Microtubule-Based Cancer Drugs

Microtubule is a part of cytoskeleton in the eukaryotic cell. Cytoskeleton is critical component of mitotic spindle and is essential for the internal movements occurring in the cytoplasm. When cell divides, the mitotic spindle plays an important role in equally partitioning of DNA into the two daughter cells. The microtubule inhibitor disrupts this process by affecting microtubule function.

Table 16. Microtubule-Based Cancer Drugs

Product	Target	Indication	Clinical Status	Manufacturer
Abraxane	Microtubule	Various tumors	Market	Abraxis Biosciences
AVE-8062	Microtubule	Various tumors	Phase I/II	Aventis
Ixabepilone	Microtubule	Various tumors P	Market	Bristol-Myers Squibb
KOS-862 (Epotholine D)	Microtubule	Breast cancer, colorectal cancer, kidney cancer, melanoma, and non-small cell lung cancer	Phase I/II	Bristol-Myers Squibb and Kosan Biosciences
Tasidotin	Tubulin	Various tumors	Phase II	Genzyme
MAC-321	Microtubule	Breast and colorectal cancers	Phase II	Wyeth
Navelbine	Microtubule	Breast and non-small cell lung cancers	Phase III	GlaxoSmithKline
Taxol	Microtubule	Various tumors	Market	Bristol-Myers Squibb
Taxotere	Microtubule	Various tumors	Market	Aventis

Taxol (paclitaxel) and Taxotere (docetaxel) are both from the same drug family - the taxanes. Taxol is the first member of taxane family used in the cancer treatment. Taxotere is a semi-synthetic product.

Abraxane is formed by nanoparticle albumin-bound technology. Paclitaxel is bound to albumin in nanoparticle to get the insoluble drug into cells without a solvent and make the drug selective for tumor cells, since normal cells are too tightly joined even for nanoparticles, but nanoparticles are able to navigate the "leaky junctions" between malformed tumor cells. Therefore, the drug targets the tumor cells and spares the normal cells.

KOS-862, or Epotholine D, appears to be promising microtubule stabilizing agents with a somewhat different spectrum of activities than the taxanes, including activity in paclitaxel-resistant tumors.

Ixabepilone is a semi-synthetic analog of epothilone B, which is strong promoters of microtubulin polymerization and has tubulin polymerizing activity that is 2-10 times stronger than paclitaxel.

Tasidotin is a novel tubulin-interactive agent. The agent is a synthetic dolastatin analog and has a unique mechanism of action that potentially differs from that of microtubule-stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and other dolastatins). It has been chemically modified to provide improved pharmacological properties and is orally bioavailable with a potentially enhanced therapeutic window over earlier-generation dolastatins.

AVE8062 (AC-7700) is a water-soluble derivative of combretastatin A and is a member of a new class of agents called vascular targeting agents. AVE8062 has an innovative mechanism of action: it inhibits tubulin polymerization in activated endothelial cells, which results in a rapid occlusion of the tumor vasculature, leading to vascular shutdown.

MAC-321 is a taxane analog with demonstrated superior antitumor activities and is believed to exert its anti-tumor cell effects through several mechanisms including tubulin binding, microtubule stabilization, apoptosis, TNF-alpha up-regulation and angiogenesis inhibition.