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.
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