The interaction of a new anti-tumour drug, KAR-2 with calmodulin

F. Orosz, B. Vértessy, C. Salerno, C. Crifo, E. Capuozzo, J. Ovádi

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

1. KAR-2 (3'-(β-chloroethyl)-2',4'-dioxo-3,5'-spiro-oxazolidino-4-deacetoxy -vinblastine) is a semisynthetic bis-indol derivative, with high anti-microtubular and anti-tumor activities but with low toxicity. KAR-2, in contrast to other biologically active bis-indols (e.g. vinblastine), did not show anti-calmodulin activity in vitro (enzyme kinetic, fluorescence anisotropy and immunological tests). 2. Direct binding studies (fluorescence resonance energy transfer, circular dichroism) provided evidence for the binding of KAR-2 to calmodulin. The binding affinity of KAR-2 to calmodulin (dissociation constant was about 5 μm in the presence of Ca2+ was comparable to that of vinblastine. 3. KAR-2 was able to interact with apo-calmodulin as well; in the absence of Ca2+ the binding was of cooperative nature. 4. The effect of drugs on Ca2+ homeostasis in human neutrophil cells was investigated by means of a specific fluorescent probe. Trifluoperazine extensively inhibited the elevation of intracellular Ca2+ level, vinblastine did not appreciably affect it, KAR-2 stimulated the Ca2+ influx and after a transient enhancement the a2+ concentration reached a new steady-state level. 5. Comparison of the data obtained with KAR-2 and bis-indols used in chemotherapy suggests that the lack of anti-calmodulin potency resides on the spiro-oxazolidino portion of KAR-2. This character of KAR-2 manifested itself in various systems and might in its low vivo toxicity, established in an anti-tumour test.

Original languageEnglish
Pages (from-to)955-962
Number of pages8
JournalBritish Journal of Pharmacology
Volume121
Issue number5
DOIs
Publication statusPublished - 1997

Fingerprint

Calmodulin
Vinblastine
Pharmaceutical Preparations
Neoplasms
deacetoxyvinzolidine
Trifluoperazine
Fluorescence Resonance Energy Transfer
Immunologic Tests
Fluorescence Polarization
Circular Dichroism
Fluorescent Dyes
Neutrophils
Homeostasis
Drug Therapy
Enzymes

Keywords

  • Bis-indols
  • Calmodulin antagonism
  • Vinblastine
  • Vinca alkaloids
  • Vincristine

ASJC Scopus subject areas

  • Pharmacology

Cite this

The interaction of a new anti-tumour drug, KAR-2 with calmodulin. / Orosz, F.; Vértessy, B.; Salerno, C.; Crifo, C.; Capuozzo, E.; Ovádi, J.

In: British Journal of Pharmacology, Vol. 121, No. 5, 1997, p. 955-962.

Research output: Contribution to journalArticle

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