Preclinical Assessment of the Cardiotoxic Potential of Anthracycline Antibiotics: N-L-Leucyl-Doxorubicin

  • G. Zbinden
  • D. DeCampeenere
  • R. Baurain
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 14)

Abstract

The primary task of industrial toxicologists is to provide a comprehensive assessment of the adverse effects of selected chemical substances in several animal species and over a broad range of doses. Increasingly, their collaboration is also required when a compound has caused serious toxicity in humans or animals, and when it is decided to modify the chemical structure, in an effort to reduce or to eliminate the undesirable properties. In such programs it is often necessary to assess a considerable number of newly synthesized substances. Moreover, the results of the toxicity tests must be available within a short period of time, and they must be quantitative, so as to provide a rational basis for the synthesis of new derivatives. It is evident that the standard toxicological procedures cannot be used for these purposes, and that a toxicological screening approach has to be developed which differs fundamentally from that on which the conventional safety assessment programs are based (Zbinden et al 1984a). The main differences between conventional safety testing programs and toxicological screening are summarized in Table 1.

Keywords

Cholesterol Toxicity Leukemia Neuropathy Doxorubicin 

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References

  1. Alder S, Zbinden G (1983) Neurobehavioral tests in single and repeated-dose toxicity studies in small rodents. Arch Toxicol 54: 1–23PubMedCrossRefGoogle Scholar
  2. Beijersbergen van Henegouven GMJ (1988) In vitro and in vivo research on phototoxic xenobiotics: structure-activity relationships. Arch Toxicol Suppl 12:3–9Google Scholar
  3. Cojocel C, Gottsche U, Tolle KL, Baumann K (1988) Nephrotoxic potential of first-, second-, and third-generation cephalosporins. Arch Toxicol 62:458–464PubMedCrossRefGoogle Scholar
  4. Deprez-DeCampeneere D, Baurain R, Masquelier M, Trouet A (1980) Toxic and chemotherapeutic effects of L-leucyl-daunorubicin and L-leucyl-doxorubicin after intravenous administration in mice. Current Chemotherapy and Infectious Diseases. Proc. 11th ICC and 19th ICAAC. American Society of Microbiology, pp. 1692–1694Google Scholar
  5. Fent K, Mayer E, Zbinden G (1988) Nephrotoxicity screening in rats. A validation study. Arch Toxicol 61:349–358PubMedCrossRefGoogle Scholar
  6. Hu ST, Brändle E, Zbinden G (1983) Inhibition of cardiotoxic, nephrotoxic and neurotoxic effects of doxorubicin by ICRF-159, Pharmacology 26:210–220CrossRefGoogle Scholar
  7. Jaenke RS, Deprez-De Campeneere D, Trouet A (1980) Cardiotoxicity and comparative pharmacokinetics of six anthracyclines. Cancer Res 40:3530–3536PubMedGoogle Scholar
  8. Jensen RA, Acton EM, Peters JH (1984) Doxorubicin cardiotoxicity in the rat: comparison of electrocardiogram, transmembrane potential, and structural effects. J Cardiovasc Pharmacol 6: 186–200PubMedCrossRefGoogle Scholar
  9. Magis AJ, Atassi G, Baurain R, DeCampeneere D, Trouet A, Zbinden G (1989) Preclinical development of N-L-leucyl-doxorubicin. Proc. 3rd ARTAC (Association pour la Recherche Thérapeutique Anticancereuse) Workshop. Paris October 19–20Google Scholar
  10. Masquelier M, Baurain R, Trouet A (1980) Amino acid and dipeptide derivatives of daunorubicin. 1. Synthesis, physicochemical properties, and lysosomal digestion. J Med Chem 23:1166–1170PubMedCrossRefGoogle Scholar
  11. Zbinden G (1981) Assessment of cardiotoxic effects in subacute and chronic rat toxicity studies. In: Cardiac Toxicology, Ed. T. Balazs, Vol. III, CRP Press Inc. Boca Raton, Fla, pp.7–32Google Scholar
  12. Zbinden G, Fent K, Thouin M (1988) Nephrotoxicity screening in rats: General approach and establishment of test criteria. Arch Toxicol 61:344–348PubMedCrossRefGoogle Scholar
  13. Zbinden G, Elsner J, Boelsterli UA (1984a) Toxicological screening. Regulatory Toxicol Pharmacol 4:275–286CrossRefGoogle Scholar
  14. Zbinden G, Beilstein AK, Bachmann E (1984b) Toxicological studies with a novel synthetic anthracycline, the bis-hydrazone bridge analog of 4-demethoxydaunorubicin (SC-33428). Arzneimittelforsch 34: 1298–1301PubMedGoogle Scholar
  15. Zbinden G, Bachmann E, Holderegger Ch (1978) Model system for cardiotoxic effects of anthracyclines. Antibiotics and Chemother 23:255–270Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • G. Zbinden
    • 1
  • D. DeCampeenere
    • 2
  • R. Baurain
    • 2
  1. 1.Institute of Toxicology Swiss Federal Institute of TechnologyUniversity of ZurichSchwerzenbachSwitzerland
  2. 2.Medgenix GroupBrusselsBelgium

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