{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T02:56:29Z","timestamp":1761101789307},"reference-count":47,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2009,2,10]],"date-time":"2009-02-10T00:00:00Z","timestamp":1234224000000},"content-version":"vor","delay-in-days":4242,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[1997,7]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>KAR\u20102 (3\u2032\u2032\u2010(\u03b2\u2010chloroethyl)\u20102\u2032\u2032,4\u2032\u2032\u2010dioxo\u20103,5\u2032\u2032\u2010spiro\u2010oxazolidino\u20104\u2010deacetoxy\u2010vinblastine) is a semisynthetic bis\u2010indol derivative, with high anti\u2010microtubular and anti\u2010tumour activities but with low toxicity. KAR\u20102, in contrast to other biologically active bis\u2010indols (e.g. vinblastine), did not show anti\u2010calmodulin activity <jats:italic>in vitro<\/jats:italic> (enzyme kinetic, fluorescence anisotropy and immunological tests).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Direct binding studies (fluorescence resonance energy transfer, circular dichroism) provided evidence for the binding of KAR\u20102 to calmodulin. The binding affinity of KAR\u20102 to calmodulin (dissociation constant was about 5\u2003\u03bc<jats:sc>M<\/jats:sc>) in the presence of Ca<jats:sup>2+<\/jats:sup> was comparable to that of vinblastine.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>KAR\u20102 was able to interact with apo\u2010calmodulin as well; in the absence of Ca<jats:sup>2+<\/jats:sup> the binding was of cooperative nature.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The effect of drugs on Ca<jats:sup>2+<\/jats:sup> homeostasis in human neutrophil cells was investigated by means of a specific fluorescent probe. Trifluoperazine extensively inhibited the elevation of intracellular Ca<jats:sup>2+<\/jats:sup> level, vinblastine did not appreciably affect it, KAR\u20102 stimulated the Ca<jats:sup>2+<\/jats:sup> influx and after a transient enhancement the Ca<jats:sup>2+<\/jats:sup> concentration reached a new steady\u2010state level.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Comparison of the data obtained with KAR\u20102 and bis\u2010indols used in chemotherapy suggests that the lack of anti\u2010calmodulin potency resides on the spiro\u2010oxazolidino portion of KAR\u20102. This character of KAR\u20102 manifested itself in various systems and might result in its low <jats:italic>in vivo<\/jats:italic> toxicity, established in an anti\u2010tumour test.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p>","DOI":"10.1038\/sj.bjp.0701190","type":"journal-article","created":{"date-parts":[[2006,8,25]],"date-time":"2006-08-25T17:11:32Z","timestamp":1156525892000},"page":"955-962","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The interaction of a new anti\u2010tumour drug, KAR\u20102 with calmodulin"],"prefix":"10.1111","volume":"121","author":[{"given":"F","family":"Orosz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B G","family":"V\u00e9rtessy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Salerno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Crifo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E","family":"Capuozzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Ov\u00e1di","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,10]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"191","article-title":"Effects of various calmodulin antagonists on contraction of rabbit aortic strips","volume":"220","author":"Asano M.","year":"1982","journal-title":"J. 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