Relationships between the expression of thymidylate synthase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase and cell proliferative activity and 5-fluorouracil sensitivity in colorectal carcinoma.
BACKGROUND
The site of action of the 5-fluorouracil (5-FU) antitumor effect has been explicated in recent years. Many studies have investigated enzymes involved in 5-FU metabolism in attempts to predict this effect, and a correlation of enzyme activity with the 5-FU drug sensitivity test has been reported. The aim of this study was to identify the biochemical response determinants of 5-FU. Additionally, we aimed to clarify the association between cell proliferative activity and the response to 5-FU of colorectal cancer.


METHODS
Our research subjects were 54 patients with colorectal carcinoma who had undergone operations between August 1999 and July 2001 in our department. Assays of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT) activities in colorectal carcinoma tissue and assays of 5-FU sensitivity by the collagen gel droplet embedded culture drug sensitivity test (CD-DST) were conducted to investigate the relationships between each enzyme activity and 5-FU sensitivity. In addition, the proliferative activity of cancer cells was evaluated with Ki-67 antibody, and the relationship of this activity to each enzyme activity and 5-FU sensitivity were investigated.


RESULTS
5-FU sensitivity was high in the low-TS-activity group and in the high-OPRT-activity group. Cancers with high cell proliferative activity showed good sensitivity to 5-FU, and TS and OPRT activities were high in such cancers.


CONCLUSIONS
The results suggest that OPRT activity can predict sensitivity to 5-FU, and high OPRT activity may cause good 5-FU sensitivity in cancers with high cell proliferative activity.
Tokyo Women's Medical University, Second Department of Surgery, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Ryuta
R
Fujii
Akiyoshi
A
Seshimo
Shingo
S
Kameoka
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP); D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009962:Orotate Phosphoribosyltransferase / Q000032:analysis / Q000378:metabolism*; D010088:Oxidoreductases / Q000032:analysis / Q000378:metabolism*; D011336:Probability; D011446:Prospective Studies; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D013940:Thymidylate Synthase / Q000032:analysis / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil