Optimization of cancer chemotherapy using DNA microarray

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 13470111
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tohoku University
• Principal Investigator: KANAMARU Ryunosuke Tohoku University, Institute of development, aging and cancer, Professor, 加齢医学研究所, 教授 (70152783)
• Co-Investigator(Kenkyū-buntansha): KATO Satoshi Tohoku University, Institute of development, aging and cancer, Research associate, 加齢医学研究所, 助手 (60333887)
• Project Period (FY): 2001 – 2002
• Keywords: MICROARRAY / CHEMOTHERAPY / OPTIMIZATION

Research Abstract

DNA microarray based optimization of cancer chemotherapy is one of the urgent themes to solve. Practically chemotherapy are underwent by combination rather than single agent, so we think most important step to optimize the cancer chemotherapy is analyze the genes that related synergy of combined administration. We made custom 11K-cDNA microarray and examined gene expression changes with it. Colon cancer models are used. Colon cell line DLD1,LSI74T and 0VK18, MCF 7 cells for control are cultured in appropriate medium. In the first step ideal condition for synergy was determined. 5FU, cisplatin (CDDP) and camptothecin (CPT-11) are administered and cell growth are counted by MTT assay. Finally CDDP 0.5μg/ml, 5FU 5μM (CDDP+5FU) and CPT-11 10μM, 5FU 5μM(CPT-11+5FU) are found to be ideal for synergy. Many single agent related genes (for example inosine monophosphate dehydrogenase 1 and adenine phosphoinosyltransferase for 5FU and heat shock protein 90 and Y-box binding protein 1 (YB-1) for CDDP, keratin 8,18, tubulin beta for CPT-11) are picked up. CPT-11+ 5FU specific genes are NF-kB activating kinase and methionyl aminopeptidase and so on. CDDP + 5FU related genes are single strand DNA binding protein, presenillin associated protein…etc. Interestingly YB-1 was up-regulated in CDDP only. CDDP, 5FU concomitant administration did not show significant expression increase on YB-1. As YB-1 regulates MDR1, it may be newly found mechanism on CDDP-5FU synergy. Furthermore IER3 which play an important role on apoptosis in anti-apoptotic manner was found to be up-regulated on 5FU but not CPT-11+5FU, CDDP+5FU combination. There should be several previously unknown mechanisms on synergistic effect in combination chemotherapy. Our result strongly suggest important profile on gene expression changes and beneficial for searching such genes to understand and customize the effect on combination chemotherapy.