2001 Fiscal Year Final Research Report Summary
MOLECULAR-BASIS AUGMENTED CHEMOTHERAPY AND CLINICAL APPLICATION IN BRAIN TUMORS
| Project/Area Number |
12470296
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
MINEURA Katsuyoshi Kyoto Prefectural University of Medicine Department of Neurosurgery, Professor, 医学部, 教授 (70134103)
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| Co-Investigator(Kenkyū-buntansha) |
OHWADA Kei Kyoto Prefectural University of Medicine Department of Neurosurgery, Instructor, 医学部, 助手 (80332948)
HASHIMOTO Naoya Kyoto Prefectural University of Medicine Department of Neurosurgery, Assistant Professor, 医学部, 助手 (90315945)
SASAJIMA Hiroyasu Kyoto Prefectural University of Medicine Department of Neurosurgery, Assistant Professor, 医学部, 講師 (80196188)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Brain tumor / Chemotherapy / Chloroethvlnitrosourea / O^6-Methylguanine-DNA methyltransferase / Immunostaining / Loss of heterozygosity (LOH) / 染色体異常 / 効果増強 |
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| Research Abstract |
0^6-Methylguanine-DNA methyltransferase (MGMT) activity and MGMT mRNA are well related with drug resistance of tumor cells to chloroethylnitrosoureas (CENUs), because MGMT removes CENU-induced 0^6-aikylguanines in DNA by accepting the alkyl group at a cysteine moiety. Inactivation of MGMT is a reasonable way to reduce MGMT-related resistance of tumor cells to CENUs. In the present study, we tested the in vivo activity of these 0^6-fluorobenzylguanines. Treatment with O^6- (4-fluorobenzyl) guanine + ACNU and 0^6- (3-fluorobenzyl) guanine + ACNU significantly decreased tumor volume and extended the delay of growth (p < 0.05). Also, these two derivatives showed significantly lower proliferating indices (p < 0.05) 12h after treatment. These results indicate that O^6- (4-and 3-fluorobenzyl) guanines as well as O^6-benzylguanines enhance the effect of ACNU on the growth of tumor xenografts in vivo.
MGMT activity and the levels of MGMT mRNA varied widely, even within different types of brain t
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umors. We examined immunohistochemical expression of 0^6-methylguanine-DNA methyltransferase in human brain tumors and its significance as an indicator of CENU sensitivity. A total of 42 patients with malignant gliomas were included in this study. Ten gliomas (24 %) had a low level of MGMT-positive cells (less than 10 %), indicative of more sensitivity to CENU chemotherapy. However, the remaining gliomas showed a high level, and indicated less sensitivity to CENU chemotherapy.
Another way of the chemotherapeutic strategies for the resistant tumor is selection and application of anticancer drugs based on the cytogenic and genetic alternations of brain tumors. Cytogenetic and LOH analysis were examined in 14 oligodendroglial tumors using fluorescent in situ hybridization (FISH) and microsatellite analysis. A combined loss of 1p and 19q in oligodendroglial tumors was highly noted and it indicated chemosensitivity to procarbazine + ACNU + vincristine (PCV) therapy.
A variety of mechanisms may affect drug resistance or sensitivity. The practically and clinically useful test for determining whether tumors will be sensitive or resistant to anticancer drugs. Also, molecular genetics-based diagnosis of brain tumors and its clinical applications on selection of sensitive brain tumors are also important in some types of brain tumors. Multidisciplinary studies on both side of anticancer drug mechanism and biologic characteristics of brain tumors are further required to accomplish chemotherapeutic cure. Less
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