Changes to the dihydropyrimidine dehydrogenase gene copy number influence the susceptibility of cancers to 5-FU-based drugs: Data mining of the NCI-DTP data sets and validation with human tumour xenografts.
Patient response to the anti-tumour drug 5-fluorouracil (5-FU) is variable, but predicting the response rate is important for the selection of effective chemotherapy. Our aim was to identify alterations in DNA copy number that influence susceptibility of cancer cells to 5-FU-based drugs. The NCI public database was used to identify chromosome loci associated with drug sensitivity and DNA copy number. One of the 11 candidates, the cytogenetic band 1p21.3, harbours the dihydropyrimidine dehydrogenase (DPD) gene. To validate this finding, the DPD copy number and in vivo sensitivity to 5-FU-based drugs were determined in 31 human tumour xenografts. Those xenografts demonstrating low sensitivity had significantly higher DPD copy numbers than highly sensitive tumours (P<0.002). Moreover, DPD mRNA expression levels were significantly correlated with DPD copy numbers (P<0.046). An assessment of copy number may be a more precise method of predicting the sensitivity of cancer patients to 5-FU related drugs.
Kobunai
Takashi
T
Department of Systematic Clinical Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kobunai-tky@umin.ac.jp
Ooyama
Akio
A
Sasaki
Shin
S
Wierzba
Konstanty
K
Takechi
Teiji
T
Fukushima
Masakazu
M
Watanabe
Toshiaki
T
Nagawa
Hirokazu
H
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D046228:Microarray Analysis / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014183:Transplantation, Heterologous
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil