To evaluate the efficacy and safety of alendronate, a double-masked, active (alfacalcidol) controlled comparative study for 48 weeks was carried out in a total of 210 Japanese patients with osteoporosis. The doses of alendronate and alfacalcidol were 5 mg/day and 1 microgram/day, respectively. The lumbar bone mineral density (LBMD) values observed at 12, 24, 36 and 48 weeks after the initiation of alendronate treatment were 3.53 +/- 0.53%, 5.37 +/- 0.62%, 5.87 +/- 0.74% and 6.21 +/- 0.59% (mean +/- SE), respectively, higher than the baseline value. Corresponding values in the alfacalcidol group were 1.50 +/- 0.43%, 0.69 +/- 0.63%, 1.12 +/- 0.60% and 1.36 +/- 0. 63%, respectively. There was a significant difference between the two groups at each time point (p<0.05 or p<0.001). The bone turnover markers were depressed during treatment in the alendronate group: -32.2% for alkaline phosphatase, -53.7% for N-terminal osteocalcin and -45.0% for urinary deoxypyridinoline compared with the corresponding baseline values. On the contrary, no notable changes in these parameters were observed in the alfacalcidol group. Treatment with alendronate caused a transient decrease in serum calcium concentrations associated with an increase in the serum level of intact parathyroid hormone. In contrast, treatment with alfacalcidol resulted in a tendency of these parameters to change in the opposite direction. No difference in fracture incidence between the two groups was observed. The overall safety of alendronate was comparable to that of alfacalcidol. In conclusion, although it was a relatively short-term study of 48 weeks, the results of the present study indicate that alendronate at the daily dose of 5 mg was effective in increasing LBMD and that no serious drug-related adverse events were observed in the alendronate-treated patients. Alendronate is more efficacious than alfacalcidol in increasing bone mineral density, although the mechanisms of the actions of the two drugs are apparently different.

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Expression of intermediate filaments (IFs) has been suggested to be a reliable marker for differentiating epithelial and non‐epithelial tumors. Moreover, the c‐erbB‐2 and p53 genes are considered to be involved relatively early in the process of human carcinogenesis. In order to elucidate the origin of uterine carcinosarcomas, we analyzed IF, c‐erbB‐2 and p53 expression in and the ultrastructural characteristics of clones derived from a human uterine‐carcinosarcoma cell line, EMTOKA. The expression of IFs and other proteins in the EMTOKA clones was identical to that in the EMTOKA cell line. It and its 7 clones all expressed cytokeratins 8, 17, 18 and 19, vimentin, epithelial membrane antigen, S‐100, myoglobin, type‐II collagen, α‐smooth‐muscle actin, placental alkaline phosphatase and epidermal‐growth‐factor receptor. The c‐erbB‐2 and p53 expression levels of all the cell types of the EMTOKA cell line and its clones were the same. Interestingly, an ultrastructural study showed that the EMTOKA cell line and its clones at early and late passages possessed the characteristics of epithelial cell types without either transitional forms between the epithelial and stromal components or differentiation into sarcomatous components. The results of this study lend particular support to the combination tumor hypothesis that a precursor (stem) cell gives rise both to epithelial and to mesenchymal components during the histogenesis of uterine carcinosarcoma, the epithelial component of which appears to be dominant, suggesting that the established cell lines derived from a common stem cell. Int. J. Cancer 72:821–827, 1997. © 1997 Wiley‐Liss, Inc.

Increased secretion of matrix metalloproteinases and serine proteinases is well known to be associated with cancer invasion and metastasis. We aimed to elucidate the implication of trypsin, a serine proteinase and a representative digestive enzyme in invasion and metastasis of human carcinomas. Northern blot, RT-PCR and Western blot analyses and immunohistochemical studies were performed to detect and analyze trypsinogen expression in 5 ovarian carcinoma cell lines and 10 human ovarian carcinoma tissues using a DNA probe for trypsinogen I, and monoclonal and polyclonal antibodies to human trypsin I. Among the 5 ovarian carcinoma cell lines, only the MCAS (mucinous cystadenocarcinoma) cell line showed a high level of trypsinogen production and mRNA expression by Western and Northern blot analyses, respectively. However, Southern blot analysis of RT-PCR products could detect considerable levels of trypsinogen mRNA in all ovarian cancer cell lines. In Northern analysis of ovarian cancer tissues, all advanced cancer samples showed trypsinogen gene expression. Serous cystadenocarcinomas exhibited particularly high levels of gene expression. Immunohistochemical staining also detected trypsin in ovarian carcinoma tissues. In contrast, normal ovaries and tumors with low malignant potential did not show trypsinogen expression. Our results demonstrate the extra-pancreatic production and distribution of trypsinogen in human ovarian carcinomas.