The purpose of this clinical research is to extend to treatment of cancer patients concepts and specific drug regimens that have produced significant increases in therapeutic effectiveness in tumor-bearing mice. These regimens were developed on the basis of specific biochemical interactions of the several drugs contained therein. The initial focus is 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 PALA + MMPR + FUra, and PALA + MTX + leucovorin + uridine rescue. The major focus is on an ATP-depleting triple combination of PALA-MMPR-6-AN which effected regressions in murine tumors. Greater tumor-regressing effects were obtained by the addition of Fura or Adriamycin to the triple chemotherapy. Clinical protocols evaluate these regimens on advanced cancers of the colon, breast, pancreas, stomach and sarcomas. Concomitant with exploring dose tolerance and therapeutic effect of the regimens in patients, we will measure the effect that the modulating dose drugs have upon the content of PRPP, ATP NAD, UTP, and 6-phosphogluconate in biopsies of accessible tumors and normal bone marrow. These studies assess the biochemical changes as guidelines to the dosage (s) to be employed clinically as well as 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 the agents in patients. An understanding of these metabolic changes may facilitate patient care, as well as indicate biochemical loci in human tumors that may be subject to further manipulation.
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