2001 Fiscal Year Final Research Report Summary
Basic study for establishment of chemotherapy of DNA mismatch repair-deficient colorectal cancers : Specificity of DNA damage and drug sensitivity
| Project/Area Number |
12671273
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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 |
Digestive surgery
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| Research Institution | TOHO UNIVERSITY |
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Principal Investigator |
FUNAHASHI Kimihiko Toho Univ Sch Med, 1st Dept Surg, Asistant Professor, 医学部, 講師 (90297698)
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| Co-Investigator(Kenkyū-buntansha) |
ARITA Michitsune Toho Univ Sch Med, Dept Mol Biol, Associate Professor, 医学部, 助手 (80307719)
HEMMI Hiromichi Toho Univ Sch Med, Dept Mol Biol, Associate Professor, 医学部, 助教授 (90165514)
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| Project Period (FY) |
2000 – 2001
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| Keywords | colorectal cancer / DNA mismatch repair genes / hMLH1 gene / hMSH2 gene / drug-resistance / chemotherapeutic agents / cell lines |
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| Research Abstract |
Accumulation of mutations in oncogenes and tumor suppressor genes is esential for generation of colorectal cancer. Defect of a DNA mismatch repair (MMR) gene is known to be responding to one of the accumulated mutations in these cancer-related genes. Seven human MMR genes including hMLH1 and hMSH2 have been identified. MMR-deficient tumor cells exhibit a drug-resistance to some anticancer agents such as cisplatin (CDDP). However, sensitivities of MMR-deficient cells to many of anticancer drugs, which are utilizing in chemotherapy for colorectal cancers, and agents that induce MMR-tumor cells are not clear. We investigated here sensitivity of MMR-deficient colorectal cancer cell lines to the anticancer agents and a physiological role of the MMR system as follows :
1) Drug-sensitivity of MMR-deficient cells
Cytotoxicities of 6 anticancer agents in the MMR-deficient HCT116 and LoVo cell lines were compared to those of paired MMR-proficient cells, HCT116+ch3 and LoVo+ch2. HCT116 exhibited re
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sistance to 5-FU, tegafur, and irinotecan, while cytotoxicity of gemicitabine in HCT116 and LoVo was greater than that of MMR-proficient cells.
2) Mechanism of high sensitivity of MMR-deficient cells
To explore why MMR-deficient cells show high sensitivity, we had several experiments with aphidicolin and hydroxurea. The results strongly indicate that MMR system is closely involved in the DNA replication completion checkpoint, though further investigation is required.
3) Establishment of a rapid and easy method for cytotoxic assay.
To estimate how different cytotoxicity of anticancer agents between MMR-deficient and -proficient cells, we developed a rapid assay system using E. coli with expression plasmids.
4) Presence of MMR-protein in tumor tissues of patients.
To know the contribution of chemotherapeutic agents to appearance of MMR-deficient cells, we screened more than 100 specimens by immunohistochemical staining. Several samples was negative for the staining, though all cases were primary tumor. Less
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