|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1995 : ¥400,000 (Direct Cost : ¥400,000)
Fiscal Year 1994 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1993 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Retinoic acid (RA) exhibits effect on the proliferation and differentiation of many hematopoietic cells. Despite information on the effects of RA on hematopoietic cellslittle is known about how RA acts on the bone marrow stromal cells. All-trans RA and 9-cis RA,a stereoisomer of all-trans RA,treatment of humen bone marrow stromal cell line KM101, which produces M-CSF and GM-CSF constitutively, enhanced mRNA levels of both cytokines in a dose-dependent manner. Both RA also stimulated M-CSF production from primary human bone marrow stromal cells. All-trans RA did not affect the expression of RAR and RXR mRNA,whereas 9-cis RA increased RXR mRNA expression in a dose-dependent manner, suggesting RXR-dependentpathway through RAR/RXR or RXR/RXR must be critical in the cytokine production from bone marrow stromal cells. Next, we have developed several series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. RXR-slective analogs had little ability to inhibit clonal growth and induce differentiation of leukemic cells. Howver, retinoid which activate both RAR/RXR and RXR/RXR dimers could inhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients with acute promyelocytic leukemia (APL). Thus, we conclude that the RAR/RXR pathway is more important than RXR/RXR pathway for differentiation and proliferation of acute myeloid leukemic cells.