| Co-Investigator(Kenkyū-buntansha) |
TAKATA Akiko KAWASAKI MEDICAL SCHOOL, RESEARCH ASSISTANT, 医学部, 助手 (30278957)
HYODOH Fuminori KAWASAKI MEDICAL SCHOOL, ASSISTANT PROFESSOR, 医学部, 講師 (80069070)
KUREBAYASHI Junichi KAWASAKI MEDICAL SCHOOL, ASSOCIATE PROFESSOR, 医学部, 助教授 (10248255)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
We have analyzed the effects of ATRA(all-trans retinoic acid), bisphosphonate(YM529), anti-HER2-monoclonal antibody, HMG-CoA reductase inhibitors(STATINs, e.g., pravastatin, and simvastatin), hypoxia and thalidomide on human myeloma cells. Two out of 12 myeloma cell lines showed enhanced growth on supplementation of ATRA and were characterized by IL-10 production, down regulation of membrane Fas and reduced upregulation of p21/Cip1 CDK-I message. The growth inhibitory effect of YM529 on human myeloma cell lines was dose dependent. The cells accumulated in [2n< <4n] of the cell cycle and subsequently formed an apoptotic sub-G1 fraction. Combined treatment with ATRA, thalidomide, or interferon alpha enhanced the growth inhibitory effects of YM529. Although the mRNA levels of HER family genes analyzed by RT-PCR were significantly mower in myeloma cells than breast cancer cells, some cell lines expressed a certain amount of HER2 and HER4 proteins. In addition, an anti-HER2 monoclonal antib
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ody, rhumAbHER2, caused significant growth inhibition in six out of eight myeloma cell lines studied and these inhibitory effects were similar to those in the breast cancer cells studied previously. The rhumAbHER2 induced upregulation of p21 family CDK-Is and down-regulation of VEGF genes. Moreover, combination treatment with antiestrogen had an additive growth inhibitory effect. We demonstrated increased expression and production levels of VEGF in myeloma compared to non-myelomatous hematological lines, resistance to hypoxia and enhancement of VEGF-A production by hypoxia in myeloma, and direct growth inhibition of myeloma cells due to apoptosis and G1 arrest caused by TNF-alpha upregulation induced by thalidomide. Although the concentrations were higher than those used clinically, 4 out of 10 myeloma lines showed growth inhibition by pravastatin. The study of factors related to the inhibition indicated IL-6 is important. Indeed, rhIL-6 abolished pravastatin-induced growth inhibition in KMS-21BM cells which did not express IL-6. Most of myeloma lines(12 out of 13) examined showed growth inhibition when cultured with various concentrations of simvastatin in a dose-dependent manner. Simvastatin in combination with other biological response modifiers such as ATRA or DEX had additional effects on growth. In addition, anti-oxides prevented the simvastatin-induced growth inhibition and apoptosis. Less
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