Abstract
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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References
Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Maillard JA, Laurie JA, Tschetter LK, Wiesenfield M: Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1407–1418, 1989
Advanced Colorectal Cancer Meta-Analysis Project: Modulation of 5-fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 10:896–903, 1992
Leichman CG, Fleming TR, Muggia FM, Tangen CM, Ardalan B, Doroshow JH, Meyers FJ, Holcombe RF, Weiss GR, Mangalik A, Macdonald JS: Phase II study of 5-FU and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 13(6):1303–1311, 1995
Corfu-A Study Group: Phase III randomized study of two fluorouracil combinations with either interferon alfa-2a or leucovorin for advanced colorectal cancer. J Clin Oncol 13:921–928, 1995
O'Dwyer PJ, Manola J, Valone FH, Ryan LM, Hines JD, Wadler S, Haller D, Arbuck SG, Weiner LM, Mayer RJ, Bebson AB III: Fluorouracil modulation in colorectal cancer: lack of improvement with N-phosphonacetyl-l-aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule - an Easter Cooperative Oncology Group/Cancer and Leukemia Group B study. J Clin Oncol 19:2413–2421, 2001.
O'Connell MJ, Laurie JA, Kahn M, Fitzgibbons RJ Jr, Erlichman C, Shepherd L, Moertel CG, Kocha WI, Pazdur R, Weiand HS, Rubin J, Vukov AM, Donohue JH, Krook JE, Figueredo A: Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 16:295–300, 1998
Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, Veeder MH, Maillard JA: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352–358, 1990
Heggie GD, Sommadossi J-P, Cross DS, Huster WJ, Diasio RB: Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine and bile. Cancer Res 47:2203–2206, 1987
Shousong C, Yousef MR, Spector T: 5-ethynyluracil (776C85): modulation of 5-FU efficacy and therapeutic index in rats bearing advanced colorectal carcinoma. Cancer Res 54:1507–1510, 1994
Baker SD, Khor SP, Adjei AA, Doucette M, Spector T, Donehower RC, Grochow LB, Sartorius SE, Noe DA, Hohneker JA, Rowinsky EK: Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Onocl 14:3085–3096, 1996
Schilsky RL, Hohneker JA, Ratain MJ, Janisch L, Smetzer L, Lucas VS, Khor SP, Diasio R, Von Hoff DD, Burris HA III: Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 16:1450–1457, 1998
Burroughs Wellcome: 776C85: Updated (3/95) summary of non-clinical and clinical (Phase I) data
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter, J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792, 2001
Bergsland E, Hurwitz H, Fehrenbacher L, Meropol NJ, Novotny WF, Gaudreault J, Lieberman G, Kabbinavar F: A Randomized Phase II trial comparing rhuMAb VEGF (recombinant humanized monoclonal antibody to vascular endothelial growth factor) plus 5-fluorouracil/leucovorin (FU/LV) to FU/LV alone in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 19:939, 2000
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Leichman, C.G., Chansky, K., Macdonald, J.S. et al. 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. Invest New Drugs 20, 419–424 (2002). https://doi.org/10.1023/A:1020662113061
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DOI: https://doi.org/10.1023/A:1020662113061