|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1992 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 1991 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Malignant tumor cells often produce many bioactive substances, and present with malignancy-associated syndromes. Hypercalcemia caused by tumor production of parathyroid hormonerelated protein (PTHrP) is the one most frequently seen in patients with malignancies. In this study, I have investigated the effects of interleukin-1alpha, glucocorticoids, TNF, phorbolester (PMA) and endothelin on the expression of PTHrP in ATL cells (MT-2). Northern blot analysis revealed the fomer two stimulated and the latter two inhibited the expression of PTHrP mRNA, although the results were not confirmative yet. A sensitive and specific PTHrP radioimmunoassay system was developed. In patients with ATL or squamous cell carcinoma of the lung, plasma concentrations of PTHrP were high when they presented with hypercalcemia, while the concentrations were normal when they became normocalcemic after chemotherapy or radiation therapy.
Endothelin is also produced by many tumors. It was shown to enhance the growth of fibroblasts stimulated by PDGF, FGF and insulin. This activity may be related to the growth of connective tissue seen in tumor masses, especially in scirrhous carcinomas. Endothelin was shown to elevate intracellular (cytoplasmic) concentration of Ca^<2+>, at least by mobilizing Ca^<2+> from intracelluar Ca pool. However, in sharp contrast with other cells, endothelin did noto increase inositol-1,4,5-triphosphate production in fibroblasts while it increased inositol-1,3,4-trisphosphate, an isomer which does not mobilize intracellular Ca^<2+>. New mechanism by which endothelin mobilizes Ca^<2+> remains to be investigated.