New anti-mitotic drugs with distinct anti-calmodulin activity.
Bisindole Vinca alkaloids target microtubule system causing anti-mitotic activity. The problem of their clinical application is the lack of selectivity resulting in toxic side effects. In this paper we review the late history of new bisindole derivatives focusing on KARs recognized as potent anti-cancer drugs with low side effect. KARs, just as other bisindoles, impede microtubule assembly of mitotic spindle, however, they display no anti-calmodulin activity. This new drug family appears to be less potent than vinblastine in vitro systems, but it shows high antitumor efficacy with considerably higher doses being well tolerated in the animal tumor models. 3D data of calmodulin complexed with KAR-2 explain the specificity and unique pharmacology of KAR derivatives.
Orosz
F
F
Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, H-1113, Budapest, Karolina 29, Hungary.
Horváth
I
I
Ovádi
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D026121:Indole Alkaloids / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects
D000970:Antineoplastic Agents; D002147:Calmodulin; D026121:Indole Alkaloids; D014404:Tubulin