Starvation tactics for solid tumors: tumor blood flow interruption via a combretastatin derivative (Cderiv), and its microcirculation mechanism

Abstract

Combretastatin can prevent the supply of nutrients to cancer cells by selectively interrupting tumor blood flow (TBF). Therefore, combretastatin may serve as a new anticancer drug that utilizes starvation tactics to attack solid tumors. Among combretastatin compounds, combretastatin A-4 and a combretastatin A-4 derivative (Cderiv) are now in phase III clinical trials. These two combretastatin compounds have similar chemical structures and provide marked TBF interruption. However, their mechanisms of action are reportedly quite different and remain controversial. Precise mechanisms of action of these agents must be elucidated so as to develop safe clinical treatments and wider clinical applications. By using various kinds of rodent tumors, we showed that Cderiv produced potent interruption of TBF in all primary tumors and metastatic foci, without exception, and had beneficial therapeutic effects including significantly improved survival. Cderiv caused host arterioles to constrict. However, a tumor vascular bed scarcely reacted to a direct topical application of Cderiv. In addition, the fact that Cderiv did not have cytotoxic drug-like accumulated toxicity usually caused by repeated administration means that inhibition of tubulin polymerization by Cderiv may not occur to a great degree in vivo. Therefore, at least for Cderiv, our studies demonstrated that TBF interruption was mainly caused indirectly, via enhancement of vascular resistance of host arterioles, rather than being caused by a direct effect of Cderiv on tumor vessels. In this review, I describe cancer therapy that utilizes such TBF interruption, which leads to Cderiv-induced necrosis, and discuss details of its microcirculation mechanism.