A continuation of studies are proposed on pharmacologic questions of probable importance to the selective antitumor action of antifolates. The basis for the differential in the interaction of folate compounds at the level of membrane transport in target tumors and normal proliferative cell populations will be further explored. Additional emphasis will also be placed on concomitant intracellular events at metabolic and enzymologic levels which also appear to be determining for cytoxicity and the selective action of these agents. For these studies we will continue to employ tumor and normal proliferative cellular systems, the latter as a model for the site of acute drug-limiting toxicity, developed in our laboratory that have established therapeutic relevance. Specific studies are proposed on the kinetics, multiplicity and specificity of membrane transport of folate compounds and their intracellular metabolic disposition as determined from capacities for polyglutamylation and hydrolysis, by folylpolyglutamyl synthetase and folyhydrolase, respectively. The effects of antifolates and their anabolites on folate-related metabolism will also be examined as a parameter of cytotoxicity. The possible differential in enzymatic conversion of 5-formyltetrahydrofolate in tumor versus normal proliferative tissue will be studied as a factor in response to therapies employing this folate with methotrexate or 5FU. Finally, exploratory studies will be initiated examining various biochemical determinants of antifolate cytoxicity as factors in the variable sensitivity observed among subclones of tumors or their metastatic derivatives.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA022764-12
Application #
3165922
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1978-02-01
Project End
1991-01-31
Budget Start
1989-02-01
Budget End
1990-01-31
Support Year
12
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Piper, J R; Ramamurthy, B; Johnson, C A et al. (1996) Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl. J Med Chem 39:614-8
Egan, M G; Sirlin, S; Rumberger, B G et al. (1995) Rapid decline in folylpolyglutamate synthetase activity and gene expression during maturation of HL-60 cells. Nature of the effect, impact on folate compound polyglutamate pools, and evidence for programmed down-regulation during maturation. J Biol Chem 270:5462-8
Bunni, M A; Sirotnak, F M; Otter, G M et al. (1994) Disposition of leucovorin and its metabolites in the plasma, intestinal epithelium, and intraperitoneal L1210 cells of methotrexate-pretreated mice. Cancer Chemother Pharmacol 34:455-8
Schlemmer, S R; Sirotnak, F M (1993) Retentiveness of methotrexate polyglutamates in cultured L1210 cells. Evidence against a role for mediated plasma membrane transport outward. Biochem Pharmacol 45:1261-6
Piper, J R; Malik, N D; Rhee, M S et al. (1992) Synthesis and antifolate evaluation of the 10-propargyl derivatives of 5-deazafolic acid, 5-deazaaminopterin, and 5-methyl-5-deazaaminopterin. J Med Chem 35:332-7
Piper, J R; Johnson, C A; Otter, G M et al. (1992) Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10- dideazaaminopterin and an alternative synthesis of 10-ethyl-10- deazaaminopterin (edatrexate). J Med Chem 35:3002-6
Barrueco, J R; O'Leary, D F; Sirotnak, F M (1992) Metabolic turnover of methotrexate polyglutamates in lysosomes derived from S180 cells. Definition of a two-step process limited by mediated lysosomal permeation of polyglutamates and activating reduced sulfhydryl compounds. J Biol Chem 267:15356-61
Barrueco, J R; Sirotnak, F M (1991) Evidence for the facilitated transport of methotrexate polyglutamates into lysosomes derived from S180 cells. Basic properties and specificity for polyglutamate chain length. J Biol Chem 266:11732-7
Rumberger, B G; Barrueco, J R; Sirotnak, F M (1990) Differing specificities for 4-aminofolate analogues of folylpolyglutamyl synthetase from tumors and proliferative intestinal epithelium of the mouse with significance for selective antitumor action. Cancer Res 50:4639-43
Rumberger, B G; Schmid, F A; Otter, G M et al. (1990) Preferential selection during therapy in vivo by edatrexate compared to methotrexate of resistant L1210 cell variants with decreased folylpolyglutamate synthetase activity. Cancer Commun 2:305-10

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