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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA025842-11
Application #
3806172
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
St. Vincent Catholic Medical Center Nursing
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
11432
Martin, D S; Spriggs, D; Koutcher, J A (2001) A concomitant ATP-depleting strategy markedly enhances anticancer agent activity. Apoptosis 6:125-31
Koutcher, J A; Alfieri, A A; Tsai, J C et al. (1997) Evaluation of chemotherapy and radiation enhancement and 31P NMR spectral changes induced by biochemical modulation. Cancer Invest 15:111-20
Koutcher, J A; Alfieri, A A; Thaler, H et al. (1997) Radiation enhancement by biochemical modulation and 5-fluorouracil. Int J Radiat Oncol Biol Phys 39:1145-52
Martin, D S; Stolfi, R L; Colofiore, J R (1997) Perspective: the chemotherapeutic relevance of apoptosis and a proposed biochemical cascade for chemotherapeutically induced apoptosis. Cancer Invest 15:372-81
Street, J C; Alfieri, A A; Koutcher, J A (1997) Quantitation of metabolic and radiobiological effects of 6-aminonicotinamide in RIF-1 tumor cells in vitro. Cancer Res 57:3956-62
Kelsen, D P; Martin, D; O'Neil, J et al. (1997) Phase I trial of PN401, an oral prodrug of uridine, to prevent toxicity from fluorouracil in patients with advanced cancer. J Clin Oncol 15:1511-7
Street, J C; Koutcher, J A (1997) Effect of radiotherapy and chemotherapy on composition of tumor membrane phospholipids. Lipids 32:45-9
Nord, L D; Stolfi, R L; Alfieri, A A et al. (1997) Apoptosis induced in advanced CD8F1-murine mammary tumors by the combination of PALA, MMPR and 6AN precedes tumor regression and is preceded by ATP depletion. Cancer Chemother Pharmacol 40:376-84
Martin, D S; Schwartz, G K (1997) Chemotherapeutically induced DNA damage, ATP depletion, and the apoptotic biochemical cascade. Oncol Res 9:1-5
Stolfi, R L; Colofiore, J R; Nord, L D et al. (1996) Enhanced antitumor activity of an adriamycin + 5-fluorouracil combination when preceded by biochemical modulation. Anticancer Drugs 7:100-4

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