The spindle inhibitors include several different chemotherapy drugs. Unlike the previous drugs discussed, these agents do not work to alter DNA structure or function. These drugs interfere with the mechanics of cell division.

During mitosis, the DNA of a cell is replicated and then divided into two new cells. The process of separating the newly replicated chromosomes into the two forming cells involves spindle fibers. These fibers are constructed with microtubules. These spindle microtubules attach to the replicated chromosomes and pull one copy to each side of the dividing cell, as shown in the animation below. Without functional spindle fibers or spindles, the cell cannot divide and will eventually die. The spindle inhibitor drugs function in a cell-cycle dependent manner, halting division during early mitosis.⁽¹⁾

The microtubules that makeup spindle fibers are formed by long chains of smaller subunits of proteins called tubulins. The process of microtubule growth (polymerization) is shown below. As seen in the animation, the process is dynamic and the tubulin subunits can add to or fall off of the microtubule.

Certain types of spindle inhibitors bind to the tubulin monomers and stop the microtubules from being made. By forming a complex with the tubulin monomers, they halt the proper formation of spindle microtubules and disable the movement of chromosomes during mitosis.

Most spindle inhibitors affect both cancerous cells and normal cells and can cause unwanted side effects.

Learn more about a specific spindle inhibitor:
Vinca Alkaloids
Paclitaxel (Taxol®)
Docetaxel (Taxotere®)
Ixabepilone (Ixempra®)

A Closer Look at Taxol - New Use for an Old Drug

Arteriosclerosis is the hardening and narrowing of the arteries in response to injury of the inner layer (endothelium).⁽²⁾ Damage to arteries may be caused by high cholesterol levels, high blood pressure, or physical injury. Risk factors for increased susceptibility to damage include obesity, smoking, diabetes and physical inactivity.⁽³⁾

Atherosclerosis, a form of arteriosclerosis, is seen in patients with high cholesterol levels.⁽³⁾ High cholesterol may lead to the accumulation of fatty molecules called low-density lipoproteins (LDL) in regions of an artery and trigger an accumulation of immune cells called macrophages. This collection of macrophages and LDLs is termed an atheroma. Once formed, atheromas stimulate the production of proteins and calcium deposits which block the arteries. Smooth muscle cells in the vessel also reproduce and help organize the atheroma, narrowing the artery.⁽⁴⁾

Angioplasty is a medical procedure used to expand contracted arteries. A small tube surrounded by a balloon is inserted into an artery and positioned in the area of the blockage. Once in place, the balloon is expanded, allowing it to push on the sides of the vessel to reopen the artery. In a related procedure, the balloon is surrounded by a steel mesh stent At the location of blockage, the balloon is allowed to expand, in turn expanding the stent and reopening the artery. The stent permanently remains in the artery and serves as a framework that holds the artery open.⁽²⁾

Stent insertion is often perceived as damage by the cells of the arterial endothelium.⁽⁵⁾ In response to stent insertion, smooth muscle cells may reproduce in the area. Additional proteins may be produced that also re-block the artery. This process is called restenosis. The re-blockage of the vessel can completely reverse the benefit of the angioplasty and is a veryy undesirable outcome. Drug eluting stents have been developed to prevent this process of blockage by preventing smooth muscle cell division and clumping.⁽⁶⁾ The first drug eluting stent was developed by the Cordis Corporation and approved by the Federal Drug Administration in 2003.⁽⁷⁾

The following video depicts the insertion of an untreated stent via angioplasty and then the insertion of a drug-coated stent.

The CYPHER® Sirolimus-Eluting Coronary Stent releases a drug called sirolimus. Sirolimus is an immunosuppressive agent that prevents the accumulation of macrophages which may stimulate the build up of new cells within the artery and reduce its diameter. Sirolimus is also used to prevent rejection of organ transplants and research for its use in cancer treatment is currently underway.⁽⁸⁾⁽⁹⁾

In 2004, the FDA approved Taxus® Express2™. The Taxus® Express2™ releases Taxol®, a spindle inhibitor chemotherapy drug, into re-expanded arteries. Taxol® is embedded into a special polymer called TransLute™ which coats the stent and controls the time release of Taxol® into the artery. Studies of patients treated with insertion of the Taxus® Express2™ showed 3-6 % restenosis rates compared to between 25-30% restenosis in bare stents.⁽¹⁰⁾⁽¹¹⁾

Learn more about the Taxus® Express2™ system from the manufacturer's website or download a brochure.

References for this page:

Schwartz AL, Ciechanover A. "The ubiquitin-proteasome pathway and pathogenesis of human diseases." Annu Rev Med (1999). 50:57-74. [PUBMED]
Berger, Alan. "Angioplasty." Medline Plus. 5/30/2006 (Accessed on 10/11/06). [http://www.nlm.nih.gov/medlineplus/ency/article/002953.htm]
Vander, Arthur J., James H. Sherman, Dorothy S. Luciano. Human Physiology, 6th Edition. McGraw-Hill, Inc. NY, NY (1994).
Libby, P. "Changing Concepts of Atherogenesis." Journal of Internal Medicine. 247 (2000): 349-358. [PUBMED]
Ormiston, John A., Fiona M. Stewart, Anthony H.G. Roche, Bruce Webber, Ralph Whitlock,Mark Webster. "Late Regression of the Dilated Site After Coronary Angioplasty: A 5 Year Quantitative Angiographic Study." Circulation. 96(1997):468-474. [PUBMED]
Rainer, Wessely, Albert Schomig, Adnan Kastrati. "Sirolimus and Paclitaxel on Polymer-Based Drug-Eluting Stents." Journal of the American College of Cardiology. 47(2006):708-714. [PUBMED]
Faxon, David P. "Bringing Reality to Drug-Eluting Stents." Circulation. 109 (2004): 140-142. [PUBMED]
Sally J. DeNardo, Gerald L. DeNardo, Arutselvan Natarajan, Laird A. Miers, Allan R. Foreman, Cordula Gruettner, Grete N. Adamson, and Robert Ivkov. "Thermal Dosimetry Predictive of Efficacy of 111In-ChL6 Nanoparticle AMF Induced Thermoablative Therapy for Human Breast Cancer in Mice." Journal Nuclear Medicine 2007 48: 437-444. [PUBMED]
Faxon, David P. "Bringing Reality to Drug-Eluting Stents." Circulation. 109 (2004): 140-142. [PUBMED]
"NIA Scientists Honored for Stent Development." NIH Record. Vol LVII No 2 (2006). [http://www.nih.gov/nihrecord/01_27_2006/story05.htm]
Heldman, Alan W. et al. "Paclitaxel Stent Coating Inhibits Neointimal Hyperplasia at 4 Weeks in a Porcine Model of Coronary Restenosis." Circulation. 103(2001):2289. [PUBMED]

Spindle Inhibitors

A Closer Look at Taxol - New Use for an Old Drug