The Roswell Park Memorial Institute and Gastrointestinal Tumor Study Group Phase III Experience with the Modulation of 5-Fluorouracil by Leucovorin in Metastatic Colorectal Adenocarcinoma

  • Nicholas J. Petrelli
  • Youcef M. Rustum
  • Howard Bruckner
  • Donald Stablein
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 131)


The therapeutic activity of 5-Fluorouracil (5-FU) in gastrointestinal (GI) malignancies may be enhanced by increasing the tumor cell reduced folate pools in vivo 1, 2, 3, 4. One of the mechanisms of action of 5-FU is its conversion into fluorodexoyuridylate (FdUMP), which inhibits thymidylate synthetase (TS) 5. FdUMP binds tightly to TS in the presence of the cofactor L-5, 10-methylene tetrahydrofolate (CH2FH4). This interaction of FdUMP and TS leads to the formation of a covalent ternary complex, TS-CH2FH4-FdUMP6. The stability of the ternary complex is maximal when the extracellular folate concentration is 10 umol/L in cell culture7. Therefore, high levels of inhibition of TS and a slow recovery of the enzyme activity can occur only in the presence of sufficient intracellular concentrations of reduced folates.


Roswell Park Memorial Institute Intravenous Hydration Thymidylate Synthetase Metastatic Colorectal Carcinoma Fatal Toxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    D. Machover, E. Goldschmidt, P. Chollet, G. Metzger, J. Zittoun, J. Marquet, et al., Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high dose folinic acid, J. Clin. Oncol. 4: 5: 685 (1986).PubMedGoogle Scholar
  2. 2.
    J. A. Houghton, S. J. Maroda, J. O. Phillips, et al., Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice, Cancer Res. 41: 144 (1981).PubMedGoogle Scholar
  3. 3.
    S. Madajewicz, N. Petrelli, Y. M. Rustum, et al., Phase I-II trial of high dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer, Cancer Res. 44: 4667 (1984).PubMedGoogle Scholar
  4. 4.
    D. Machover, L. Schwarzenberg, E. Goldsmith, et al., Treatment of advanced colorectal and gastric adenocarcinoma with 5-FU combined with high-dose folinic acid: A pilot study, Cancer Treat. Rep. 66: 1803 (1982).PubMedGoogle Scholar
  5. 5.
    C. Heidelberger, Fluorinated pyrimidines and their nucleosides, in: “Handbook of Experimental Pharmacology, Antineoplastic and Immunosuppressive Agents”, A. C. Sartorelli and D. G. Johns, eds., Springer Verlag, New York (1975).Google Scholar
  6. 6.
    D. V. Santi, C. S. McHenry and H. Sommer, Mechanism of interaction of thymydilate synthetase with 5-fluorodeoxyuridylate, Biochemistry 13: 471 (1974).PubMedCrossRefGoogle Scholar
  7. 7.
    R. M. Evans, J. D. Laskin and M. T. Hakala, Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil, Cancer Res. 41: 3283 (1981).Google Scholar
  8. 8.
    N. Petrelli, L. Herrera, Y. Rustum, P. Burke, P. Creaven, J. Stulc, L. Emrich and A. Mittelman, A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma, J. Clin. Oncol. 5: 10: 1559 (1987).PubMedGoogle Scholar
  9. 9.
    C. G. Moertel, Chemotherapy of gastrointestinal cancer, N. Engl. J. Med. 299: 1049 (1978).PubMedCrossRefGoogle Scholar
  10. 10.
    H. L. Davis, Chemotherapy of large bowel cancer, Cancer 50: 2638 (1982).PubMedCrossRefGoogle Scholar
  11. 11.
    C. A. Presant, A. E. Denes, C. Liu, et al., Prospective randomized reappraisal of 5-fluorouracil in metastatic colorectal carcinoma: A comparative trial with 6-thioguanine, Cancer 53: 2610 (1984).PubMedCrossRefGoogle Scholar
  12. 12.
    P. F. Engstrom, J. M. Maclntyre, A. Mittelman, et al., Chemotherapy of advanced colorectal carcinoma: Fluorouracil alone vs two drug combinations using fluorouracil, hydroxyurea, semustine, decarbazine, razoxane and mitomycin: A phase III trial by the Eastern Cooperative Oncology Group, Am. J. Clin. Oncol. 7: 313 (1984).PubMedCrossRefGoogle Scholar
  13. 13.
    S. G. Arbuck, F. Trave, H. O. Douglass, Jr., H. Nava, S. Zakrzewski and Y. M. Rustum, Phase I and pharmacologic studies of intraperitoneal leucovorin and 5-fluorouracil in patients with advanced cancer, J. Clin. Oncol. 4: 1510 (1986).PubMedGoogle Scholar
  14. 14.
    F. Trave, Y. M. Rustum, N. J. Petrelli, L. Herrera, A. Mittelman, C. Frank and P. J. Creaven, Plasma and tumor tissue pharmacology of high dose intravenous 5-formyltetrahydrofolate inhibition with 5-fluorouracil in patients with advanced colorectal carcinoma, J. Clin. Oncol. in press (1988).Google Scholar
  15. 15.
    J. A. Straw, D. Szapary and W. T. Wynn, Pharmacokinetics of the diastereroisomers of leucovorin after intravenous oral administration to normal subjects, Cancer Res. 44: 3114 (1984).PubMedGoogle Scholar
  16. 16.
    N. Petrelli, D. Stablein, H. Bruckner, A. Megibow, R. Mayer and H. Douglass, A prospective randomized phase III trial of 5-fluorouracil (5FU) versus 5FU and high dose leucovorin (HDCF) versus 5FU and low dose leucovorin (LDCF) in patients (pts) with metastatic colorectal carcinoma: A report of the Gastrointestinal Tumor Study Group, Proc. Am. Assoc. Cancer Pes. 7: p. 94 (abst. No. 357 ) (1988).Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Nicholas J. Petrelli
    • 1
  • Youcef M. Rustum
    • 1
  • Howard Bruckner
    • 2
  • Donald Stablein
    • 3
  1. 1.Roswell Park Memorial Institute, Department of Surgical Oncology (NJP)Grace Cancer Drug Center (YMR)BuffaloUSA
  2. 2.Department of Medicine and Neoplastic DiseasesMount Sinai School of MedicineNew YorkUSA
  3. 3.The EMMES CorporationPotomacUSA

Personalised recommendations