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Selectivity of CF and 5-Fluorouracil: Critical Role of Polyglutamylation

  • Janet A. Houghton
  • Larry G. Williams
  • Siebold S. N. deGraaf
  • Saeed Radparvar
  • Irving W. Wainer
  • John R. Rodman
  • Peter J. Houghton
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 131)

Abstract

Earlier studies from these laboratories have indicated that in human colon adenocarcinoma xenografts, the mechanism of intrinsic resistance to 5-fluoropyrimidines may be a consequence of low levels of CH2-H4PteGlu in tumor cells. Thus, after administration of FUra or FdUrd, the inhibitory complex between FdUMP, CH2-H4PteGlu and TS may form relatively slowly, or may dissociate quite rapidly (1,2). Due to the influence of CH2-H4PteGlu on the stability of the ternary complex, leucovorin, a stable form of reduced folate, has been used in cultured cells (3) and clinically (4,5) to attempt to increase the pool of CH2-H4PteGlu, the stability of the ternary complex, and the inhibition of TS. However, preclinical studies that document the fate of leucovorin in neoplastic tissues are currently lacking.

Keywords

Bolus Injection Ternary Complex Excess Formaldehyde Combine Pool Polyglutamate Form 
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.

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References

  1. 1.
    J. A. Houghton, S. J. Maroda, J. 0. Phillips, and P. J. Houghton, Biochemical determinants of responsivenss to 5-fluorouracil and its derivatives in xenografts of human colorectal adenocarcinomas in mice, Cancer Res. 41: 144 (1981).PubMedGoogle Scholar
  2. 2.
    J. A. Houghton, P. M. Torrance, S. Radparvar, L. G. Williams, and P. J. Houghton, Binding of 5-fluorodeoxyuridylate to thymidylate synthase in human colon adenocarcinoma xenografts, Eur. J. Cancer Clin Oncol. 22: 505 (1986).PubMedCrossRefGoogle Scholar
  3. 3.
    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: 3288 (1981).PubMedGoogle Scholar
  4. 4.
    E. Newman, J. Doroshow, M. Bertrand, P. Burgeson, D. Villacorte, D. Blayney, D. Goldberg, B. Carr, L. Leong, K. Margolin, G. Cecchi, and R. Staples, Pharmacokinetics of high-dose folinic acid (dl-CF) administered by continuous intravenous (iv) infusion, Proc. Am. Assoc. Cancer Res. 26: 158 (1985).Google Scholar
  5. 5.
    D. Machover, E. Goldschmidt, P. Chollet, G. Metzger, J. Zittoun, J. Marquet, J.-M. Vandenbulcke, J.-L. Misset, L. Schwarzenberg, J. B. Fourtillan, H. Gaget, and G. Mathé, Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid, J. Clin. Oncol. 4: 685 (1986).PubMedGoogle Scholar
  6. 6.
    R. L. Kisliuk, Pteroylpolyglutamates, Mol. Cell Biochem. 39: 331 (1981).CrossRefGoogle Scholar
  7. 7.
    C. J. Allegra, B. A. Chabner, J. C. Drake, R. Lutz, D. Rodbard, and J. Jolivet, Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates, J. Biol. Chem. 260: 9720 (1985).PubMedGoogle Scholar
  8. 8.
    D. G. Priest, and M. Mangum, Relative affinity of 5,10-methylene- tetrahydrofolylpolyglutamates for the Lactobacillus casei thymidylate synthetase-5-fluorodeoxyuridylate binary complex, Arch. Biochem. Biophys. 210: 118 (1981).CrossRefGoogle Scholar
  9. 9.
    P. V. Danenberg, and A. Lockshin, Tight-binding complexes of thymidy- late synthetase, folate analogs, and deoxyribonucleotides, Adv. Enz. Regul. 20: 99 (1982).CrossRefGoogle Scholar
  10. 10.
    J. A. Houghton, and P. J. Houghton, On the mechanism of cytotoxicity of fluorinated pyrimidines in four human colon adenocarcinoma xenografts maintained in immune-deprived mice, Cancer 45: 1159 (1980).PubMedCrossRefGoogle Scholar
  11. 11.
    J. A. Houghton, K. D. Weiss, L. G. Williams, P. M. Torrance, and P. J. Houghton, Relationship between 5-fluoro-2’-deoxyuridylate, 2’-deoxyuridylate, and thymidylate synthase activity subsequent to 5-fluorouracil administration, in xenografts of human colon adenocarcinomas, Biochem. Pharmacol. 35: 1351 (1986).Google Scholar
  12. 12.
    J. A. Houghton, L. G. Williams, S. Radparvar, and P. J. Houghton, Characterization of the pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in xenografts of human colon adenocarcinoma, Cancer Res., in press (1988).Google Scholar
  13. 13.
    D. G. Priest, and M. T. Doig, Tissue folate polyglutamate chain length determination by electrophoresis as thymidylate synthase - fluorodeoxyuridylate ternary complexes. Meth. Enzymol. 122: 313 (1986).PubMedCrossRefGoogle Scholar
  14. 14.
    U. K. Laemmli, Cleavage of structural proteins during the assembly of the head of bacteriophage T4, Nature (London) 227: 680 (1970).CrossRefGoogle Scholar
  15. 15.
    I. W. Wainer, and R. M. Stiffin, Direct resolution of the stereoisomers of leucovorin and 5-methyltetrahydrofolate using a bovine serum albumin high-performance liquid chromatographic chiral stationary phase coupled to an achiral phenyl column, J. Chromatogr. 424: 158 (1988).PubMedCrossRefGoogle Scholar
  16. 16.
    D. Z. D’Argenio, and A. Schumitzky, A program package for simulation and parameter estimation in pharmacokinetic systems, Comp. Progr. Biomed. 9: 115 (1979).CrossRefGoogle Scholar
  17. 17.
    J. M. Gilbert, Adjuvant chemotherapy of large bowel cancer, Cancer Treat. Rev. 9: 195 (1982).Google Scholar
  18. 18.
    M.-B. Yin, S. F. Zakrzewski, and M. T. Hakala, Relationship of cellular folate cofactor pools to the activity of 5-fluorouracil, Mol. Pharmacol. 32: 190 (1983).Google Scholar
  19. 19.
    J. A. Straw, D. Szapary, and W. T. Wynn, Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects, Cancer Res. 44: 3114 (1984).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Janet A. Houghton
    • 1
  • Larry G. Williams
    • 1
  • Siebold S. N. deGraaf
    • 1
  • Saeed Radparvar
    • 1
  • Irving W. Wainer
    • 1
  • John R. Rodman
    • 1
  • Peter J. Houghton
    • 1
  1. 1.Departments of Biochemical and Clinical Pharmacology, and PharmacokineticsSt. Jude Children’s Research HospitalMemphisUSA

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