1996 Fiscal Year Final Research Report Summary
Experimental Study of Inhibition for Spontaneous Lung Metastases of Transplantable Rat Osteosarcoma
| Project/Area Number |
06671472
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Nara Medical University |
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Principal Investigator |
MIYAUCHI Yoshizumi Nara Medical University, Dept.of Orthop.Surg., Assistant Professor, 医学部, 講師 (20221608)
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| Project Period (FY) |
1994 – 1996
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| Keywords | Osteosarcoma / Rat / Metastasis / Angiogenesis / Chemotherapy / p53 |
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| Research Abstract |
We have maintained two transplantable rat osteosarcomas, J.H.1-OS is spontaneous osteosarcoma and J.H.2-OS is induced by 4-HAQO,in Fischer 344/Nslc rats and successfully established highly metastatic tumors (S-SLM and C-SLM) by selectively transplanting lung metastatic nodules (in vivo selection). In this study, we have attempted inhibition for spontaneous lung metastases of these highly metastatic rat osteosarcomas.
1. Angiogenesis is a crucial event not only for the establishment of secondary growths but also the allow the primary tumor to grow to a size capable of giving rise to metastases. So angiogenesis inhibitor has the potential to prevent the cascade of metastasis. Combination therapy of TNP470, an analog of fumagillin, and CDDP successfully inhibited the spontaneous lung metastasis of S-SLM.The anti-metastatic effect of CDDP is increased 3 days after continuous administration of TNP-470. We considered this phenomenon is vascular synchronization by pre-treatment of TNP470.
2. New drug delivery systems for CDDP incorporated into vesicles, such as polymethylmethacrylate (PMMA), fibrin glue (FG), alpha-tricalciumphosphate (TCP) and ethylenevinyleacetate copolymer (Polymer) were examined using a rat osteosarcoma model. The direct implantation of TCP containing CDDP into tumors gave significantly better inhibition of tumor growth and metastasis than either non-treatment or subcutaneous implantation.
3. Mutations of p53 in exon 7 were detected in J.H.2-OS,but not in J.H.1-OS,irrespective of the metastatic potentials. Direct sequencing revealed a CGC to CAC transition with an amino acid change of Arg to His, at codon 246. Neither Ki-ras mutation nor mdm2 amplification were detected in any of the transplantable tumors. The results suggest that while p53 mutations occurred during J.H.2-OS without mdm2 amprification and ki-ras mutation dose not contribute to osteosarcoma development in rats.
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