Chemoseusitily and its regulatory we chanism in gastrointestinal cancer

2000 Fiscal Year Final Research Report Summary

• Project/Area Number: 10671225
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Fujita Health University
• Principal Investigator: FUNABIKI Takahiko School of Medicine, Fujita Health University, Professor, 医学部, 教授 (40084537)
• Co-Investigator(Kenkyū-buntansha): JINBO Yasuko School of Medicine, Fujita Health University, Assistant Professor, 医学部, 助手 (50308871) ; SAKURAI Yoichi School of Medicine, Fujita Health University, Associate Professor, 医学部, 助教授 (60170651)
• Project Period (FY): 1998 – 2000
• Keywords: Chemosensitivity / Gastrointestinal cancer / Thymidylate synthase / DPD / P-glycoprotein / Thymidine phosphorylase / p53 protein / p53 gene mutations

Research Abstract

Chemosensitivities against 5-fluorouracil(5-FUra), mitomycin C(MMC)and cisplatin(CDDP)were examined using a newly developed collagen-gel droplet embedded culture method(presented in ASCO 2000)in 40 cases with colorectal and stomach cancers and evaluated the relationshp between the expression p53 protein and p53 gene mutation. Chemosensitivity of 5-FUra was evaluated by the T/C ratio(the ratio of the cell number after drug exposure in the collagen gels to those of control). Thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase activities in tumor tissues were also evaluated. Expression of p53 protein was evaluated immunohistochemically and p53 gene mutations in exon 5 through 8 were examined by a PCR-SSCP method. Cases of positive p53 mutation were defined as the cases with at least one gene mutation in these exons examined. T/C ratio of p53 protein positive cases was 89.1+/-10.6%, which was significantly higher than that of p53 protein negative cases(71.3+/-13. 7%, P=0.0261). T/C ratio of positive p53 gene mutation cases was 89.9+/-8.4%, which was also significantly higher than that of negative p53 gene mutation cases(73.6+/-15.9%, P=0.0330). T/C ratio of cases with positive p53 protein and positive p53 mutation was 93.1+/-7.0%, which was significantly higher that of the remainders(75.5+/-13.4%, P=0.0147). The predictability of the chemosensitivity against 5-FUra was the highest when evaluating the expression of p53 protein and gene mutation. Conversely, T/C ratio of cases with negative p53 protein and negative p53 mutation was 62.5±15.6%, which was significantly lower than that of the remainders. T/C ratios of MMC and cisplatin of cases with p53 protein positive and/or positive p53 mutation were uniformly higher than those of negative cases, but the difference was not statistically significant. These results suggest that chemosensitivity of gastrointestinal cancers against 5-FUra could easily be evaluated by this test and was predictable by examining the expression of p53 protein and p53 gene mutation, p53 status provides a useful adjunct to determine whether intravenous and/or oral fluoropyrimidine should be applied as an adjuvant chemotherapy immediately after surgery.