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Time Course of the Effect of 4-Hydroperoxycyclophosphamide on Limb Differentiation in Vitro

  • Barbara F. Hales
  • Pierre Brissette
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)

Abstract

Cyclophosphamide is a commonly used anti-tumor and immunosuppressive agent. It is also mutagenic and teratogenic in a variety of species. Studies of the embryo have demonstrated that exposure to cyclophosphamide during organogenesis results in a spectrum of malformations that include exencephaly or hydrocephaly, open eyes, cleft palate, phocomelia, adactyly, syndactyly, polydactyly and kinky tail as well as disturbances in skeletal ossification (Gibson & Becker, 1968; Mirkes, 1985). Cyclophosphamide is usually teratogenic in a narrow dose range — lower doses have no apparent effects while higher doses are highly embryolethal.

Keywords

Alkaline Phosphatase Activity Cleft Palate Buthionine Sulfoximine Phosphoramide Mustard Limb Morphology 
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. Barrach, H. J., Baumann, I., and Neubert, D., 1978, The applicability of in vitro systems for the evaluation of the significance of pharmacokinetic parameters for the induction of an embryotoxic effect, in: “Role of Pharmacokinetics in Prenatal and Perinatal Toxicology”, D. Neubert, H. J. Merker, H. Nau & J. Languran, eds., Georg Thieme Publishers, Stuttgart, pp 323–349.Google Scholar
  2. Barrach, H. J. and Neubert, D., 1980, Significance of organ culture techniques for evaluation of prenatal toxicity, Arch. Toxicol., 45: 161–187.PubMedCrossRefGoogle Scholar
  3. Brock, N., 1976, Comparative pharmacologic study in vitro and in vivo with cyclophosphamide (NSC-26271), cyclophosphamide metabolites, and plain nitrogen mustard compounds, Cancer Treat. Rep., 60: 301–307.PubMedGoogle Scholar
  4. Burton, K., 1968, Determination of DNA concentration with diphenylamine, Methods Enzymology, 12: 163–166.CrossRefGoogle Scholar
  5. Chung, L. W. K. and Coffey, D. S., 1971, Biochemical characteristics of prostatic nuclei. II Relationship between DNA synthesis and protein synthesis, Biochim. Biophys. Acta., 247: 584–596.PubMedGoogle Scholar
  6. Fantel, A. G., Greenaway, J. C., Juchau, M. R., and Shepard, T. H., 1979, Teratogenic bioactivation of cyclophosphamide in vitro, Life Sci., 25: 67–72.PubMedCrossRefGoogle Scholar
  7. Fleer, R. and Brendel M., 1982, Toxicity, interstrand cross-links and DNA fragmentation by activated cyclophosphamide in yeast — comparative studies on 4-hydroperoxy-cyclophosphamide, its monofunctional analog on, acrolein, phosphoramide mustard, and nor-nitrogen mustard, Chem. Biol. Interact., 39: 1–15.PubMedCrossRefGoogle Scholar
  8. Foley, G. E., Friedman, O. M., and Drolet, B. P., 1961, Studies on the mechanism of action of cytoxan–evidence of activation in vivo and in vitro, Cancer Res., 21: 57–63.PubMedGoogle Scholar
  9. Garen, A. and Levinthal, C., 1960, A fine structure genetic and chemical study of the enzyme alkaline phosphatase of E. coli. I. Purification and characterization of alkaline phosphatase, Biochim. Biophys. Acta., 38: 470–483.PubMedCrossRefGoogle Scholar
  10. Gibson, J. E. and Becker, B. A., 1968, The teratogenicity of cyclophosphamide in mice, Cancer Res., 28: 475–480.PubMedGoogle Scholar
  11. Greenaway, J. C., Fantel, A. G., Shepard, T. H.,Juchau, M. R.,1982, The in vitro teratogenicity of cyclophosphamide in rat embryos, Teratology, 25: 335–343.PubMedCrossRefGoogle Scholar
  12. Hales, B. F., and Jain, R., 1980, Characteristics of the activation of cyclophosphamide to a mutagen by rat liver, Biochem. Pharmacol., 29: 256–259.PubMedCrossRefGoogle Scholar
  13. Hilton, J., 1984, Deoxyribonucleic-acid crosslinking by 4-hydroperoxycyclophosphamide in cyclophosphamide-sensitive and cyclophosphamide-resistant L1210 cells, Biochem. Pharmacol., 33: 1867–1872.PubMedCrossRefGoogle Scholar
  14. Kitchin, K. T., Schmid, B. P., and Sanyal, M. K., 1981, Teratogenicity of cyclophosphamide on a coupled microsomal activating/embryo culture system, Biochem. Pharmacol., 30: 59–64.PubMedCrossRefGoogle Scholar
  15. Klein, N. W., Vogler, M. A., Chatot, C. L., and Pierro, L. J.,1980, The use of cultured rat embryos to evaluate the teratogenic activity of serum:cadmium and cyclophosphamide, Teratology, 21: 199–208.PubMedCrossRefGoogle Scholar
  16. Kochhar, D. M., 1983, Embryonic organs in culture, in: “Handbook of Experimental Pharmacology,”,Johnson, E. M., and Kochhar, D. M., eds. Springer-Verlag, Heidelberger Platz, pp. 301–314.Google Scholar
  17. Kohler, E. and Merker, H. J., 1973, The effect of cyclophosphamide pretreatment of pregnant animals on the activity of nuclear DNA-dependent RNA-polymerases in different parts of rat embryos, Naunyn-Schmeid. Arch. Pharmacol., 277: 71–88.CrossRefGoogle Scholar
  18. Kwasigroch, T. E.,and Neubert, D., 1978, A simple method to test chondrogenic and myogenic tissues for differential effects of drugs, in: “Role of Pharmacokinetics in Prenatal and Perinatal Toxicology”, D. Neubert, H.-J. Merker, H. Nau, and J. Languran, eds.,Georg Thieme Publishers, Stuttgart, pp. 621–630.Google Scholar
  19. Low, J. E., Borch, R. F., and Sladek, N. E., 1982, Conversion of 4-hydroperoxycyclophosphamide and 4-hydroxycyclophosphamide to phosphoramide mustard and acrolein mediated by bifunctional catalysts, Cancer Res., 42: 830–837.PubMedGoogle Scholar
  20. Lowry, O. H., Rosebrough, N. J., Farr, A. L. and Randall, R. J., 1951, Protein measurement with the folin phenol reagent, J. Biol. Chem., 193: 265–275.PubMedGoogle Scholar
  21. Manson, J. M., and Simons, R., 1979, In vitro metabolism of cyclophosphamide in limb bud culture, Teratology, 19: 149–158.PubMedCrossRefGoogle Scholar
  22. Manson, J. M., and Smith, C. C., 1977, Influence of cyclophosphamide and 4-ketocyclophosphamide on mouse limb development, Teratology, 15: 291–300.PubMedCrossRefGoogle Scholar
  23. Mirkes, P. E., 1985, Cyclophosphamide teratogenesis - a review, Teratogen. Carcinogen. Nutagen., 5: 75–88.CrossRefGoogle Scholar
  24. Mirkes, P. E., and Greenaway, J. C., 1985, Uptake and binding of tritium from [chloroethyl3H] cyclophosphamide by rat embryos in vitro, Teratology, 31: 373–380.PubMedCrossRefGoogle Scholar
  25. Mirkes, P. E., Greenaway, J. C., Rogers, J. G., and Brundrett, R. B., 1984, Role of acrolein in cyclophosphamide teratogencity in rat embryos in vitro, Toxicol. Appl. Pharmacol., 72: 281–291.PubMedCrossRefGoogle Scholar
  26. Mirkes, P. E., Fantel, A. G., Greenaway, J. C., and Shepard, T. H., 1981, Teratogenicity of cyclophosphamide metabolites: phosphoramide mustard, acrolein and 4-ketocyclophosphamide in rat embryos cultured in vitro, Toxicol, Appl, Pharmacol., 58: 322–330.CrossRefGoogle Scholar
  27. Mirkes, P. E., Greenaway, J. C., and Shepard, T. H.,1983, A kinetic analysis of rat embryo response to cyclophosphamide exposure in vitro, Teratology, 28: 249–256.PubMedCrossRefGoogle Scholar
  28. Murthy, V. V., Becker, B. A., and Steele, W. S., 1973, Effects of dosage, phenobarbital and 2 diethylaminoethyl 2, 2-diphenylvalerate on the binding of cyclophosphamide and/or its metabolites to the DNA, RNA and protein of the embryo and liver of pregnant mice, Cancer Res., 33: 664–670.PubMedGoogle Scholar
  29. Neubert, D., 1982, The use of culture techniques in studies on prenatal toxicity, Pharmac. Ther., 18: 397–434.CrossRefGoogle Scholar
  30. Oliver, I. T., 1955, A spectrophotometric method for the determination of creatine phosphokinase and myokinase, Biochem. J. 61: 116–122.PubMedGoogle Scholar
  31. Osdoby, P., and Caplan, A. I., 1981, First bone formation in the developing chick limb, Develop. Biol., 86: 147–156.PubMedCrossRefGoogle Scholar
  32. Schneider, W. C., 1957, Determination of nucleic acids in tissues by pentose analysis, Methods Enzymology, 3: 680–691.CrossRefGoogle Scholar
  33. Short, R. D., Rao, K. S. and Gibson, J. E., 1972, The in vivo biosynthesis of DNA, RNA and proteins by mouse embryos after a teratogenic dose of cyclophosphamide, Teratology, 6: 129–138.PubMedCrossRefGoogle Scholar
  34. Slott, V. and Hales, B. F., 1985, Effect of glutathione (GSH) depletion by buthionine sulfoximine (BSO) on the in vitro teratogenicity and embryolethality of acrolein ( AC ), Teratology, 31: 33A.Google Scholar
  35. Takazimawa, A., Matsumoto, S., Iwata, T., Tochino, Y., Katagiri, K., Yamaguchi, K., and Shiratori, O., 1975, Studies on cyclophosphamide metabolites and their related compounds.2. Preparation of an active species of cyclophosphamide and related compounds, J. Med. Chem., 18: 376–383.CrossRefGoogle Scholar
  36. Voelker, G., Draeger, U., Peter, G. and Hohorst, H.-J., 1974, Studien zum spontanzerfall von 4-hydroxycyclophosphamid and 4-hydroperoxycyclophosphamid mit hilfe der dunnschichtchromatographie, Arzneim. Forsch./Drug Res., 24: 1172–1176.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Barbara F. Hales
    • 1
  • Pierre Brissette
    • 1
  1. 1.Department of Pharmacology and Therapeutics and Centre for The Study of ReproductionMcGill UniversityMontrealCanada

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