Anti-cancer Therapy: Anti-cancer Therapy: Antimitotic Agents Antimitotic Agents

By: Kristin Gillis By: Kristin Gillis

Discussion PointsDiscussion Points

What is cancer?What is cancer?

Mitosis and mitotic Mitosis and mitotic checkpointscheckpoints

How deregulation of How deregulation of the above contributes the above contributes to cancer formationto cancer formation

Antimitotic agents as Antimitotic agents as a treatmenta treatment

Taxanes Taxanes

Vinca alkaloids Vinca alkaloids

Colchicine Colchicine

Problems with Problems with antimitotics overallantimitotics overall

What's new with What's new with antimitotics?antimitotics?

What is Cancer?What is Cancer?

Cancer is the deregulation of normal cellular Cancer is the deregulation of normal cellular processes.  Cells that have been transformed processes.  Cells that have been transformed tend to proliferate in an uncontrolled and tend to proliferate in an uncontrolled and deregulated way and, in some cases, to deregulated way and, in some cases, to metastasize (spread). metastasize (spread). Cancer is not one disease, but a group of more Cancer is not one disease, but a group of more than 100 different and distinctive diseases.than 100 different and distinctive diseases.Cancer can involve any tissue of the body and Cancer can involve any tissue of the body and take on many different forms in each area.take on many different forms in each area.Cancer is the 2nd leading cause of death in the Cancer is the 2nd leading cause of death in the U.S., surpassed only by heart disease.U.S., surpassed only by heart disease.

What Happens in Cancer Cells?What Happens in Cancer Cells?

Cancer cells become deregulated in many Cancer cells become deregulated in many different ways.different ways.– One way: Mutations in one or more mitotic One way: Mutations in one or more mitotic

checkpoints allow the cell to move from one phase of checkpoints allow the cell to move from one phase of mitosis to another unchecked.mitosis to another unchecked.

– Another way: Mutations in cellular machinery itself so Another way: Mutations in cellular machinery itself so that mitotic errors are not properly detected/repaired, that mitotic errors are not properly detected/repaired, and the cell is allowed to move through mitosis and the cell is allowed to move through mitosis unchecked.unchecked.

But what is ‘mitosis?’But what is ‘mitosis?’

What is Mitosis? What is Mitosis? “It’s been so long, I’ve forgotten…”“It’s been so long, I’ve forgotten…”

Here’s a video to remind everybody exactly what Here’s a video to remind everybody exactly what mitosis, also known as the ‘Cell Cycle,’ entails:mitosis, also known as the ‘Cell Cycle,’ entails:

Short video first Short video first http://youtube.com/watch?v=eFuCE22agyMhttp://youtube.com/watch?v=eFuCE22agyM

More detailMore detail

http://www.youtube.com/watch?v=VlN7K1-9QB0http://www.youtube.com/watch?v=VlN7K1-9QB0&NR=1&NR=1

Stages of Mitosis Stages of Mitosis

Interphase: Technically not Interphase: Technically not part of mitosis, but rather part of mitosis, but rather encompasses stages G1, S, encompasses stages G1, S, and G2 of the cell cycle which and G2 of the cell cycle which prepare the cell for mitosis.prepare the cell for mitosis.

Prophase: Chromatin in Prophase: Chromatin in nucleus condense; nucleolus nucleus condense; nucleolus disappears. Centrioles begin disappears. Centrioles begin moving to opposite ends of the moving to opposite ends of the cell and fibers extend from the cell and fibers extend from the centromeres. centromeres.

Metaphase: Spindle fibers Metaphase: Spindle fibers align the chromosomes along align the chromosomes along the middle of the cell nucleus. the middle of the cell nucleus. This line is referred to as the This line is referred to as the ‘metaphase plate.’ ‘metaphase plate.’

Anaphase: The paired Anaphase: The paired chromosomes separate at the chromosomes separate at the kinetochores and move to kinetochores and move to opposite sides of the cell. opposite sides of the cell. Motion results from the Motion results from the physical interaction of polar physical interaction of polar microtubules.microtubules.

Stages of Mitosis (cont.)Stages of Mitosis (cont.)

Telophase: Chromatids arrive Telophase: Chromatids arrive at opposite poles of cell, and at opposite poles of cell, and new membranes form around new membranes form around the daughter nuclei. The the daughter nuclei. The chromosomes disperse.chromosomes disperse.

Cytokinesis: Results when a Cytokinesis: Results when a fiber ring composed of a fiber ring composed of a protein called actin around the protein called actin around the center of the cell contracts, center of the cell contracts, pinching the cell into two pinching the cell into two daughter cells, each with one daughter cells, each with one nucleus. nucleus.

Mitosis SummaryMitosis Summary

Mitosis is the process by which a cell duplicates the Mitosis is the process by which a cell duplicates the chromosomes in its cell nucleus in order to generate two, chromosomes in its cell nucleus in order to generate two, identical, daughter nuclei.identical, daughter nuclei.It is followed immediately by cytokinesis, which divides It is followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into the nuclei, cytoplasm, organelles and cell membrane into two daughter cells containing roughly equal shares of two daughter cells containing roughly equal shares of these cellular components.these cellular components.Mitosis and cytokinesis together define the mitotic (M) Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle.phase of the cell cycle.Mitosis is a normal cellular process necessary to sustain Mitosis is a normal cellular process necessary to sustain life, but its deregulation in one form or another is found in life, but its deregulation in one form or another is found in all cancer cells. all cancer cells. Mitosis can often become abnormal by the change in, or Mitosis can often become abnormal by the change in, or absence of, the normal mitotic checkpoints.absence of, the normal mitotic checkpoints.

Mitotic Checkpoints Mitotic Checkpoints

Mitotic checkpoints are points in the cell cycle which act Mitotic checkpoints are points in the cell cycle which act to ensure correct transmission of genetic information to ensure correct transmission of genetic information during cell division.  These checkpoints look for during cell division.  These checkpoints look for abnormalities within the cycle, specifically chromosomal abnormalities within the cycle, specifically chromosomal aberrancy.aberrancy.Checkpoints take place towards the end of each phase Checkpoints take place towards the end of each phase of mitosis and must be passed before the cell can get of mitosis and must be passed before the cell can get clearance to enter into the next stage of mitosis.clearance to enter into the next stage of mitosis.If errors are found during checkpoints, the cell acts If errors are found during checkpoints, the cell acts quickly to correct them, arresting cell growth and not quickly to correct them, arresting cell growth and not proceeding with mitosis until the error has been fixed.proceeding with mitosis until the error has been fixed.If these errors cannot be fixed, the cell normally If these errors cannot be fixed, the cell normally undergoes apoptosis, or programmed cell death. undergoes apoptosis, or programmed cell death. 

How ‘Cancer’ Arises How ‘Cancer’ Arises

The cell is allowed to move through the cell cycle and The cell is allowed to move through the cell cycle and grow unchecked, and more mutations are accumulated grow unchecked, and more mutations are accumulated over time that extend past the cell cycle to the cellular over time that extend past the cell cycle to the cellular machinery itself.machinery itself.These mutations, in combination with the genetic These mutations, in combination with the genetic mutations accrued through abnormal mitotic progression, mutations accrued through abnormal mitotic progression, eventually cause the cell to be completely deregulated in eventually cause the cell to be completely deregulated in its growth and proliferation.its growth and proliferation.It becomes unstoppable and even immortal.It becomes unstoppable and even immortal.

You get CANCER!You get CANCER!

Antimitotic Agents: One Possible Antimitotic Agents: One Possible Treatment Treatment

Antimitotic agents: Anti-tumor Antimitotic agents: Anti-tumor agents that inhibit the function agents that inhibit the function of of microtubulesmicrotubules through the through the binding of their subunits or binding of their subunits or through direct cessation of their through direct cessation of their growth.growth.What are microtubules (MTs)?What are microtubules (MTs)?Protein polymers formed by a-Protein polymers formed by a-Tubulin and B-tubulin Tubulin and B-tubulin heterodimers that play an heterodimers that play an important role in critical cell important role in critical cell functions such as movement, functions such as movement, phagocytosis and axonal phagocytosis and axonal transport.  They also play a key transport.  They also play a key role in the formation of the role in the formation of the mitotic spindle apparatus and mitotic spindle apparatus and cytokinesis at the end of cytokinesis at the end of mitosis.  mitosis. 

In normal cells, microtubules In normal cells, microtubules are formed when a cell starts are formed when a cell starts dividing during mitosis.  Once dividing during mitosis.  Once the cell stops dividing, the cell stops dividing, microtubules are broken down microtubules are broken down or destroyed.or destroyed.

The crucial involvement of The crucial involvement of MTs in mitosis makes them a MTs in mitosis makes them a prime target for anti-cancer prime target for anti-cancer agents.agents.

Antimitotic Agents Antimitotic Agents

Three distinct classes of antimitotic agents have Three distinct classes of antimitotic agents have been identified thus far.been identified thus far.1.) 1.) TaxanesTaxanes; include: paclitaxel and docetaxel.; include: paclitaxel and docetaxel.2.) 2.) Vinca alkaloidsVinca alkaloids; include: vincristine, ; include: vincristine, vinblastine, vindesine, and vinorelbine.vinblastine, vindesine, and vinorelbine.3.) 3.) ColchicineColchicine..

All must be administrated via intravenous All must be administrated via intravenous infusion.infusion.

Taxanes (First Antimitotic Group)Taxanes (First Antimitotic Group)

Prevent the growth of cancer cells by affecting Prevent the growth of cancer cells by affecting microtubules.microtubules.

Overall, they encourage microtubule formation, Overall, they encourage microtubule formation, then they stop the microtubules from being then they stop the microtubules from being broken down so that the cells become so broken down so that the cells become so clogged with microtubules that they cannot clogged with microtubules that they cannot continue to grow and divide.  This results in the continue to grow and divide.  This results in the cell’s arrest in mitosis.cell’s arrest in mitosis.

Eventually, cell DEATH by apoptosis. Eventually, cell DEATH by apoptosis.

Taxanes: HistoryTaxanes: History

Isolated from the bark of the Western Isolated from the bark of the Western yew tree in 1971, this compound yew tree in 1971, this compound became useful in the treatment of became useful in the treatment of cancer when it was discovered that it cancer when it was discovered that it possessed the unique ability to possessed the unique ability to promote the formation of microtubules promote the formation of microtubules by binding to their B-tubulin subunit by binding to their B-tubulin subunit and antagonizing their disassembly.and antagonizing their disassembly.However, the amount of paclitaxel in However, the amount of paclitaxel in yew bark was small, and extracting it yew bark was small, and extracting it was a complicated and expensive was a complicated and expensive process. In addition, bark collection process. In addition, bark collection was restricted because the Western was restricted because the Western yew is a limited resource located in yew is a limited resource located in forests that are home to the forests that are home to the endangered spotted owl.endangered spotted owl.

As demand for paclitaxel grew, As demand for paclitaxel grew, government agencies and the government agencies and the pharmaceutical company Bristol-Myers pharmaceutical company Bristol-Myers Squibb, worked to increase availability Squibb, worked to increase availability and find other sources of paclitaxel and find other sources of paclitaxel besides the bark of the Western yew besides the bark of the Western yew tree. tree. This work led to the production of a This work led to the production of a semi-synthetic form of paclitaxel semi-synthetic form of paclitaxel (docetaxel) derived from the needles (docetaxel) derived from the needles and twigs of the Himalayan yew tree and twigs of the Himalayan yew tree Taxus bacattaTaxus bacatta, which is a renewable , which is a renewable resource. The FDA approved resource. The FDA approved docetaxel in the spring of 1995. docetaxel in the spring of 1995.

Taxanes: Paclitaxel Taxanes: Paclitaxel

Paclitaxel [Taxol] was the first Paclitaxel [Taxol] was the first compound of the series to be compound of the series to be discovered and used in cancer discovered and used in cancer treatment.treatment.

Used in the treatment of: Used in the treatment of: ovarian cancer, breast cancer, ovarian cancer, breast cancer, AIDS-related Kaposi's AIDS-related Kaposi's sarcoma and lung cancer.sarcoma and lung cancer.

Side effects include: bone Side effects include: bone marrow loss, hypersensitivity, marrow loss, hypersensitivity, muscle aches, peripheral muscle aches, peripheral neuropathy, bradycardia and neuropathy, bradycardia and tachycardia.tachycardia.

Taxanes: Docetaxel Taxanes: Docetaxel

Docetaxel [Taxotere] is Docetaxel [Taxotere] is partially-synthetic derivative of partially-synthetic derivative of Taxol and results from the Taxol and results from the modification of paclitaxel’s side modification of paclitaxel’s side chain.chain.While it is paclitaxel’s While it is paclitaxel’s structural analog, it is much structural analog, it is much more potent in terms of more potent in terms of potential patient toxicity.potential patient toxicity.It acts to kill cancer cells in the It acts to kill cancer cells in the same way as paclitaxel.same way as paclitaxel.

Taxanes: Docetaxel (cont.)Taxanes: Docetaxel (cont.)

Useful in the treatment of: mainly prostate Useful in the treatment of: mainly prostate cancer, but also breast, ovarian and lung cancer, but also breast, ovarian and lung cancer.cancer.

Must be co-administered with dexamethasone to Must be co-administered with dexamethasone to prevent progressive, often disabling, fluid prevent progressive, often disabling, fluid retention in the peripheries, lungs and abdomen.retention in the peripheries, lungs and abdomen.

Side effects are more severe but more short-Side effects are more severe but more short-lived than Taxol and include: leukopenia, lived than Taxol and include: leukopenia, peripheral edema, neutropenia. peripheral edema, neutropenia.

Taxanes: Complicating Factors Taxanes: Complicating Factors

Resistance to taxanes is a complicating factor to successful Resistance to taxanes is a complicating factor to successful treatment and is often associated with increased expression treatment and is often associated with increased expression of the of the mdr-1mdr-1 gene and its product, the P-glycoprotein.  gene and its product, the P-glycoprotein. Other resistant cells have B-tubulin mutations which inhibit Other resistant cells have B-tubulin mutations which inhibit the binding of taxanes to the correct place on the the binding of taxanes to the correct place on the microtubules; this renders the drug ineffective.  In addition, microtubules; this renders the drug ineffective.  In addition, some resistant cells also display increased aurora kinase, an some resistant cells also display increased aurora kinase, an enzyme that promotes completion of mitosis.  Some cells enzyme that promotes completion of mitosis.  Some cells display a heightened amount of survivin, an anti-apoptotic display a heightened amount of survivin, an anti-apoptotic factor.factor.Side effects can be debilitating.Side effects can be debilitating.These drugs are very expensive and must be administered in These drugs are very expensive and must be administered in large amounts at once due to the fact that much of the drug is large amounts at once due to the fact that much of the drug is excreted in the urine or allocated to the plasma. This large excreted in the urine or allocated to the plasma. This large administration volume cannot be tolerated in many patients. administration volume cannot be tolerated in many patients.

Vinca Alkaloids (Second Antimitotic Vinca Alkaloids (Second Antimitotic Group)Group)

The Vincas work through their ability to bind to the B-tubulin subunit The Vincas work through their ability to bind to the B-tubulin subunit of microtubules, blocking their ability to polymerize with the a-tubulin of microtubules, blocking their ability to polymerize with the a-tubulin subunit to form complete microtubules.  This causes the cell cycle to subunit to form complete microtubules.  This causes the cell cycle to arrest in metaphase because, in absence of an intact mitotic arrest in metaphase because, in absence of an intact mitotic spindle, duplicated chromosomes cannot align along the division spindle, duplicated chromosomes cannot align along the division plate.  The ultimate fate of such cells is to undergo apoptosis.plate.  The ultimate fate of such cells is to undergo apoptosis.The Vinca alkaloids are all derived from the Madagascan periwinkle The Vinca alkaloids are all derived from the Madagascan periwinkle plant, plant, Vinca roseaVinca rosea.  The plant was reputed to be useful in the .  The plant was reputed to be useful in the treatment of diabetes. Attempts to verify the antidiabetic properties treatment of diabetes. Attempts to verify the antidiabetic properties of the plant’s extracts in the 1950’s led instead to the discovery and of the plant’s extracts in the 1950’s led instead to the discovery and isolation of vinblastine.isolation of vinblastine.Scientists first observed its anticancer properties in a lab in 1962 Scientists first observed its anticancer properties in a lab in 1962 with the observation of regression of lymphocytic leukemia in rats.with the observation of regression of lymphocytic leukemia in rats.Several years later, the successful purification of the plant’s Several years later, the successful purification of the plant’s alkaloids yielded three other active dimers: vincristine, vinorelbine, alkaloids yielded three other active dimers: vincristine, vinorelbine, vinrosidine.vinrosidine.

Vinca Alkaloids: Vinblastine Vinca Alkaloids: Vinblastine

Vinblastine [Velban] was Vinblastine [Velban] was the first of the Vincas to the first of the Vincas to be used in the treatment be used in the treatment of cancer.of cancer.Useful in the treatment of: Useful in the treatment of: bladder and testicular bladder and testicular cancers, Kaposi’s cancers, Kaposi’s sarcoma, neuroblastoma sarcoma, neuroblastoma and Hodgkin’s disease.and Hodgkin’s disease.Side effects include: Side effects include: leukopenia, GI leukopenia, GI disturbances, cellulitis, disturbances, cellulitis, phlebitis.  phlebitis. 

Vinca Alkaloids: Vincristine Vinca Alkaloids: Vincristine Vincristine [Oncovin]Vincristine [Oncovin]Useful in the treatment of: Useful in the treatment of: pediatric leukemias and pediatric leukemias and lymphomas, non-Hodgkin’s lymphomas, non-Hodgkin’s lymphoma, neuroblastoma and lymphoma, neuroblastoma and rhabdomyosarcoma. rhabdomyosarcoma. Better tolerated by children than Better tolerated by children than adults.adults.Side effects: myelosuppression, Side effects: myelosuppression, hyponatremia, numbness/tingling hyponatremia, numbness/tingling of extremities, loss of deep tendon of extremities, loss of deep tendon reflexes, and loss of motor reflexes, and loss of motor function.function.Intrathecal administration results Intrathecal administration results in in fatalfatal central neurotoxicity. central neurotoxicity.   

Vinca Alkaloids: Vinorelbine Vinca Alkaloids: Vinorelbine

Vinorelbine [Navelbine]Vinorelbine [Navelbine]

Used in the treatment of: Used in the treatment of: lung carcinoma, breast lung carcinoma, breast cancer.cancer.

Side effects include: Side effects include: granulocytopenia, granulocytopenia, thrombocytopenia, thrombocytopenia, myelosuppression, and myelosuppression, and lessless neurotoxicity than all neurotoxicity than all of the other Vincas.of the other Vincas.

Vinca Alkaloids:Vinca Alkaloids:VindesineVindesine

Vindesine [Eldisine]Vindesine [Eldisine]Useful in the Useful in the treatment of: breast treatment of: breast and lung cancer, and lung cancer, leukemia.leukemia.Side effects: Side effects: immunodeficiency, immunodeficiency, anemia, myalgia, anemia, myalgia, fatigue, mouth ulcers, fatigue, mouth ulcers, GI upset.GI upset.

Vinca Alkaloids: Complicating Vinca Alkaloids: Complicating Factors Factors

Resistance to the Vinca alkaloids comes in the form of Resistance to the Vinca alkaloids comes in the form of cross-resistance due to the structural similarity of the four cross-resistance due to the structural similarity of the four compounds, and their antitumor effects are blocked by compounds, and their antitumor effects are blocked by multidrug resistance in which tumor cells become cross-multidrug resistance in which tumor cells become cross-resistant to a wide variety of agents after exposure to a resistant to a wide variety of agents after exposure to a single drug.  Resistant cells can also display chromosomal single drug.  Resistant cells can also display chromosomal abnormalities consistent with gene amplification, and these abnormalities consistent with gene amplification, and these cells contain increased levels of the P-glycoprotein.  Other cells contain increased levels of the P-glycoprotein.  Other forms of resistance stem from mutations in B-tubulin that forms of resistance stem from mutations in B-tubulin that prevent the binding of the inhibitors to their target.prevent the binding of the inhibitors to their target.Also, because of the heavy concentration of microtubules Also, because of the heavy concentration of microtubules in the brain and the drug’s disruption of this, patients in the brain and the drug’s disruption of this, patients treated with Vinca alkaloids can experience severe treated with Vinca alkaloids can experience severe neurotoxicity. neurotoxicity. 

Colchicine (Third Antimitotic Group) Colchicine (Third Antimitotic Group)

Colchicine was originally extracted Colchicine was originally extracted from plants of the genus from plants of the genus Colchicum Colchicum and used to treat and used to treat rheumatic complaints, specifically rheumatic complaints, specifically gout.gout.The colchicine alkaloid was initially The colchicine alkaloid was initially isolated in 1820 and was found to isolated in 1820 and was found to bind tubulin, the protein subunit of bind tubulin, the protein subunit of MTs.MTs.It is a relatively small molecule It is a relatively small molecule and inhibits its target in a and inhibits its target in a mechanism similar to the taxanes: mechanism similar to the taxanes: by binding to the colchicine by binding to the colchicine binding site of microtubules and binding site of microtubules and promoting their polymerization, promoting their polymerization, thus causing cell clogging and thus causing cell clogging and eventually apoptosis. eventually apoptosis. 

Colchicine (cont.)Colchicine (cont.)

While it has been shown to kill cancer cells, the While it has been shown to kill cancer cells, the drug’s usefulness in the treatment of cancer is drug’s usefulness in the treatment of cancer is hindered by its cytotoxicity; in addition, it is a hindered by its cytotoxicity; in addition, it is a known emetic and teratogen.known emetic and teratogen.

Colchicine has proven to have a fairly narrow Colchicine has proven to have a fairly narrow range of effectiveness as a chemotherapy agent, range of effectiveness as a chemotherapy agent, so it is only FDA-approved to treat gout.so it is only FDA-approved to treat gout.

Currently, investigation of colchicine as an Currently, investigation of colchicine as an antimitotic agent is underway.antimitotic agent is underway.

Drug Resistance is a Drug Resistance is a REALREAL Problem for Cancer Patients Problem for Cancer Patients

Multidrug resistance is a major drawback of cancer Multidrug resistance is a major drawback of cancer chemotherapy and can result in patients becoming chemotherapy and can result in patients becoming immune to the effects of many different drugs at once.immune to the effects of many different drugs at once.A major mechanism of multidrug resistance occurs via A major mechanism of multidrug resistance occurs via an over-expression of ATP transmembrane efflux pumps an over-expression of ATP transmembrane efflux pumps which pump the drug outside of the cell after its which pump the drug outside of the cell after its entrance.entrance.Resistance can often result in patient death as a result of Resistance can often result in patient death as a result of lack of effective treatment available. lack of effective treatment available. This remains a problem with all anti-cancer therapies.This remains a problem with all anti-cancer therapies.

More Problems With Antimitotic More Problems With Antimitotic Agents Agents

Side effects with antimitotic agents, as with Side effects with antimitotic agents, as with many chemotherapies, can be debilitating and many chemotherapies, can be debilitating and even fatal.  Chemotherapy targets rapidly-even fatal.  Chemotherapy targets rapidly-dividing cells, which includes cancer cells but dividing cells, which includes cancer cells but also hair and gut cells.  This results in hair loss also hair and gut cells.  This results in hair loss and nausea in patients.  Much research remains and nausea in patients.  Much research remains to be done in this area of cancer treatment to to be done in this area of cancer treatment to minimize toxicity.minimize toxicity.There are many drug interactions with antimitotic There are many drug interactions with antimitotic agents, so patients can often only take these agents, so patients can often only take these drugs alone. drugs alone. 

What’s New - Antimitotic AgentsWhat’s New - Antimitotic Agents

New taxanes and Vinca New taxanes and Vinca alkaloids with oral alkaloids with oral bioavailability are currently bioavailability are currently undergoing clinical testing.undergoing clinical testing.Inhibitors of mitotic kinesin Inhibitors of mitotic kinesin motors, such as KSP-1A and motors, such as KSP-1A and monastrol, are currently being monastrol, are currently being tested and could soon become tested and could soon become the newest members of the the newest members of the antimitotic drug family.antimitotic drug family.A less toxic form of colchicine A less toxic form of colchicine is currently being investigated.is currently being investigated.

Drugs specifically targeting the Drugs specifically targeting the Aurora kinase are in various Aurora kinase are in various stages of clinical stages of clinical development.  One is MK-0457 development.  One is MK-0457 in Phase II clinical trials at in Phase II clinical trials at Merck.Merck.Drugs formulated specifically Drugs formulated specifically to target CNEP-E, a mitotic to target CNEP-E, a mitotic kinase that is responsible for kinase that is responsible for the segregation of the segregation of chromosomes during mitosis, chromosomes during mitosis, are currently in the making; are currently in the making; one is GSK-923296 at one is GSK-923296 at GlaxoSmithKline.GlaxoSmithKline.

ReferencesReferences

http://en.wikipedia.org/wiki/Mitosishttp://en.wikipedia.org/wiki/Mitosis

http://www.biologyreference.com/Bl-Ce/Cehttp://www.biologyreference.com/Bl-Ce/Cell-Cycle.htmlll-Cycle.html

http://chem.sis.nlm.nih.gov/chemidplus/http://chem.sis.nlm.nih.gov/chemidplus/