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In postmenopausal breast cancer tissue, steroid sulfatase (STS) activity is high and much estrone sulfate also exists; these facts reveal that estrone sulfate may be involved in the growth of breast cancer as an estrogen source. Steroid sulfatase is an enzyme, which catalyzes hydrolysis from estrone sulfate to estrone, and the development of steroid sulfatase inhibitors is expected as novel therapeutic drugs for postmenopausal breast cancer. We have developed a novel compound 2',4'-dicyanobiphenyl-4-O-sulfamate (TZS-8478), which has potent steroid sulfatase-inhibitory activity and exhibits no estrogenicity in vitro and in vivo. To elucidate its usefulness as a therapeutic drug for postmenopausal breast cancer, we examined the breast cancer cell proliferation- and breast tumor growth-inhibitory activity of TZS-8478 in postmenopausal breast cancer model rats. TZS-8478 dose-dependently suppressed the estrone sulfate-stimulated proliferation of MCF-7 cells. Regarding nitrosomethylurea (NMU)-induced postmenopausal breast cancer models, furthermore, TZS-8478 (0.5 mg/kg per day) markedly inhibited the estrone sulfate-stimulated growth of breast tumors similarly to estrone sulfate-depletion. TZS-8478 completely inhibited steroid sulfatase activity in tumor, uterus and liver, and also markedly lowered plasma concentrations of estrone and estradiol. The above mentioned results suggested that TZS-8478 may be useful as a therapeutic drug for estrogen-dependent postmenopausal breast cancer.

To elucidate the effects of synthetic salmon calcitonin (sCT) on the cells in the rat pituitary gland, we histopathologically and immunohistochemically examined the early changes after 4 or 13 weeks treatment with sCT 120 IU/kg. Focal proliferative lesions of the anterior pituitary glands were consistently found after treatment with sCT for 13 weeks. Histologically, the cells with the focal proliferative lesions were classified into the following three groups: 1) enlarged basophilic cell focus, 2) vacuolated cell focus and 3) chromophobe cell focus. These focal proliferative lesions had positive staining only for the alpha-subunit and failed to show Pit-1 protein immunoreactivity. The sCT treatment also increased the thickness of the pars intermedia. Hypertrophy of the pars intermediate cells was characteristically seen. Furthermore, Pit-1 protein immunoreactivity was clearly detected in the nuclei of the hyperplastic pars intermediate cells. All pars intermediate cells were equally stained by alpha- or beta-MSH and beta-endorphin in both vehicle- and sCT-treatment. No difference was seen. These findings strongly suggest a very close relationship between Pit-1 protein immunoreactivity and cellular proliferation induced by sCT.

The effect of ethinylestradiol (EE), a synthetic estrogen which is tumorigenic to the mammary gland, pituitary gland, and liver, on the cell proliferation in 5 organs was investigated in male rats. Cell proliferation was estimated by bromodeoxyuridine (BrdU) immunohistochemistry after 72 hr continuous administration of BrdU through an osmotic minipump prior to sacrifice. Two experimental protocols were applied. In one, EE was administered to rats at l ppm in feed for 3, 7, 14, 28, and 91 days. The BrdU labeling indices (LI) in the pars distalis of the pituitary gland were significantly increased in the EE-treated rats compared to the control rats throughout the experimental period. The LI in the Harderian gland, a non-target organ of EE tumorigenesis, were also higher in the EE-treated rats on day 14 and thereafter. Other non-target organs, including the adrenal cortex and medulla, kidneys, and pancreas, showed variable or consistently lower LI in the EE-treated rats. In the other protocol, EE wa administered to rats at 0.1, 0.5, and 2 ppm in feed for 3, 7, and 14 days, and the serum prolactin (PRL) concentration and LI in the pars distalis were compared. EE treatment increased the serum PRL concentration, the LI in the pars distalis, and the numerical density (No. of cells/mm2) of BrdU-labeled PRL cells in a dose-dependent manner with complete parallelism among them. The increase in LI was observed within 14 days after the start of EE treatment, and the profiles of cell proliferation were unique to each organ, including tumorigenic target and non-target organs.

TZT-1027 (Soblidotin), an antimicrotubule drug, has shown potent antitumor efficacy in various antitumor models, and has entered into phase I clinical trials. To determine those anticancer drugs to be combined with TZT-1027 in clinical trials, the combination effects of TZT-1027 with other anticancer drugs were examined.Two in vivo antitumor models, the murine P388 leukemia ascites tumor model and the human non-small cell lung cancer A549 solid tumor model, were used and cisplatin (CDDP), gemcitabine (GEM), irinotecan hydrochloride (CPT-11), fluorouracil (5-FU), paclitaxel (PTX) and docetaxel (DTX) were selected to be combined with TZT-1027. Regarding the schedule of combination administration, simultaneous administration and sequential administration (TZT-1027 first and combined drugs administered 24 h later, and vice versa) were employed.A significant increase in lifespan was observed when TZT-1027 was combined with CDDP, GEM and CPT-11 in the P388 cell ascites tumor model, and a significant inhibition of growth was observed when TZT-1027 was combined with CDDP, GEM and DTX in the A549 solid tumor model. Sequential administration, particularly when the combined drug was administered first, showed the most potent antitumor efficacy.These findings strongly suggest that a significant combination effect of TZT-1027 and these antitumor drugs can be expected in clinical trials for solid tumors.

In postmenopausal breast cancer tissue, steroid sulfatase (STS) activity is high and much estrone sulfate also exists; these facts reveal that estrone sulfate may be involved in the growth of breast cancer as an estrogen source. Steroid sulfatase is an enzyme, which catalyzes hydrolysis from estrone sulfate to estrone, and the development of steroid sulfatase inhibitors is expected as novel therapeutic drugs for postmenopausal breast cancer. We have developed a novel compound 2',4'-dicyanobiphenyl-4-O-sulfamate (TZS-8478), which has potent steroid sulfatase-inhibitory activity and exhibits no estrogenicity in vitro and in vivo. To elucidate its usefulness as a therapeutic drug for postmenopausal breast cancer, we examined the breast cancer cell proliferation- and breast tumor growth-inhibitory activity of TZS-8478 in postmenopausal breast cancer model rats. TZS-8478 dose-dependently suppressed the estrone sulfate-stimulated proliferation of MCF-7 cells. Regarding nitrosomethylurea (NMU)-induced postmenopausal breast cancer models, furthermore, TZS-8478 (0.5 mg/kg per day) markedly inhibited the estrone sulfate-stimulated growth of breast tumors similarly to estrone sulfate-depletion. TZS-8478 completely inhibited steroid sulfatase activity in tumor, uterus and liver, and also markedly lowered plasma concentrations of estrone and estradiol. The above mentioned results suggested that TZS-8478 may be useful as a therapeutic drug for estrogen-dependent postmenopausal breast cancer.

Treatment with 0.01, 0.1 and 1.0% chlormadinone acetate (CMA) contained diets for 33 days to guinea pigs showed no signs of the depression in adrenal, thymus and leucocyte count and no elevation of serum cholesterol. By the treatment with 0.01 and 0.1% cortisol contained diets, however, the atrophy of adrenal and thymic cortex, hypercholesterolemia and the enlargement of liver were noted in this species. It was therefore concluded that CMA had no cortisone-like properties in guinea pigs even at the excessive doses.

The in vivo induction of chromosome aberrations has been studied in the liver cells of rats exposed to N-nitrosodiethylamine (DEN). Rats were treated with DEN before or pfter partial hepatectomy. For chromosome analysis, liver cells were isolated by a collagenase digesting procedure. In both treatment schedules, DEN caused significant and dose-dependent chromosome structural aberrations at dose levels as low as 0.5–4.0 mg/kg which are comparable to the range employed in lifetime carcinogenicity tests. Repeated exposures to DEN increased the rates of aberrations. By the procedure described above, detection of clastogenic activities of other hepatocarcinogens will be possible.