Predicting 5-FU sensitivity using human colorectal cancer specimens: comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU.
BACKGROUND
In tumor cells, the enzyme orotate phosphoribosyl transferase (OPRT) contributes to 5-fluorouracil (5-FU) phosphorylation and another enzyme, dihydropyrimidine dehydrogenase (DPD), is associated with 5-FU catabolic action. We measured OPRT and DPD activities and, to determine whether their levels might serve as indicators of 5-FU sensitivity, simultaneously assayed in vitro chemosensitivity to 5-FU.


METHODS
Tissue specimens were obtained from colorectal cancer patients and in vitro chemosensitivity was tested using fluorescein diacetate assay (FDA) or histoculture drug response assay (HDRA). DPD and OPRT activities were measured by radioassay.


RESULTS
The chemosensitivity assay was performed on 62 colorectal cancer specimens. Results were evaluable in 29 of 30 cases (96.7%) for FDA and 30 of 32 cases (98.3%) for HDRA. The positive sensitivity rate was 37.9% by FDA assay and 30% by HDRA assay. In positive specimens, the mean DPD activity was 44.9 +/- 32.6 pmol/min per mg protein, and in negative specimens, it was 53.8 +/- 33.7 pmol/min per mg protein ( P= 0.875). In contrast, the mean OPRT value was significantly higher in positive specimens (0.418 +/- 0.180 nmol/min per mg protein) than in negative specimens (0.325 +/- 0.153 nmol/min per mg protein; P < 0.05). The chemosensitivity test proved positive in 60% of the specimens with ORPT activity of 0.413 or above and 50% of those with DPD activity of 30 or below. Of the patient specimens showing OPRT activity of 0.413 or above and DPD activity of 30 or below, 88.9% were positive for 5-FU sensitivity, suggesting the possibility that the combination of these two levels may be predictive of 5-FU positive sensitivity.


CONCLUSIONS
DPD and OPRT activities within cancer cells may predict positive sensitivity to 5-FU.
Isshi
Kimio
K
Department of Surgery (Aoto Hospital), The Jikei University School of Medicine, 6-41-2 Aoto, Katushika-ku, Tokyo 125-8506, Japan. isshi-ki@jikei.ac.jp
Sakuyama
Toshikazu
T
Gen
Tomoyasu
T
Nakamura
Yasuyuki
Y
Kuroda
Toru
T
Katuyama
Toshiyuki
T
Maekawa
Yoshimi
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002470:Cell Survival; D004796:Clinical Enzyme Tests; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D042943:Dihydrouracil Dehydrogenase (NADP); D004354:Drug Screening Assays, Antitumor; D005260:Female; D005452:Fluoresceins; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000032:analysis*; D010088:Oxidoreductases / Q000032:analysis*; D011237:Predictive Value of Tests; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D005452:Fluoresceins; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil; C018506:diacetylfluorescein