Microtubule Active Agents: Beyond the Taxane Frontier

Abstract

Microtubules are essential to cell transport, signaling, and mitosis. An increasing range of anticancer drugs interferes with the normal formation and function of microtubules.Vinca alkaloids act as microtubule destabilizers and the taxanes act as microtubule stabilizers. Taxanes are widely used cytotoxic agents that are active in a range of solid tumor malignancies and are routinely used in a variety of settings. Significant limitations with the taxanes exist, including acquired and intrinsic tumor resistance through the expression of multidrug resistance proteins such as P-glycoprotein, risk of hypersensitivity reactions, dose-limiting hematopoietic toxicity, and cumulative neurotoxicity. Hence, there is a need to develop novel agents that act on the microtubules. Epothilones are macrolide antibiotics that bind near the taxane-binding site on microtubules and have been extensively studied in recent and ongoing clinical trials. A variety of other agents that act on the microtubules at different sites with a variety of structures are at varying stages of development.

Pharmacogenomics of Second-Line Drugs Used for Treatment of Unresponsive or Relapsed Osteosarcoma Patients

“…The main toxic effect of Vinca alkaloids is neutropenia (which is the principal dose-limiting toxicity of these drugs), but they can also induce peripheral neurotoxicity and gastrointestinal toxicities [26].…”

“…Docetaxel , Bristol-Myers Squibb, NJ, USA) are the most commonly used taxanes, which have been included in several neoadjuvant, adjuvant and secondline chemotherapy protocols, alone or in combination with drugs with different mechanisms of action and nonoverlapping toxicity profiles. The taxanes bind to tubulin (to binding sites that are distinct from those of the Vinca alkaloids), stabilize the microtubule and inhibit its disassembly, leading ultimately to cell death by apoptosis [19,26].…”

“…Resistance occurs through a variety of mechanisms, the most common of which is the overexpression of ABCB1 that causes the efflux of taxanes from tumor cells (Tables 2 & 3) [26]. Other described mechanisms of taxanes resistance are intrinsic and acquired mutations of tubulin or altered expression of microtubuleassociated proteins, which can interfere or prevent the normal binding of tubulin with these drugs [26].…”

“…Other described mechanisms of taxanes resistance are intrinsic and acquired mutations of tubulin or altered expression of microtubuleassociated proteins, which can interfere or prevent the normal binding of tubulin with these drugs [26].…”

The power of chemotherapeutic engineering: Arresting cell cycle and suppressing senescence to protect from mitotic inhibitors

“…5,[37][38][39][40] Microtubule-targeting drugs kill proliferating cells. [6][7][8]41 Undesirably, mitotic inhibitors kill proliferating normal cells too.…”