Antitumor agents containing the 1,2-dihydroxybenzene moiety represent a new structural class of antitumor agent with activity against a broad spectrum of experimental tumors including L1210, P388 leukemia and B-16 melanoma. Mechanistic studies have suggested that the drugs interfere selectively with DNA synthesis primarily through effects upon ribonucleotide reductase, DNA polymerase and thymidylate synthase. Emphasis will be placed upon the study of the mechanism of action of these drugs and the relationship of redox potential to antitumor activity. Specifically, the effect of the drugs upon 3 additional redox sensitive DNA synthetic enzymes, DHFR, thioredoxin reductase and glutaredoxin reductase will be evaluated using isolated enzyme preparations. The effect of dihydroxybenzene compounds on ribonucleotide reductase and DHFR will be examined using in situ assays. The general concept of the influence of reducing agents upon DNA synthesis in eukaryotic cells will be addressed with specific emphasis upon the effect on the level of endogenous reductants. A correlation between the antiproliferative effects and depletion of levels NADPH and other cellular reductants will be investigated. Detailed studies of the effects of catechols upon nucleotide pools will be performed in order to gain additional information as to the causes and biochemical consequences of the inhibition of DNA synthesis. Hopefully, this work will lead to a better understanding of the mechanism of suppression of DNA synthesis by catechols and the remarkable antitumor selectivity observed. In particular, the studies of the effects on the intracellular redox state might provide insight into metabolic difference between normal and malignant cells with respect to the manner in which they interact with these antiproliferative reducing agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA024988-09
Application #
3166626
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1979-07-01
Project End
1991-04-30
Budget Start
1989-05-01
Budget End
1991-04-30
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Prezioso, J A; FitzGerald, G B; Wick, M M (1992) Melanoma cytotoxicity of buthionine sulfoximine (BSO) alone and in combination with 3,4-dihydroxybenzylamine and melphalan. J Invest Dermatol 99:289-93
Lee, M M; Ratliff, J; FitzGerald, G B et al. (1991) The mechanism of differential sensitivity to methotrexate of normal and malignant human epidermal cells. Cancer Chemother Pharmacol 28:181-4
Husain, Z; Pathak, M A; Flotte, T et al. (1991) Role of ultraviolet radiation in the induction of melanocytic tumors in hairless mice following 7,12-dimethylbenz(a)anthracene application and ultraviolet irradiation. Cancer Res 51:4964-70
FitzGerald, G B; Bauman, C; Hussoin, M S et al. (1991) 2,4-Dihydroxybenzylamine: a specific inhibitor of glutathione reductase. Biochem Pharmacol 41:185-90
Hussoin, S; FitzGerald, G B; Wick, M M (1991) Polyhydroxylated phenylacrylic acid derivatives as new anti-tumor agents. J Pharm Sci 80:416-8
Prezioso, J A; Fitzgerald, G B; Wick, M M (1990) Effects of tyrosinase activity on the cytotoxicity of 3,4-dihydroxybenzylamine and buthionine sulfoximine in human melanoma cells. Pigment Cell Res 3:49-54
Firestone, W M; FitzGerald, G B; Wick, M M (1990) A comparison of the effects of antitumor agents upon normal human epidermal keratinocytes and human squamous cell carcinoma. J Invest Dermatol 94:657-61
Wick, M M (1989) Levodopa/dopamine analogs as inhibitors of DNA synthesis in human melanoma cells. J Invest Dermatol 92:329S-331S
FitzGerald, G B; Wick, M M (1989) A comparison of dihydrofolate reductase activity in intact leukemia cells and squamous cell carcinoma. Anticancer Drug Des 4:79-87
FitzGerald, G B; Ratliff, J; Wick, M M (1987) Inhibition of thymidylate synthase in intact L1210 cells by ara-C, daunomycin, hydroxyurea and 3,4-dihydroxybenzylamine. Anticancer Drug Des 1:281-9

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