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
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Purpose. To investigate thehypothesis that a systemic agent designedto inhibit dihydropyrimidine dehydrogenase(DPD), the first enzyme in thefluoropyrimidine degradative pathway, couldimprove the effective amount of5-fluorouracil (5-FU) delivered to a tumorresulting in enhanced response.
Patients and methods. Eligibility includedcytologically or pathologically verifieddiagnosis of colorectal cancer thatrecurred during or within 12 months ofcompletion of adjuvant therapy,representing patients generally consideredresistant to fluorinated pyrimidinetherapy. Stratification was into twocohorts: recurrence while receivingadjuvant therapy, and relapse within 12months of completing adjuvant therapy.Treatment consisted of 28 days of oraltherapy every five weeks with eniluraciland 5-FU administered in a 10:1 ratio. Thedaily dose of eniluracil was 10 mg/m2with 5-FU 1 mg/m2, divided into twodoses.
Results. Twenty-five patientsare evaluable for response: 9 relapsedduring therapy and 16 relapsed within oneyear of adjuvant therapy. In the firstgroup, there was one partial response (9%;95% CI 0–41%); in the second cohort therewas one confirmed complete response (5%;95% CI 0–23%) and one unconfirmed partialresponse, for an overall response rate of10%.
Conclusions. This regimen lackssignificant activity in this targetpopulation. Pre-treatment intratumoral DPDexpression was not assessed, therefore themechanism of fluorinated pyrimidineresistance cannot be specificallyattributed to elevated DPD levels.Attempting restoration of chemotherapysensitivity through blockade of enzymes orsignal transduction molecules responsiblefor resistance is rational, provided thattumor target expression is the basis fortrial entry.
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Investigational New Drugs
Volume 20, Issue 4 , pp 419-424
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers
- Additional Links
- colorectal cancer
- Industry Sectors
- Author Affiliations
- 1. Comprehensive Cancer Centers of the Desert, Palm Springs, CA, USA
- 2. Southwest Oncology Group Statistical Center, Seattle, WA, USA
- 3. St. Vincent's CCC, New York, NY, USA
- 4. University of Kentucky Medical Center, Lexington, KY, USA
- 5. Cleveland Clinic Foundation, Cleveland, OH, USA
- 6. Greenville CCOP, Greenville, SC, USA
- 7. MD Anderson Cancer Center, University of Texas, Houston, TX, USA