| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263 [S. C., Y. M. R.], and Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709 [T. S.]
5-Ethynyluracil (EU; 776C85) is a potent inactivator of dihydropyrimidine dehydrogenase, the enzyme that rapidly degrades 5-fluorouracil (FUra). We have investigated the antitumor activity and toxicity of FUra alone and in combination with EU in rats bearing advanced colon carcinoma. Two schedules were studied: (a) FUra daily for 4 days i.v. push (daily x 4); and (b) FUra administered i.v. push weekly for 3 weeks (weekly x 3). EU was administered at 1 mg/kg 1 h before FUra and for two additional days post-FUra therapy. The maximum tolerated doses of FUra alone were 35 and 100 mg/kg/day and for FUra plus EU were 10 and 15 mg/kg/day for the daily x 4 and weekly x 3 schedules, respectively. The dose-limiting toxicities were diarrhea and stomatitis both for FUra alone and for FUra in combination with EU. Although EU was not toxic and not active as an antitumor agent, it markedly improved the efficacy and therapeutic index of FUra. The antitumor activity of FUra was schedule dependent, yielding 13% complete and sustained tumor regression on the weekly schedule and no complete and sustained tumor regression on the daily schedule. The combination of FUra and EU produced 100% complete and sustained tumor regression on both schedules. The therapeutic index was 
1 for FUra alone and 6 for FUra with EU. EU was considerably more effective than either leucovorin or N-(phosphonacetyl)-L-aspartate as a modulator of FUra. Leucovorin or N-(phosphonacetyl)-L-aspartate induced minimum improvements on the daily schedule and only increased the therapeutic index to 1.5 on the weekly schedule. Because a 4-day continuous infusion of FUra alone at the maximum tolerated dose did not improve FUra therapy, we conclude that the improvements by EU involve additional modulations that complement the enhanced exposure of FUra.
1 Supported in part by Burroughs Wellcome Laboratory and a program project Grant CA 13038 from the National Cancer Institute.
2 To whom requests for reprints should be addressed, at Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263.
Received 11/ 1/93. Accepted 1/18/94.
This article has been cited by other articles:
|
|
 |
|
  R. G. Azrak, S. Cao, H. K. Slocum, K. Toth, F. A. Durrani, M.-b. Yin, L. Pendyala, W. Zhang, H. L. McLeod, and Y. M. Rustum Therapeutic Synergy Between Irinotecan and 5-Fluorouracil against Human Tumor Xenografts Clin. Cancer Res., February 1, 2004; 10(3): 1121 - 1129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Bading, P. B. Yoo, J. D. Fissekis, M. M. Alauddin, D. Z. D'Argenio, and P. S. Conti Kinetic Modeling of 5-Fluorouracil Anabolism in Colorectal Adenocarcinoma: A Positron Emission Tomography Study in Rats Cancer Res., July 1, 2003; 63(13): 3667 - 3674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Rothenberg, J. K. Benedetti, J. S. Macdonald, T. E. Seay, M. A. Neubauer, C. S. George, M. S. Tanaka, J. K. Giguere, B. T. Pruitt, and J. L. Abbruzzese Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study Ann. Onc., October 1, 2002; 13(10): 1576 - 1582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. F. Jones, F. A. Greco, J. D. Hainsworth, J. W. Patton, J. H. Barton, N. T. Willcutt, M. N. Baker, P. V. McGuirt, J. Levin, and H. A. Burris III A Phase I Trial of Weekly Paclitaxel Plus Prolonged Oral Eniluracil/5-Fluorouracil in Patients with Refractory Malignancies Oncologist, October 1, 2002; 7(5): 444 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Schilsky, J. Levin, W. H. West, A. Wong, B. Colwell, M. P. Thirlwell, R. H. Ansari, W. N. Bell, R. L. White, B. B. Yates, et al. Randomized, Open-Label, Phase III Study of a 28-Day Oral Regimen of Eniluracil Plus Fluorouracil Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Therapy in Patients With Metastatic/Advanced Colorectal Cancer J. Clin. Oncol., March 15, 2002; 20(6): 1519 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Grem, N. Harold, J. Shapiro, D.-Q. Bi, M. G. Quinn, S. Zentko, B. Keith, J. M. Hamilton, B. P. Monahan, S. Donavan, et al. Phase I and Pharmacokinetic Trial of Weekly Oral Fluorouracil Given With Eniluracil and Low-Dose Leucovorin to Patients With Solid Tumors J. Clin. Oncol., December 1, 2000; 18(23): 3952 - 3963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Bading, M. M. Alauddin, J. D. Fissekis, A. H. Shahinian, J. Joung, T. Spector, and P. S. Conti Blocking Catabolism with Eniluracil Enhances PET Studies of 5-[18F]Fluorouracil Pharmacokinetics J. Nucl. Med., October 1, 2000; 41(10): 1714 - 1724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Tewson Enzyme Inhibition as an Aid to Simplify Pharmacokinetic Measurements? J. Nucl. Med., October 1, 2000; 41(10): 1725 - 1726. [Full Text] [PDF]
|
|
|
|
|
|
S. Mani, H. Hochster, T. Beck, E. M. Chevlen, M. A. O'Rourke, C. H. Weaver, W. N. Bell, R. White, C. McGuirt, J. Levin, et al. Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal Cancer J. Clin. Oncol., August 15, 2000; 18(15): 2894 - 2901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cao and Y. M. Rustum Synergistic Antitumor Activity of Irinotecan in Combination with 5-Fluorouracil in Rats Bearing Advanced Colorectal Cancer: Role of Drug Sequence and Dose Cancer Res., July 1, 2000; 60(14): 3717 - 3721. [Abstract] [Full Text]
|
|
|
|
|
|
D. Salonga, K. D. Danenberg, M. Johnson, R. Metzger, S. Groshen, D. D. Tsao-Wei, H.-J. Lenz, C. G. Leichman, L. Leichman, R. B. Diasio, et al. Colorectal Tumors Responding to 5-Fluorouracil Have Low Gene Expression Levels of Dihydropyrimidine Dehydrogenase, Thymidylate Synthase, and Thymidine Phosphorylase Clin. Cancer Res., April 1, 2000; 6(4): 1322 - 1327. [Abstract] [Full Text]
|
|
|
|
|
|
S. Sharma and L. B. Saltz Oral Chemotherapeutic Agents for Colorectal Cancer Oncologist, April 1, 2000; 5(2): 99 - 107. [Abstract] [Full Text]
|
|
|
|
|
|
S. D. Baker, R. B. Diasio, S. O’Reilly, V. S. Lucas, S. P. Khor, S. E. Sartorius, R. C. Donehower, L. B. Grochow, T. Spector, J. A. Hohneker, et al. Phase I and Pharmacologic Study of Oral Fluorouracil on a Chronic Daily Schedule in Combination With the Dihydropyrimidine Dehydrogenase Inactivator Eniluracil J. Clin. Oncol., February 14, 2000; 18(4): 915 - 915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Guo, S. Cao, K. Tóth, R. G. Azrak, and Y. M. Rustum Overexpression of Bax Enhances Antitumor Activity of Chemotherapeutic Agents in Human Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., February 1, 2000; 6(2): 718 - 724. [Abstract] [Full Text]
|
|
|
|
|
|
D. Papamichael The Use of Thymidylate Synthase Inhibitors in the Treatment of Advanced Colorectal Cancer: Current Status Oncologist, December 1, 1999; 4(6): 478 - 487. [Abstract] [Full Text]
|
|
|
|
|
|
E. B. Lamont and R. L. Schilsky The Oral Fluoropyrimidines in Cancer Chemotherapy Clin. Cancer Res., September 1, 1999; 5(9): 2289 - 2296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Y. Ahmed, S. J. Johnston, J. Cassidy, T. O'Kelly, N. Binnie, G. I. Murray, A. H. van Gennip, N. G.G.M. Abeling, S. Knight, and H. L. McLeod Eniluracil Treatment Completely Inactivates Dihydropyrimidine Dehydrogenase in Colorectal Tumors J. Clin. Oncol., August 1, 1999; 17(8): 2439 - 2439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cao, J. J. McGuire, and Y. M. Rustum Antitumor Activity of ZD1694 (Tomudex) against Human Head and Neck Cancer in Nude Mouse Models: Role of Dosing Schedule and Plasma Thymidine Clin. Cancer Res., July 1, 1999; 5(7): 1925 - 1934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tateishi, M. Watanabe, H. Nakura, M. Tanaka, T. Kumai, S. F. Sakata, N. Tamaki, K. Ogura, T. Nishiyama, T. Watabe, et al. Dihydropyrimidine Dehydrogenase Activity and Fluorouracil Pharmacokinetics with Liver Damage Induced by Bile Duct Ligation in Rats Drug Metab. Dispos., June 1, 1999; 27(6): 651 - 654. [Abstract] [Full Text]
|
|
|
|
|
|
S. Cao, K. Lu, K. Toth, H. K. Slocum, T. Shirasaka, and Y. M. Rustum Persistent Induction of Apoptosis and Suppression of Mitosis as the Basis for Curative Therapy with S-1, an Oral 5-Fluorouracil Prodrug in a Colorectal Tumor Model Clin. Cancer Res., February 1, 1999; 5(2): 267 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Vogel and J.-M. Nabholtz Monotherapy of Metastatic Breast Cancer: A Review of Newer Agents Oncologist, February 1, 1999; 4(1): 17 - 33. [Abstract] [Full Text]
|
|
|
|
|
|
E. R. Adams, J. J. Leffert, D. J. Craig, T. Spector, and G. Pizzorno In Vivo Effect of 5-Ethynyluracil on 5-Fluorouracil Metabolism Determined by 19F Nuclear Magnetic Resonance Spectroscopy Cancer Res., January 1, 1999; 59(1): 122 - 127. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
