The long term objectives of the planned studies on human endometrial cancer are: (a) to identify biochemical parameters in endometrial cancer that could serve as markers for transformation, provide information about cancer cell physiology and suggest new therapeutic approaches; (b) to develop methods which could be used to determine whether endometrial cancer in individual patients is responsive to hormones and might be susceptible to hormonal treatment; (c) to determine whether the response of endometrial cancer tissue to hormone therapy can be altered by agents regulating cyclic nucleotide levels, previously shown to affect the levels of estrogen specific binders; (d) to develop means, other than hormonal treatment, to inhibit proliferation of human endometrial cancer cells in culture or in nude mice.
Specific aims of these investigations are to compare synthesis and metabolism of prostaglandins F2Alpha and E2 in normal and neoplastic endometrium, to measure and characterize peroxidase activity in cancer tissue, to compare in vitro incorporation or uridine and orotic acid (and intermediate in the de novo synthesis of pyrimidines) into nucleotides, to evaluate the effect of increases in uridine mono and triphosphate pools on rates of RNA synthesis, and to relate levels of intracellular steroid receptors to in vivo and in vitro responses of endometrial cancer tissue to estrogens and progestins. The studies on responsiveness to hormones will be carried out on minced endometrial adenocarcinoma tissue under organ culture conditions or on primary cultures of cancer cells, and in vivo, by administering progestins to patients with endometrial cancer before hysterectomy or by treating nude mice in which human endometrial cancer cells are inoculated to form tumors. Effects of estrogens, progesterone and glucocorticoids will be evaluated by measuring prostaglandin F2Alpha and E2 output and metabolism, DNA polymerase-Alpha activity, CA 125 antigen and IgA secretory component output, estrodiol 17Beta dehydrogenase activity and glycogen accumulation. In addition, the effects that ornithine decarboxylase inhibitors (difluoromethyl) ornithine, sodium molybdate), cyclic nucleotides (or agents affecting their intracellular levels) and antitumor antibodies may have on enzymatic activities, cell proliferation and estrogen receptor levels will be investigated using endometrial cancer cells growing in plastic dishes or in nude mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015648-16
Application #
3164246
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1977-02-01
Project End
1990-07-31
Budget Start
1989-02-01
Budget End
1990-07-31
Support Year
16
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Anzai, Y; Gong, Y; Holinka, C F et al. (1992) Effects of transforming growth factors and regulation of their mRNA levels in two human endometrial adenocarcinoma cell lines. J Steroid Biochem Mol Biol 42:449-55
Holinka, C F; Gurpide, E (1992) Growth-promoting effects of progesterone in a human endometrial cancer cell line (Ishikawa-Var I). J Steroid Biochem Mol Biol 43:635-40
Littlefield, B A; Gurpide, E; Markiewicz, L et al. (1990) A simple and sensitive microtiter plate estrogen bioassay based on stimulation of alkaline phosphatase in Ishikawa cells: estrogenic action of delta 5 adrenal steroids. Endocrinology 127:2757-62
Holinka, C F; Anzai, Y; Hata, H et al. (1989) Proliferation and responsiveness to estrogen of human endometrial cancer cells under serum-free culture conditions. Cancer Res 49:3297-301
Kassan, S; Mechanick, J I; Gurpide, E (1989) Altered estrogen receptor system in estrogen-unresponsive human endometrial adenocarcinoma cells. J Steroid Biochem 33:327-33
Watanabe, J; Holinka, C F; Anzai, Y et al. (1989) Effects of serine and glycine on proliferation of an Ishikawa cell variant. J Steroid Biochem 34:165-8
Weiss, D J; Gurpide, E (1988) Regulation of phosphoinositide hydrolysis in transformed human endometrial cells. Endocrinology 123:981-90
Weiss, D J; Gurpide, E (1988) Non-genomic effects of estrogens and antiestrogens. J Steroid Biochem 31:671-6
Hata, H; Holinka, C F; Pahuja, S L et al. (1987) Estradiol metabolism in Ishikawa endometrial cancer cells. J Steroid Biochem 26:699-704
Holinka, C F; Hata, H; Gravanis, A et al. (1986) Effects of estradiol on proliferation of endometrial adenocarcinoma cells (Ishikawa line). J Steroid Biochem 25:781-6

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