clinic (Project 4, Clinical Studies) 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 and 2, lead to guidelines for specific clinical trails; feedback from Project 4, Clinical Studies, may suggest new experimental studies and refinements.
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