Cancer Chemotherapy and Pharmacology

, Volume 42, Issue 6, pp 461–470

Preclinical pharmacology, toxicology and efficacy of sphingomyelin/cholesterol liposomal vincristine for therapeutic treatment of cancer

  • Murray S. Webb
  • Patricia Logan
  • Peter M. Kanter
  • Ginette St.-Onge
  • Karen Gelmon
  • Troy Harasym
  • Lawrence D. Mayer
  • Marcel B. Bally
ORIGINAL ARTICLE

DOI: 10.1007/s002800050846

Cite this article as:
Webb, M., Logan, P., Kanter, P. et al. Cancer Chemother Pharmacol (1998) 42: 461. doi:10.1007/s002800050846
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Abstract

Purpose: To establish the pharmacodynamic relationships between drug biodistribution and drug toxicity/efficacy, a comprehensive preclinical evaluation of sphingomyelin/cholesterol (SM/chol) liposomal vincristine and unencapsulated vincristine in mice was undertaken. Methods: Pharmaceutically acceptable formulations of unencapsulated vincristine and liposomal vincristine at drug/lipid ratios of 0.05 or 0.10 (wt/wt) were evaluated for toxicity, antitumor activity and pharmacokinetics following intravenous administration. Results: Mice given liposomal vincristine at 2 mg/kg vincristine had concentrations of vincristine in blood and plasma at least two orders of magnitude greater then those achieved after an identical dose of unencapsulated drug. One day after administration of the liposomal vincristine, there were at least tenfold greater drug quantities, relative to unencapsulated vincristine, in the axillary lymph nodes, heart, inguinal lymph nodes, kidney, liver, skin, small intestines and spleen. Increased plasma and tissue exposure to vincristine as a result of encapsulation in SM/chol liposomes was not associated with increased drug toxicities. Treatment of the murine P388 ascitic tumor with a single intravenous dose of unencapsulated drug at 2, 3 and 4 mg/kg, initiated 1 day after tumor cell inoculation, resulted in a 33 to 38% increase in lifespan. In contrast, long-term survival rates of 50% or more were achieved in all groups treated with the SM/chol liposomal vincristine formulations at doses of 2, 3 and 4 mg/kg. At the 4 mg/kg dose, eight of ten and nine of ten animals survived past day 60 when treated with SM/chol liposomal vincristine prepared at the 0.05 and 0.1 drug/lipid ratios, respectively. Conclusions: Overall, increased and prolonged plasma concentrations of vincristine achieved by liposomal encapsulation were correlated with dramatically increased antitumor activity in comparison with the unencapsulated drug, but no correlations could be established between pharmacokinetic parameters and toxicity.

Key words Vincristine Liposome Pharmacology 

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Murray S. Webb
    • 1
  • Patricia Logan
    • 1
  • Peter M. Kanter
    • 2
  • Ginette St.-Onge
    • 3
  • Karen Gelmon
    • 3
  • Troy Harasym
    • 3
  • Lawrence D. Mayer
    • 3
  • Marcel B. Bally
    • 3
  1. 1.Inex Pharmaceuticals Corporation, 100-8900 Glenlyon Parkway Burnaby, British Columbia, Canada V5J 5J8CA
  2. 2.Laboratory of Preclinical Toxicology, Roswell Park Cancer Institute, Buffalo, NY 14263, USAUS
  3. 3.British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6 Tel.:+1-604-877-6010; Fax: +1-604-877-6011; E-mail: mbally@unixg.ubc.caCA

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