Glucarate is a potential non-toxic anti-tumor agent which also interacts at sub-optimal (i.e. ineffective) doses, synergistically with other agents such as N-(4-hydroxyphenyl)retinamide (HPR) to inhibit tumor growth and in fact cause tumor shrinkage. When given p.o. glucarate is given in a sustained release form. The present investigation focuses on the chemotherapeutic effects of glucarate in combination with HPR on the 7,12-dimethylbenz(a) anthracene-induced rat mammary tumor in vivo and the human breast cancer MCF-7 cell line in vitro. The purpose of this investigation is to optimize the synergistic interaction of glucarate and HPR in the mammary cancer system in such a way as to determine whether glucarate acts as an adjuvant in its synergism with other agents or as an effector. Two theories are evaluated: (i) Glucarate alters the metabolism of HPR or other agents so as to increase their anti-tumor cell activity and (ii) Glucarate directly or indirectly alters the tumor cells themselves so as to enhance the anti-tumor action of HPR. The study takes advantage of hormone sensitive and insensitive mammary tumor cell systems in vivo and in vitro.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA051756-01A1
Application #
3196410
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1990-12-01
Project End
1993-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Curley Jr, R W; Humphries, K A; Koolemans-Beynan, A et al. (1994) Activity of D-glucarate analogues: synergistic antiproliferative effects with retinoid in cultured human mammary tumor cells appear to specifically require the D-glucarate structure. Life Sci 54:1299-303
Webb, T E; Pham-Nguyen, M H; Darby, M et al. (1994) Pharmacokinetics relevant to the anti-carcinogenic and anti-tumor activities of glucarate and the synergistic combination of glucarate:retinoid in the rat. Biochem Pharmacol 47:1655-60
Abou-Issa, H; Dwivedi, C; Curley Jr, R W et al. (1993) Basis for the anti-tumor and chemopreventive activities of glucarate and the glucarate:retinoid combination. Anticancer Res 13:395-9
Webb, T E; Abou-Issa, H; Stromberg, P C et al. (1993) Mechanism of growth inhibition of mammary carcinomas by glucarate and the glucarate: retinoid combination. Anticancer Res 13:2095-9
Abou-Issa, H; Koolemans-Beynen, A; Meredith, T A et al. (1992) Antitumour synergism between non-toxic dietary combinations of isotretinoin and glucarate. Eur J Cancer 28A:784-8