The purpose of this research is to extend to treatment with advanced cancer concepts and specific drug regimens that have produced significant increases in therapeutic effectiveness in mice with transplanted tumors. These regimens were developed on the basis of specific biochemical interactions of the several drugs contained therein. The focus will be upon the modulation of the effects of 5-fluorouracil (FUra) by N-phosphonacetyl-L-aspartate (PALA), which depletes intracellular pyrimidine pools, and methylmercaptopurine ribonucleoside (MMPR) or methotrexate, which enhance phosphorylation of FUra by increasing cellular content of phosphoribosyl pyrophosphate (PRPP), and uridine for """"""""rescue"""""""" from the toxicity of FUra. Two specific regimens will be studied which produced a significant increase in FUra effect in mice. These are MMPR + PALA + FUra, and PALA + MTX + FUra + leucovorin + uridine rescue. Six clinical protocols evaluate these regimens on advanced cancers of the colon, the breast, head and neck and adenocarcinomas of unknown primary. Concomitant with exploring dose tolerance and therapeutic effect of the two regimens in patients, we will measure the effect that the modulating dose drugs have upon the content of PRP and UTP in tumors, normal skin, and normal bone marrow. These studies will assess whether or not the proposed biochemical changes occur in patients at the drug doses used and whether or not the changes are selective. By means of these studies we hope not only to improve the therapy of patients with cancer, but also to establish a mechanism for examining the metabolic changes produced by doses of conventional anticancer drugs.
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