Biochemical modulation of 5-fluorouacil through dihydropyrimidine dehydrogenase inhibition: a Southwest Oncology Group phase II trial of eniluracil and 5-fluorouracil in advanced resistant colorectal cancer.
OBJECTIVE
To investigate the hypothesis that a systemic agent designed to inhibit dihydropyrimidine dehydrogenase (DPD), the first enzyme in the fluoropyrimidine degradative pathway, could improve the effective amount of 5-fluorouracil (5-FU) delivered to a tumor resulting in enhanced response.


METHODS
Eligibility included cytologically or pathologically verified diagnosis of colorectal cancer that recurred during or within 12 months of completion of adjuvant therapy, representing patients generally considered resistant to fluorinated pyrimidine therapy. Stratification was into two cohorts: recurrence while receiving adjuvant therapy, and relapse within 12 months of completing adjuvant therapy. Treatment consisted of 28 days of oral therapy every five weeks with eniluracil and 5-FU administered in a 10:1 ratio. The daily dose of eniluracil was 10 mg/m2 with 5-FU 1 mg/m2, divided into two doses.


RESULTS
Twenty-five patients are evaluable for response: 9 relapsed during therapy and 16 relapsed within one year of adjuvant therapy. In the first group, there was one partial response (9%; 95% CI 0-41%); in the second cohort there was one confirmed complete response (5%; 95% CI 0-23%) and one unconfirmed partial response, for an overall response rate of 10%.


CONCLUSIONS
This regimen lacks significant activity in this target population. Pre-treatment intratumoral DPD expression was not assessed, therefore the mechanism of fluorinated pyrimidine resistance cannot be specifically attributed to elevated DPD levels. Attempting restoration of chemotherapy sensitivity through blockade of enzymes or signal transduction molecules responsible for resistance is rational, provided that tumor target expression is the basis for trial entry.
Leichman
Cynthia G
CG
Comprehensive Cancer Centers of the Desert, Palm Springs, CA 92262, USA. leichman@earthlink.net
Chansky
Kari
K
Macdonald
John S
JS
Doukas
Michael A
MA
Budd
G Thomas
GT
Giguere
Jeffrey K
JK
Abbruzzese
James L
JL
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D024221:Antineoplastic Protocols; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D016001:Confidence Intervals; D042943:Dihydrouracil Dehydrogenase (NADP); D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015206:Southwestern United States; D015996:Survival Rate; D017211:Treatment Failure; D014498:Uracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil