Paclitaxel (Taxol) is an anticancer agent with clinical activity against various human cancer types.
METHODS AND RESULTS:
Paclitaxel blocks cell division by stabilizing microtubules, a mechanism that also underlies its major side effects (neutropenia and neurotoxicity). Paclitaxel can also alter cardiac function, and to elucidate the mechanism of this activity, we tested the mechanical and electrical effects of paclitaxel and a series of analogs (docetaxel, taxol B, taxol C and N-Methyltaxol C; 5-20 microM) on two different cardiac preparations, the isolated coronary perfused heart and the papillary muscle of the guinea pig. Paclitaxel and N-Methyltaxol C induced conduction arrhythmias and reduced coronary flow and left ventricular systolic pressure in the isolated heart, whereas the other taxol derivatives tested had no significant effect. Moreover, paclitaxel blocked the vasodilator effect of bradykinin in the isolated heart. Paclitaxel and N-Methyltaxol C produced a positive inotropic effect in papillary muscle, without alterations in the action potential. In the latter preparation, no significant variations were observed after treatment with the other taxol derivatives.
CONCLUSIONS:
The in vitro cardiodepressant and arrhythmogenic activity of paclitaxel is similar to that reported after its clinical administration and might be due to coronary vasoconstriction.
The precise role of microtubules as modulators of intracellular calcium in cardiac and smooth muscle cells is at present unclear, because docetaxel and other taxol analogs, though they exhibited similar activity on tubulin, lacked cardiac effects. |
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