2004 Fiscal Year Final Research Report Summary
Novel chmosensitivity testing using molecular dynamics responding to anticancer drugs
| Project/Area Number |
15591360
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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 |
General surgery
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| Research Institution | Keio University |
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Principal Investigator |
YOSHIRO Saikawa Keio University, Department of Medicine, Assistant, 医学部, 助手 (00225682)
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| Project Period (FY) |
2003 – 2004
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| Keywords | chemosensitivity test / cisplatin / 5- fluorouracil / gadd153 / p21 / c-jun / c-jun |
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| Research Abstract |
We hypothesized that the altered gene expression levels of several molecules in tumors could be utilized to predict the future chemotherapeutic outcomes at early stages after exposure to anticancer agents. As candidate genes we chose GADD153, p21, and c-Jun, as these three molecules are known to be involved in different signal transduction pathways involved in responses to anticancer agents. Expression levels of the three genes were increased in transient, concentration-dependent manners in human gastric cancer cell lines TMK-1, MKN-45, and MKN74 when treated with 5-FU or CDDP, both in vitro and when grown as tumor xenografts in nude mice. We also quantitated expression levels of the three genes in normal and tumor tissues sampled from different locations of the stomach from 11 advanced gastric cancer patients. Our results showed only small intra-stomach and intra-tumor variation for each gene, and that the inter-individual variation was also small for normal and non-therapeutic tumor tissues. However, biopsies from 12 patients with stage IIIB/IV gastric cancer obtained 3-7 days after neo-adjuvant treatment revealed that there was a statistically significant relationship between the magnitude of increased mRNA levels of the three genes and response rate. In conclusion, our results indicated that the magnitude of increased GADD153, p21, and c-Jun expression was a promising marker of response to gastric cancer treatment. The altered mRNA levels of the three genes appeared to reflect the actual extent of injuries sustained by tumors due to chemotherapy, and therefore make the molecules particularly attractive as potential markers.
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