The objective is to achieve effective combination chemotherapy of cancer with the aid of metabolic modulation of relevant enzymatic pathways by appropriate metabolite-antimetabolite combinations selected on the basis of both existing biochemical knowledge and that generated from the proposed biochemical studies. Normal and comparatively innocuous compounds will be employed either to selectively enhance the antitumor potency of known agents (e.g., thymidine with 5-fluorouracil), or to protect normal tissue from toxicity (e.g., testosterone and/or uridine with 5-FU). The methodology is step-wise. First, agents selected on the basis of a biochemical rationale are combined in vivo for potential gain in anti-cancer activity. If this is accompanied by untoward toxicity, the next step is the addition of an agent or normal metabolite to selectively protect the host. This procedure continues with the addition of another drug to yield further augmentation of tumor toxicity, and so on. This approach is unique in that the control of serious host toxicity is considered to be essential to the achievement of chemotherapeutic cure, because the resulting operational increase in drug selectivity will allow both a quantitative and a qualitative increase in the chemotherapeutic drug combination. The validity of this approach is substantiated by previous work.
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