Therapeutic selectivity of vinca alkaloids: A role for guanosine 5'-triphosphate?

P. J. Houghton, J. A. Houghton, L. C. Bowman, B. J. Hazelton

Research output: Contribution to journalReview article

1 Scopus citations

Abstract

Tubulin, the protein subunit of microtubules, is considered a target for antimitotic agents such as colchicine, maytansine and the vinca alkaloids vincristine and vinblastine. Of these agents, only vincristine and vinblastine have been found to have clinical utility for treatment of human neoplastic disease. The basis for therapeutic selectivity was examined in a comprehensive model in which human rhabdomyosarcomas were grown as xenografts in mice. This model has allowed a detailed examination of differences between neoplastic and non-neoplastic tissues with respect to binding, retention and metabolism of vinca alkaloids. Of note is that in tumor tissue, vincristine is tenaciously bound whereas vinblastine is not. In non-neoplastic tissue, retention of both agents is poor. The mechanisms responsible for differential retention between vinca alkaloids and between neoplastic and non-neoplastic tissues were examined. Results suggest that guanosine 5-triphosphate may be implicated in the formation and stability of vinca-tubulin complexes in tissue cytosols. Two models consistent with the data are proposed, and the significance to therapeutic efficacy is discussed.

Original languageEnglish (US)
Pages (from-to)165-179
Number of pages15
JournalAnti-Cancer Drug Design
Volume2
Issue number2
StatePublished - Dec 1 1987
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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