Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity.
OBJECTIVE
The aim of the present study was to analyze the role of thymidylate synthase (TS; main cellular target of fluorouracil [FU]) and dihydropyrimidine dehydrogenase (DPD; rate-limiting enzyme of FU catabolism) in tumoral biopsies with respect to FU responsiveness.


METHODS
This prospective study was conducted on 62 head and neck cancer patients (six stage II, 16 stage III, and 40 stage IV). All received first-line chemotherapy with biomodulated FU (5-day continuous infusion). Before treatment, a tumor biopsy and control biopsy (symmetrical nontumoral area) were obtained. Cytosolic TS and DPD activities were measured using radioenzymatic assays.


RESULTS
DPD activity was detectable in all samples, without a significant difference between tumoral (median, 60 pmol/min/mg protein; range, 13 to 193) and nontumoral samples (median, 68 pmol/min/mg protein; range, 12 to 150). Tumoral TS and tumoral DPD were not significantly influenced by tumor localization or tumor staging. Among 52 tumors assessable for clinical response, we observed 46% complete responses (CRs), 33% partial responses (PRs), and 21% no responses (NRs). No relationship was demonstrated between TS activity and response to FU therapy. The comparison of tumoral DPD between complete responders and partial or nonresponders showed a trend toward significance (P = .06). In an attempt to reduce variability, we analyzed the tumoral/nontumoral DPD activity ratio; complete responders exhibited a significantly lower normalized DPD than partial or nonresponding patients (median, 0.86, 1.18, and 1.42 for CR, PR, and NR, respectively; CR v PR plus NR, P = .03).


CONCLUSIONS
Although resistance to FU is multifactorial, the present clinical study suggests that FU catabolism in target cells is probably a determinant factor for FU responsiveness in cancer patients and justifies the clinical use of specific DPD inhibitors as FU biomodulators.
Etienne
M C
MC
Centre Antoine Lacassagne, Nice, France.
Chéradame
S
S
Fischel
J L
JL
Formento
P
P
Dassonville
O
O
Renée
N
N
Schneider
M
M
Thyss
A
A
Demard
F
F
Milano
G
G
D000328:Adult; D000368:Aged; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010088:Oxidoreductases / Q000032:analysis*; D011446:Prospective Studies; D013940:Thymidylate Synthase / Q000032:analysis*
D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil