Changes in expression and subcellular localization of nuclear retinoic acid receptors in human endometrial epithelium during the menstrual cycle.

The endometrium is a uniquely dynamic tissue in that it undergoes monthly cycles of proliferation and secretory activity, and is regulated by ovarian steroid hormones. In this study, we focused on retinoic acid receptors (RAR and RXR) which are ligand-dependent transcription factors belonging to the large family of steroid hormones and are expected to affect to cell growth and differentiation in the endometrium. We analysed the expression and subcellular localization of the RA receptors in 57 samples of human endometrium by immunohistochemistry and Western blotting. In the nuclei of the endometrial epithelium, the RA receptors were expressed strongly in the proliferative phase. However, RAR were drastically reduced in the epithelial nuclei during the secretory phase in association with changes in serum oestradiol and in the expression of the oestrogen receptor. The expression of RXR was localized in the epithelial nuclei throughout the menstrual cycle. Confocal laser scanning microscopical observation clearly showed the difference in the localization between RAR and RXR in the secretory phase. Furthermore the findings of immuno-electron microscopy showed pooled RAR around the rough endoplasmic reticulum, suggesting that transport of these receptors to the nuclei is inhibited. These findings suggest that RAR and RXR work mainly in the proliferative phase and that in the endometrium RXR may play a different role to RAR during the secretory phase.

Over-expression of heat shock proteins in carcinogenic endometrium.

We have previously shown that the subcellular localization of beta-catenin changes according to the cell proliferation status of the human endometrium, suggesting a role of intercellular transduction in cell growth control in human endometrium not only in the physiological but also in the carcinogenic condition. To further study the possible role of heat shock proteins (HSPs) in growth control, we immunohistochemically analyzed 92 endometrial samples, 30 of normal endometrium, 20 of endometrial hyperplasia and 42 of endometrial cancer, for expression of HSP27, HSP70, HSP90, estrogen receptor (ER) and progesterone receptor. HSP27 and HSP90 were detected in endometrial epithelium strongly in the proliferative phase and weakly in the secretory phase during the menstrual cycle according to the serum estradiol level. However, they were over-expressed in endometrial hyperplasia, especially HSP27. In endometrial cancer, HSP27 expression was heterogenic among the glands and lower than that in the proliferative phase and endometrial hyperplasia. HSP27 over-expression was also observed in samples including endometrial cancer and associated hyperplasia. Results of Western blotting followed those of immunohistochemistry. HSP70 was not changed during the menstrual cycle, as HSP27 and HSP90 were, and was rather stably expressed in endometrial hyperplasia and cancer. Our results suggest that HSP27 and HSP90 contribute to cell proliferation in endometrial epithelium and that over-expression of HSP27 in endometrial hyperplasia occurs as a result of the activated condition of ER, though in cancer it decreases according to the loss of function of ER.

[A randomized cross-over comparative study of granisetron alone and combination of granisetron, methylprednisolone and droperidol as antiemetic prophilaxis in CDDP-based chemotherapy for gynecologic cancer].

A cross-over clinical trial was carried out to compare the efficacy and safety of granisetron alone (40 micrograms/kg) as a "single" group, with that of granisetron, methylprednisolone (250 mg/ body) and droperidol (0.5 ml/body) as a "cocktail" group for control of emesis and vomiting induced by CDDP-based chemotherapy in 68 courses of 34 patients with gynecologic malignancies. At the first course, "single" or "cocktail" drugs were administered at day 1, 2, and 3 of chemotherapy, and at the second course, "cocktail" or "single" drugs in as cross-over fashion. We examined the degree of nausea and frequency of vomiting during the first 7 days of chemotherapy. As for the severity of nausea, the "single" group showed prominent nausea immediately after CDDP and the most severe level at the 3rd or 4th day. The "cocktail" group showed mild symptoms from the next day and it lasted for several days. Vomiting started 12 hours later in the "single" group and the most frequent peak was the 2nd day, whereas the "cocktail" group showed less than one vomiting at the 2nd or 3rd day throughout the treatment. Clinical response (extremely good, good) in the current series of 68 courses of chemotherapy was also evaluated to be 45% and 35% in the "single" group, respectively, against 75% and 20% in the "cocktail" group, respectively. There was no clinical toxicity or side effects in either treatment group. We conclude that the cocktail treatment is very useful for not only acute, but also late emesis in CDDP-based chemotherapy in gynecologic malignancies.