Mitotic inhibitor

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The structure of paclitaxel, a widely used mitotic inhibitor. Taxol.svg
The structure of paclitaxel, a widely used mitotic inhibitor.

A mitotic inhibitor, microtubule inhibitor, or tubulin inhibitor, is a drug that inhibits mitosis, or cell division, and is used in treating cancer, gout, and nail fungus. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow through continuous division that eventually spread through the body (metastasize). Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics (the study of chromosomes), where they stop cell division at a stage where chromosomes can be easily examined. [1]

Contents

Mitotic inhibitors are derived from natural substances such as plant alkaloids, and prevent cells from undergoing mitosis by disrupting microtubule polymerization, thus preventing cancerous growth. Microtubules are long, ropelike proteins that extend through the cell and move cellular components around. Microtubules are long polymers made of smaller units (monomers) of the protein tubulin. Microtubules are created during normal cell functions by assembling (polymerizing) tubulin components, and are disassembled when they are no longer needed. One of the important functions of microtubules is to move and separate chromosomes and other components of the cell for cell division (mitosis). Mitotic inhibitors interfere with the assembly and disassembly of tubulin into microtubule polymers. This interrupts cell division, usually during the mitosis (M) phase of the cell cycle when two sets of fully formed chromosomes are supposed to separate into daughter cells. [2] [3] Tubulin binding molecules have generated significant interest after the introduction of the taxanes into clinical oncology and the general use of the vinca alkaloids.

Examples of mitotic inhibitors frequently used in the treatment of cancer include paclitaxel, docetaxel, vinblastine, vincristine, and vinorelbine. [1] Colchicine and griseofulvin are mitotic inhibitors used in the treatment of gout and nail fungus, respectively.

Microtubules

Formation of microtubule Formation of Microtubule.png
Formation of microtubule

Microtubules are the key components of the cytoskeleton of eukaryotic cells and have an important role in various cellular functions such as intracellular migration and transport, cell shape maintenance, polarity, cell signaling and mitosis. [4] They play a critical role in cell division by involving in the movement and attachment of the chromosomes during various stages of mitosis. Therefore, microtubule dynamics is an important target for the developing anti-cancer drugs. [5]

Structure

Microtubules are composed of two globular protein subunits, α- and β-tubulin. These two subunits combine to form an α,β-heterodimer which then assembles in a filamentous tube-shaped structure. The tubulin hetero-dimers arrange themselves in a head to tail manner with the α-subunit of one dimer coming in contact with the β-subunit of the other. This arrangement results in the formation of long protein fibres called protofilaments.

These protofilaments form the backbone of the hollow, cylindrical microtubule which is about 25 nanometers in diameter and varies from 200 nanometers to 25 micrometers in length. About 12–13 protofilaments arrange themselves in parallel to form a C-shaped protein sheet, which then curls around to give a pipe-like structure called the microtubule. The head to tail arrangement of the hetero dimers gives polarity to the resulting microtubule, which has an α-subunit at one end and a β-subunit at the other end. The α-tubulin end has negative (–) charges while the β-tubulin end has positive (+) charges. [4] The microtubule grows from discrete assembly sites in the cells called Microtubule organizing centers (MTOCs), which are a network of microtubule associated proteins (MAP). [6] [7]

Two molecules of energy rich guanosine triphosphate (GTP) are also important components of the microtubule structure. One molecule of GTP is tightly bound to the α-tubulin and is non-exchangeable whereas the other GTP molecule is bound to β-tubulin and can be easily exchanged with guanosine diphosphate (GDP). The stability of the microtubule will depend on whether the β-end is occupied by GTP or GDP. A microtubule having a GTP molecule at the β-end will be stable and continue to grow whereas a microtubule having a GDP molecule at the β-end will be unstable and will depolymerise rapidly. [6] [7]

Microtubule dynamics

Microtubules are not static but they are highly dynamic polymers and exhibit two kinds of dynamic behaviors : 'dynamic instability' and 'treadmilling'. Dynamic instability is a process in which the microtubule ends switches between periods of growth and shortening. The two ends are not equal, the α-tubulin ringed (-)end is less dynamic while the more dynamic β-tubulin ringed (+) end grows and shortens more rapidly. Microtubule undergoes long periods of slow lengthening, brief periods of rapid shortening and also a pause in which there is neither growth nor shortening. [4] [7] [8] Dynamic instability is characterized by four variables: the rate of microtubule growth; the rate of shortening; frequency of transition from the growth or paused state to shortening (called a 'catastrophe') and the frequency of transition from shortening to growth or pause (called a 'rescue').

The other dynamic behavior called treadmilling is the net growth of the microtubule at one end and the net shortening at the other end. It involves the intrinsic flow of tubulin sub-units from the plus end to the minus end. Both the dynamic behaviors are important and a particular microtubule may exhibit primarily dynamic instability, treadmilling or a mixture of both. [8] [9]

Mechanism of action

Agents which act as inhibitors of tubulin, also act as inhibitors of cell division. A microtubule exists in a continuous dynamic state of growing and shortening by reversible association and dissociation of α/β-tubulin heterodimers at both the ends. This dynamic behavior and resulting control over the length of the microtubule is vital to the proper functioning of the mitotic spindle in mitosis i.e., cell division.

Microtubule is involved in different stages of the cell cycle. During the first stage or prophase, the microtubules required for cell division begins to form and grow towards the newly formed chromosomes forming a bundle of microtubules called the mitotic spindle. During prometaphase and metaphase this spindle attaches itself to the chromosomes at a particular point called the kinetochore and undergoes several growing and shortening periods in tuning with the back and forth oscillations of the chromosomes. In anaphase also, the microtubules attached to the chromosomes maintain a carefully regulated shortening and lengthening process. Thus the presence of a drug which can suppress the microtubule dynamics is sufficient to block the cell cycle and result in the death of the cells by apoptosis. [5] [10] [11]

Tubulin inhibitors thus act by interfering with the dynamics of the microtubule, i.e., growing (polymerization) and shortening (depolymerization). One class of inhibitors operate by inhibiting polymerization of tubulin to form microtubules and are called polymerization inhibitors like the colchicine analogues and the vinca alkaloids. They decrease the microtubule polymer mass in the cells at high concentration and act as microtubule-destabilizing agents. The other class of inhibitors operate by inhibiting the depolymerization of polymerized tubulin and increases the microtubule polymer mass in the cells. They act as microtubule-stabilizing agents and are called depolymerization inhibitors like the paclitaxel analogues. [4] These three classes of drugs seems to operate by slightly different mechanism.

Tubulin inhibitors binding site Tubulin inhibitors binding site.png
Tubulin inhibitors binding site

Colchicine analogues blocks cell division by disrupting the microtubule. It has been reported that the β-subunit of tubulin is involved in colchicine binding. It binds to the soluble tubulin to form colchicine-tubulin complex. This complex along with the normal tubulins then undergoes polymerization to form the microtubule. However the presence of this T-C complex prevents further polymerization of the microtubule . This complex brings about a conformational change which blocks the tubulin dimers from further addition and thereby prevents the growth of the microtubule. As the T-C complex slows down the addition of new dimers, the microtubule disassembles due to structural imbalance or instability during the metaphase of mitosis. [13]

The Vinca alkaloids bind to the β-subunit of tubulin dimers at a distinct region called the Vinca-binding domain. They bind to tubulin rapidly, and this binding is reversible and independent of temperature (between 0 °C and 37 °C). In contrast to colchicine, vinca alkaloids bind to the microtubule directly. They do not first form a complex with the soluble tubulin nor do they copolymerize to form the microtubule, however they are capable of bringing about a conformational change in tubulin in connection with tubulin self-association. [8] Vinca alkaloids bind to the tubulin with high affinity at the microtubule ends but with low affinity at the tubulin sites present along the sides of the microtubule cylinder. The binding of these drugs at the high affinity sites results in strong kinetic suppression of tubulin exchange even at low drug concentration while their binding to the low affinity sites in relatively high drug concentration depolymerizes microtubules. [5]

In contrast to colchicine and vinca alkaloids, paclitaxel enhances microtubule polymerization promoting both the nucleation and elongation phases of the polymerization reaction, and it reduces the critical tubulin sub-unit concentration (i.e., soluble tubulin concentration at steady- state). Microtubules polymerized in presence of paclitaxel are extremely stable. [5] The binding mechanism of the paclitaxel mimic that of the GTP nucleotide along with some important differences. GTP binds at one end of the tubulin dimer keeping contact with the next dimer along each of the protofilament while the paclitaxel binds to one side of β-tubulin keeping contact with the next protofilament. GTP binds to unassembled tubulin dimers whereas paclitaxel binding sites are located only in assembled tubulin. The hydrolysis of GTP permits the disassembly and the regulation of the microtubule system; however, the activation of tubulin by paclitaxel results in permanent stabilization of the microtubule. Thus the suppression of microtubule dynamics was described to be the main cause of the inhibition of cell division and of tumor cell death in paclitaxel treated cells. [14]

Structure activity relationship (SAR)

SAR of colchicine analogous SAR of Colchine analogous.png
SAR of colchicine analogous

Colchicine is one of the oldest known antimitotic drugs and in the past years[ when? ] much research has been done in order to isolate or develop compounds having similar structure but high activity and less toxicity. This resulted in the discovery of a number of colchicine analogues. The structure of colchicine is made up of three rings, a trimethoxy benzene ring (ring A), a methoxy tropone ring (ring C) and a seven-membered ring (ring B) with an acetamido group located at its C-7 position. The trimethoxy phenyl group of colchicine not only helps in stabilizing the tubulin-colchicine complex but is also important for antitubulin activity in conjunction with the ring C. The 3-methoxy group increased the binding ability whereas the 1-methoxy group helped in attaining the correct conformation of the molecule. The stability of the tropone ring and the position of the methoxy and carbonyl group are crucial for the binding ability of the compound. The 10-methoxy group can be replaced with halogen, alkyl, alkoxy or amino groups without affecting tubulin binding affinity, while bulky substituents reduce the activity. Ring B when expanded showed reduced activity, however the ring and its C-7 side chain is thought to affect the conformation of the colchicine analogues rather than their tubulin binding ability. Substitution at C-5 resulted in loss of activity whereas attachment of annulated heterocyclic ring systems to ring B resulted in highly potent compound. [13]

SAR of paclitaxel analogous SAR of Palitaxel analogous.png
SAR of paclitaxel analogous

Paclitaxel has achieved great success as an anti-cancer drug, yet there has been continuous effort to improve its efficacy and develop analogues which are more active and have greater bioavailability and specificity. The importance of C-13 substituted phenylisoserine side chain to bioactivity of paclitaxel has been known for a long time. Several replacements at the C-3' substitution have been tested. Replacement of the C-3' phenyl group with alkyl or alkyneyl groups greatly enhanced the activity, and with CF3 group at that position in combination with modification of the 10-Ac with other acyl groups increased the activity several times. Another modification of C-3' with cyclopropane and epoxide moieties were also found to be potent. Most of the analogues without ring A were found to be much less active than paclitaxel itself. The analogues with amide side chain at C-13 are less active than their ester counterpart. Also deoxygenation at position 1 showed reduced activity. Preparation of 10-α-spiro epoxide and its 7-MOM ether gave compounds having comparable cytotoxicity and tubulin assembly activity as that of paclitaxel. Substitution with C-6-α-OH and C-6-β-OH gave analogues which were equipotent to paclitaxel in tubulin assembly assay. Finally the oxetane ring is found to play an important role during interaction with tubulin. [15]

SAR of Vinblastine analogues SAR of Vinca alkaloids.png
SAR of Vinblastine analogues

Vinblastine is a highly potent drug which also has serious side effects especially on the neurological system. Therefore, new synthetic analogues were developed with the goal of obtaining more efficient and less toxic drugs. The stereochemical configurations at C-20', C-16' and C-14' in the velbanamine portion are critical and inversion leads to loss of activity. The C-16' carboxymethyl group is important for activity since decarboxylated dimer is inactive. Structural variation at C-15'- C-20' in the velbanamine ring is well tolerated. The upper skeletal modification of vinblastine gave vinorelbine which shows comparable activity as that of vinblastine. Another analogue prepared was the difluoro derivative of vinorelbine which showed improved in vivo antitumor activity. It was discovered that fluorination at C-19' position of vinorelbine dramatically increased the in vivo activity. Most of the SAR studies involve the vindoline portion of bis-indole alkaloids because modification at C-16 and C-17 offers good opportunities for developing new analogues. The replacement of the ester group with an amide group at the C-16 resulted in the development of vindesine. Similarly replacement of the acetyl group at C-16 with L-trp-OC2H5, d-Ala(P)-(OC2H5)2, L-Ala(P)-(OC2H5)2 and I-Vla(P)-(OC2H5)2 gave rise to new analogues having anti- tubulin activity. Also it was found that the vindoline's indole methyl group is a useful position to functionalize potentially and develop new, potent vinblastine derivatives. A new series of semi-synthetic C-16 -spiro-oxazolidine-1,3-diones prepared from 17-deacetyl vinblastine showed good anti-tubulin activity and lower cytotoxicity. Vinglycinate a glycinate prodrug derived from the C-17-OH group of vinblastine showed similar antitumor activity and toxicity as that of vinblastine. [16]

Use in cytogenetics

Cytogenetics, the study of chromosomal material by analysis of G-Banded chromosomes, uses mitotic inhibitors extensively. In order to prepare a slide for cytogenetic study, a mitotic inhibitor is added to the cells being studied. This stops the cells during mitosis, while the chromosomes are still visible. Once the cells are centrifuged and placed in a hypotonic solution, they swell, spreading the chromosomes. After preparation, the chromosomes of the cells can be viewed under a microscope to have the banding patterns of the chromosomes examined. This experiment is crucial to many forms of cancer research.

Tubulin binding drugs

Tubulin binding molecules differ from the other anticancer drugs in their mode of action because they target the mitotic spindle and not the DNA. Tubulin binding drugs have been classified on the basis of their mode of action and binding site [6] [17] [18] as:

I. Tubulin depolymerization inhibitors

a) Paclitaxel site ligands, includes the paclitaxel, epothilone, docetaxel, discodermolide etc.

II. Tubulin polymerization inhibitors

a) Colchicine binding site, includes the colchicine, combrestatin, 2-methoxyestradiol, methoxy benzenesulfonamides (E7010) etc.

b) Vinca alkaloids binding site, [19] includes vinblastine, vincristine, vinorelbine, vinflunine, dolastatins, halichondrins, hemiasterlins, cryptophysin 52, etc.

Table: Tubulin inhibitors with their binding sites, therapeutic uses and stages of clinical development. [8] [20]
Classes of tubulin inhibitorsBinding domainRelated drugs or analogsTherapeutic usesStage of clinical development
Polymerization inhibitorsVinca domain Vinblastine Hodgkin's disease, testicular germ cell cancerin clinical use; 22 combination trials in progress
Vincristine Leukemia, lymphomas In clinical use; 108 combination trials in progress
Vinorelbine Solid tumours, lymphomas, lung cancer In clinical use; 29 phase I–III clinical trials in progress (single and combination)
Vinflunine Bladder, non-small-cell lung cancer, breast cancer Phase III
Crytophycin 52 Solid tumoursPhase III finished
Halichondrins Phase I
Dolastatins Potential vascular-targeting agentPhase I; phase II completed
Hemiasterlins Phase I
Colchicine domain Colchicine Non-neoplastic diseases (gout, familial mediterranean fever)Approved in 2009 by FDA under the Unapproved Drugs Initiative[ citation needed ]
Combretastatins Potential vascular-targeting agentPhase I
2-Methoxyestradiol Phase I
E7010Solid tumoursPhase I, II
Depolymerization inhibitorsTaxan site Paclitaxel (Taxol) Ovarian, breast and lung tumours, Kaposi's sarcoma; trials with numerous other tumoursIn clinical use; 207 Phase I–III trials in the United States; TL00139 is in Phase I trials
Docetaxel (Taxotere) Prostate, brain and lung tumours8 trials in the United States (Phases I–III)
Epothilone Paclitaxel-resistant tumoursPhases I–III
Discodermolide Phase I
Tubulin inhibitors
Vinca domain Vinblastine.svg Vincristine.svg Vinorelbine.svg
Vinblastine Vincristine Vinorelbine
Vinflunine.svg Cryptophycin 52.svg Halichondrin B.svg
Vinflunine Cryptophycin 52 Halichondrin B
Dolastatin10.svg Dolastatin15.svg Hemiasterlin A.svg
Dolastatin 10 Dolastatin 15 Hemiasterlin A
Hemiasterlin B.svg
Hemiasterlin B
Colchicine domain Colchicine structure.png Combretastatin.svg Methoxybenzene-sulphonamide.svg
Colchicine Combretastatin E7010
2-Methoxyestradiol.svg
2-Methoxyestradiol
TAXANE SITE Docetaxel.svg Taxol.svg (-)-Epothilone A.svg
Docetaxel Paclitaxel Epothilone A
(-)-Epothilone B.svg Discodermolide.svg
Epothilone B Discodermolide

Specific agents

Taxanes

Taxanes are complex terpenes produced by the plants of the genus Taxus (yews). Originally derived from the Pacific yew tree, they are now synthesized artificially. Their principal mechanism is the disruption of the cell's microtubule function by stabilizing microtubule formation. Microtubules are essential to mitotic reproduction, so through the inactivation of the microtubule function of a cell, taxanes inhibit the cell's division.

Vinca alkaloids

Skeletal formula of vinblastine Vinblastine.svg
Skeletal formula of vinblastine

Vinca alkaloids are amines produced by the hallucinogenic plant Catharanthus roseus (Madagascar Periwinkle). Vinca alkaloids inhibit microtubule polymerization.

Colchicine

Colchicine is an alkaloid derived from the autumn crocus ( Colchicum autumnale ). It inhibits mitosis by inhibiting microtubule polymerization. While colchicine is not used to treat cancer in humans, it is commonly used to treat acute attacks of gout. [26]

Colchicine is an anti-inflammatory drug that has been in continuous use for more than 3000 years. Colchicine is an oral drug, known to be used for treating acute gout and preventing acute attacks of familial Mediterranean fever (FMF). However, the use of colchicine is limited by its high toxicity in other therapies. Colchicine is known to inhibit cell division and proliferation. Early study demonstrated that colchicine disrupts the mitotic spindle. Dissolution of microtubules subsequently was shown to be responsible for the effect of colchicine on the mitotic spindle and cellular proliferation. [27]

Podophyllotoxin

Podophyllotoxin derived from the may apple plant, is used to treat viral skin infections and synthetic analogues of the molecule are used to treat certain types of cancer.

Griseofulvin

Griseofulvin, derived from a species of Penicillium is an mitotic inhibitor that is used as an antifungal drug. It inhibits the assembly of fungal microtubules

Others

Limitations

Side effects

Human factors

Limitations in anticancer therapy occur mainly due to two reasons; because of the patient's organism, or because of the specific genetic alterations in the tumor cells. From the patient, therapy is limited by poor absorption of a drug which can lead to low concentration of the active agent in the blood and small amount delivery to the tumor. Low serum level of a drug can be also caused by rapid metabolism and excretion associated with affinity to intestinal or/and liver cytochrome P450. Another reason is the instability and degradation of the drugs in gastro-intestinal environment. Serious problem is also variability between patients what causes different bioavailability after administration equal dose of a drug and different tolerance to effect of chemotherapy agents. The second problem is particularly important in treatment elderly people. Their body is weaker and need to apply lower doses, often below therapeutic level. Another problem with anticancer agents is their limited aqueous solubility what substantially reduces absorption of a drug. Problems with delivery of drags to the tumor occur also when active agent has high molecular weight which limits tissue penetration or the tumor has large volume prevent for penetration. [4] [33]

Drug resistance

Multidrug resistance is the most important limitation in anticancer therapy. It can develop in many chemically distinct compounds. Until now, several mechanisms are known to develop the resistance. The most common is production of so-called "efflux pumps". The pumps remove drugs from tumor cells which lead to low drug concentration in the target, below therapeutic level. Efflux is caused by P-glycoprotein called also the multidrug transporter. This protein is a product of multidrug resistance gene MDR1 and a member of family of ATP-dependent transporters (ATP-binding cassette). P-glycoprotein occurs in every organism and serves to protect the body from xenobiotics and is involved in moving nutrients and other biologically important compounds inside one cell or between cells. P-glycoprotein detects substrates when they enter the plasma membrane and bind them which causes activation of one of the ATP-binding domains. The next step is hydrolysis of ATP, which leads to a change in the shape of P-gp and opens a channel through which the drug is pumped out of the cell. Hydrolysis of a second molecule of ATP results in closing of the channel and the cycle is repeated. P-glycoprotein has affinity to hydrophobic drugs with a positive charge or electrically neutral and is often over-expressed in many human cancers. Some tumors, e.g. lung cancer, do not over-express this transporter but also are able to develop the resistance. It was discovered that another transporter MRP1 also work as the efflux pump, but in this case substrates are negatively charged natural compounds or drugs modified by glutathione, conjugation, glycosylation, sulfation and glucuronylation. Drugs can enter into a cell in few kinds of ways. Major routes are: diffusion across the plasma membrane, through receptor or transporter or by the endocytosis process. Cancer can develop the resistance by mutations to their cells which result in alterations in the surface of cells or in impaired endocytosis. Mutation can eliminate or change transporters or receptors which allows drugs to enter into the tumor cell. Other cause of drug resistance is a mutation in β tubulin which cause alterations in binding sites and a given drug cannot be bound to its target. Tumors also change expression isoforms of tubulin for these ones, which are not targets for antimitotic drugs e.g. overexpress βIII-tubulin. In addition tumor cells express other kinds of proteins and change microtubule dynamic to counteract effect of anticancer drugs. Drug resistance can also develop due to the interruption in therapy. [4] [7] [8] [33]

Others


Discovery and development

The first known compound which binds to tubulin was colchicine, it was isolated from the autumn crocus, Colchicum autumnale , but it has not been used for cancer treatment. First anticancer drugs approved for clinical use were Vinca alkaloids, vinblastine and vincristine in the 1960s.

They were isolated from extracts leaves of the Catharanthus roseus (Vinca rosea) plant at the University of Western Ontario in 1958. [5] First drug belong to the taxanes and paclitaxel, discovered in extracts from the bark of the yew tree, Taxus brevifolia , in 1967 by Monroe Wall and Mansukh Wani but, its tubulin inhibition activity was not known until 1979.

Yews trees are poor source of active agents that limited the development of taxanes for over 20 years until discover the way of synthesis. [5] In December 1992 paclitaxel was approved to use in chemotherapy. [37]

Future drug development

Because of numerous adverse effect and limitations in use, new drugs with better properties are needed. Especially are desired improvements in antitumor activity, toxicity profile, drug formulation and pharmacology. [35] Currently have been suggested few approaches in development of novel therapeutic agents with better properties

See also

Related Research Articles

<span class="mw-page-title-main">Microtubule</span> Polymer of tubulin that forms part of the cytoskeleton

Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 and 15 nm. They are formed by the polymerization of a dimer of two globular proteins, alpha and beta tubulin into protofilaments that can then associate laterally to form a hollow tube, the microtubule. The most common form of a microtubule consists of 13 protofilaments in the tubular arrangement.

<span class="mw-page-title-main">Nocodazole</span> Chemical compound

Nocodazole is an antineoplastic agent which exerts its effect in cells by interfering with the polymerization of microtubules. Microtubules are one type of fibre which constitutes the cytoskeleton, and the dynamic microtubule network has several important roles in the cell, including vesicular transport, forming the mitotic spindle and in cytokinesis. Several drugs including vincristine and colcemid are similar to nocodazole in that they interfere with microtubule polymerization.

<span class="mw-page-title-main">Tubulin</span> Superfamily of proteins that make up microtubules

Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoskeleton. It was discovered and named by Hideo Mōri in 1968. Microtubules function in many essential cellular processes, including mitosis. Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division.

<span class="mw-page-title-main">Vincristine</span> Chemical compound; chemotherapy medication

Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's disease, neuroblastoma, and small cell lung cancer among others. It is given intravenously.

<span class="mw-page-title-main">Vinorelbine</span> Pharmaceutical drug

Vinorelbine (NVB), sold under the brand name Navelbine among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer and non-small cell lung cancer. It is given by injection into a vein or by mouth.

<span class="mw-page-title-main">Vinblastine</span> Chemotherapy medication

Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small-cell lung cancer, bladder cancer, brain cancer, melanoma, and testicular cancer. It is given by injection into a vein.

A spindle poison, also known as a spindle toxin, is a poison that disrupts cell division by affecting the protein threads that connect the centromere regions of chromosomes, known as spindles. Spindle poisons effectively cease the production of new cells by interrupting the mitosis phase of cell division at the spindle assembly checkpoint (SAC). However, as numerous and varied as they are, spindle poisons are not yet 100% effective at ending the formation of tumors (neoplasms). Although not 100% effective, substantive therapeutic efficacy has been found in these types of chemotherapeutic treatments. The mitotic spindle is composed of microtubules that aid, along with regulatory proteins, each other in the activity of appropriately segregating replicated chromosomes. Certain compounds affecting the mitotic spindle have proven highly effective against solid tumors and hematological malignancies.

<span class="mw-page-title-main">Taxane</span> Chemical compound

Taxanes are a class of diterpenes. They were originally identified from plants of the genus Taxus (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA approved to treat hormone-refractory prostate cancer.

<i>Vinca</i> alkaloid

Vinca alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant Catharanthus roseus and other vinca plants. They block beta-tubulin polymerization in a dividing cell.

<span class="mw-page-title-main">Epothilone</span> Class of chemical compounds

Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.

<span class="mw-page-title-main">Vindesine</span> Chemical compound

Vindesine, also termed Eldisine, is a semisynthetic vinca alkaloid derived from the flowering plant Catharanthus roseus. Like the natural and semisynthetic vinca alkaloids derived from this plant, vindesine is an inhibitor of mitosis that is used as a chemotherapy drug. By inhibiting mitosis, vinedsine blocks the proliferation of cells, particularly the rapidly proliferation cells of certain types of cancer. It is used, generally in combination with other chemotherapeutic drugs, in the treatment of various malignancies such as leukaemia, lymphoma, melanoma, breast cancer, and lung cancer.

<span class="mw-page-title-main">Rhizoxin</span> Chemical compound

Rhizoxin is an antimitotic agent with anti-tumor activity. It is isolated from the fungus Rhizopus microsporus which causes rice seedling blight.

<span class="mw-page-title-main">Combretastatin</span> Chemical compound

Combretastatin is a dihydrostilbenoid found in Combretum afrum.

<span class="mw-page-title-main">Eribulin</span> Pharmaceutical drug

Eribulin, sold under the brand name Halaven among others, is an anti-cancer medication used to treat breast cancer and liposarcoma.

<span class="mw-page-title-main">Demecolcine</span> Chemical compound

Demecolcine is a drug used in chemotherapy. It is closely related to the natural alkaloid colchicine with the replacement of the acetyl group on the amino moiety with methyl, but it is less toxic. It depolymerises microtubules and limits microtubule formation, thus arresting cells in metaphase and allowing cell harvest and karyotyping to be performed.

<span class="mw-page-title-main">Paclitaxel trevatide</span> Chemical compound

Paclitaxel trevatide is an experimental chemotherapy drug that is under development by Angiochem Inc, a Canadian biotech company. Phase II clinical trials have completed for several indications, and the company is preparing for phase III trials.

<span class="mw-page-title-main">Taccalonolide</span> Class of chemical compounds

Taccalonolides are a class of microtubule-stabilizing agents isolated from Tacca chantrieri that has been shown to have selective cancer-fighting properties. Other examples of microtubule-stabilizing agents include taxanes and epothilones, both of which prevent cancer cells from dividing by interfering with tubulin. While taxanes like Paclitaxel and docetaxel have been used successfully against breast, ovarian, prostate, and non–small-cell lung cancers, intrinsic and acquired drug resistance limit their anticancer properties. Unlike taxanes, taccalonolides appear to work through a different mechanism of action that does not involve tubulin, although recently isolated taccalonolides AF and AJ have shown tubulin-interaction activity. The discovery of taccalonolides opens up new possibilities to treat cancer cells, especially ones that are taxane- or epithilone-resistant.

<span class="mw-page-title-main">Moroidin</span> Chemical compound

Moroidin is a biologically active compound found in the plants Dendrocnide moroides and Celosia argentea. It is a peptide composed of eight amino acids, with unusual leucine-tryptophan and tryptophan-histidine cross-links that form its two rings. Moroidin has been shown to be at least one of several bioactive compounds responsible for the painful sting of the Dendrocnide moroides plant. It also has demonstrated anti-mitotic properties, specifically by inhibition of tubulin polymerization. Anti-mitotic activity gives moroidin potential as a chemotherapy drug, and this property combined with its unusual chemical structure has made it a target for organic synthesis.

<span class="mw-page-title-main">2-Methoxyestradiol disulfamate</span> Chemical compound

2-Methoxyestradiol disulfamate is a synthetic, oral active anti-cancer medication which was previously under development for potential clinical use. It has improved potency, low metabolism, and good pharmacokinetic properties relative to 2-methoxyestradiol (2-MeO-E2). It is also a potent inhibitor of steroid sulfatase, the enzyme that catalyzes the desulfation of steroids such as estrone sulfate and dehydroepiandrosterone sulfate (DHEA-S).

<span class="mw-page-title-main">Sabizabulin</span> Chemical compound

Sabizabulin is a chemical compound from the group of indole and imidazole derivatives that was first reported in 2012 by Dalton, Li, and Miller. It is being studied as a mitotic inhibitor and chemotherapeutic agent in castration-resistant metastatic prostate cancer and in SARS-CoV-2 (COVID-19) infections.

References

  1. 1 2 "What Are the Different Types of Chemotherapy Drugs?". American Cancer Society. Archived from the original on 17 July 2007. Retrieved 5 August 2007.
  2. "Definition of mitotic inhibitor". National Cancer Institute. Archived from the original on 13 August 2024. Retrieved 5 August 2007.
  3. "Treatment Options: Mitotic Inhibitors". Drug Digest. Archived from the original on 16 February 2007. Retrieved 5 August 2007.
  4. 1 2 3 4 5 6 Perez, E. A. (2009). "Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance". Molecular Cancer Therapeutics. 8 (8): 2086–95. doi: 10.1158/1535-7163.MCT-09-0366 . PMID   19671735.
  5. 1 2 3 4 5 6 7 8 Jordan, M. (2012). "Mechanism of Action of Antitumor Drugs that Interact with Microtubules and Tubulin". Current Medicinal Chemistry. Anti-Cancer Agents. 2 (1): 1–17. doi:10.2174/1568011023354290. PMID   12678749.
  6. 1 2 3 4 5 6 7 8 9 10 Islam, Mohd.; Iskander, Magdy (2004). "Microtubulin Binding Sites as Target for Developing Anticancer Agents". Mini-Reviews in Medicinal Chemistry. 4 (10): 1077–104. doi:10.2174/1389557043402946. PMID   15579115.
  7. 1 2 3 4 Pellegrini, Federico; Budman, Daniel R (2005). "Review: Tubulin Function, Action of Antitubulin Drugs, and New Drug Development". Cancer Investigation. 23 (3): 264–73. doi:10.1081/CNV-200055970. PMID   15948296. S2CID   45866448.
  8. 1 2 3 4 5 6 Jordan, Mary Ann; Wilson, Leslie (2004). "Microtubules as a target for anticancer drugs". Nature Reviews Cancer. 4 (4): 253–65. doi:10.1038/nrc1317. PMID   15057285. S2CID   10228718.
  9. TitoFojo, The role of microtubules in Cell Biology, Neurobiology and Oncology, Humana Press.[ page needed ]
  10. 1 2 3 4 Jordan, Allan; Hadfield, John A.; Lawrence, Nicholas J.; McGown, Alan T. (1998). "Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle". Medicinal Research Reviews. 18 (4): 259–96. doi:10.1002/(SICI)1098-1128(199807)18:4<259::AID-MED3>3.0.CO;2-U. PMID   9664292. S2CID   32194348.
  11. Bhalla, Kapil N (2003). "Microtubule-targeted anticancer agents and apoptosis". Oncogene. 22 (56): 9075–86. doi: 10.1038/sj.onc.1207233 . PMID   14663486.
  12. 1 2 3 4 5 6 Morris, P. G.; Fornier, M. N. (2008). "Microtubule Active Agents: Beyond the Taxane Frontier". Clinical Cancer Research. 14 (22): 7167–72. doi: 10.1158/1078-0432.CCR-08-0169 . PMID   19010832.
  13. 1 2 Chen, Jing; Liu, Tao; Dong, Xiaowu; Hu, Yongzhou (2009). "Recent Development and SAR Analysis of Colchicine Binding Site Inhibitors". Mini-Reviews in Medicinal Chemistry. 9 (10): 1174–90. doi:10.2174/138955709789055234. PMID   19817710.
  14. Abal, M.; Andreu, J.; Barasoain, I. (2003). "Taxanes: Microtubule and Centrosome Targets, and Cell Cycle Dependent Mechanisms of Action". Current Cancer Drug Targets . 3 (3): 193–203. doi:10.2174/1568009033481967. PMID   12769688.
  15. Fang, W.-; Liang, X.- (2005). "Recent Progress in Structure Activity Relationship and Mechanistic Studies of Taxol Analogues". Mini-Reviews in Medicinal Chemistry. 5 (1): 1–12. doi:10.2174/1389557053402837. PMID   15638787.
  16. Lixin Zhang, Arnold L. Demain (2005), Natural products: drug discovery and therapeutic medicine.Natural products: drug discovery and therapeutic medicine Archived 30 October 2023 at the Wayback Machine [ page needed ]
  17. Hamel, Ernest (1996). "Antimitotic natural products and their interactions with tubulin". Medicinal Research Reviews. 16 (2): 207–31. doi:10.1002/(SICI)1098-1128(199603)16:2<207::AID-MED4>3.0.CO;2-4. PMID   8656780. S2CID   647015. Archived from the original on 22 August 2020. Retrieved 21 January 2024.
  18. Kingston, David G. I. (2009). "Tubulin-Interactive Natural Products as Anticancer Agents(1)". Journal of Natural Products. 72 (3): 507–15. doi:10.1021/np800568j. PMC   2765517 . PMID   19125622.
  19. Cragg, Gordon M.; Newman, David J. (2004). "A Tale of Two Tumor Targets: Topoisomerase I and Tubulin. The Wall and Wani Contribution to Cancer Chemotherapy†". Journal of Natural Products. 67 (2): 232–44. doi:10.1021/np030420c. PMID   14987065.
  20. 1 2 3 4 Kuppens, Isa (2006). "Current State of the Art of New Tubulin Inhibitors in the Clinic". Current Clinical Pharmacology. 1 (1): 57–70. doi:10.2174/157488406775268200. PMID   18666378.
  21. Saville, M. W.; Lietzau, J.; Pluda, J. M.; Wilson, W. H.; Humphrey, R. W.; Feigel, E.; Steinberg, S. M.; Broder, S.; Yarchoan, R.; Odom, J.; Feuerstein, I. (1995). "Treatment of HIV-associated Kaposi's sarcoma with paclitaxel". Lancet. 346 (8966): 26–28. doi:10.1016/S0140-6736(95)92654-2. PMID   7603142. Archived from the original on 26 June 2019. Retrieved 5 July 2019.
  22. Lyseng-Williamson, K. A.; Fenton, C. (2005). "Docetaxel: A Review of its Use in Metastatic Breast Cancer". Drugs. 65 (17): 2513–2531. doi:10.2165/00003495-200565170-00007. PMID   16296875.
  23. Clarke, S. J.; Rivory, L. P. (1999). "Clinical Pharmacokinetics of Docetaxel". Clinical Pharmacokinetics. 36 (2): 99–114. doi:10.2165/00003088-199936020-00002. PMID   10092957.
  24. 1 2 3 "Vincristine (Oncovin)". Archived from the original on 29 June 2007. Retrieved 5 August 2007.
  25. Okouneva, Tatiana; Hill, Bridget T.; Wilson, Leslie; Jordan, Mary Ann (2003). "The Effects of Vinflunine, Vinorelbine, and Vinblastine on Centromere Dynamics". Molecular Cancer Therapeutics. 2 (5): 427–36. PMID   12748304. Archived from the original on 13 August 2024. Retrieved 21 January 2024.
  26. Lu Y, Chen J, Xiao M, Li W, Miller DD (November 2012). "An overview of tubulin inhibitors that interact with the colchicine binding site". Pharm Res. 29 (11): 2943–71. doi:10.1007/s11095-012-0828-z. PMC   3667160 . PMID   22814904.
  27. Molad, Yair (2002). "Update on colchicine and its mechanism of action". Current Rheumatology Reports. 4 (3): 252–6. doi:10.1007/s11926-002-0073-2. PMID   12010611. S2CID   4507579.
  28. Writer, GEN Staff (29 June 2016). "Fighting Cancer with a Pinch of Parsley and Dill". GEN – Genetic Engineering and Biotechnology News. Retrieved 26 October 2023.
  29. Lakhani, Nehal J.; Sarkar, Mohamadi A.; Venitz, Jurgen; Figg, William D. (2003). "2-Methoxyestradiol, a Promising Anticancer Agent". Pharmacotherapy. 23 (2): 165–72. doi:10.1592/phco.23.2.165.32088. PMID   12587805. S2CID   1541302. Archived from the original on 25 June 2023. Retrieved 21 January 2024.
  30. http://www.paclitaxel.org/%5B%5D
  31. del Pino BM (23 February 2010). "Chemotherapy-induced Peripheral Neuropathy". NCI Cancer Bulletin. p. 6. Archived from the original on 11 December 2011.
  32. Hazardous Substances Data Bank (HSDB) http://toxnet.nlm.nih.gov Archived 11 June 2019 at the Wayback Machine [ full citation needed ]
  33. 1 2 Gottesman, Michael M. (2002). "Mechanisms of cancer drug resistance". Annual Review of Medicine. 53: 615–27. doi:10.1146/annurev.med.53.082901.103929. PMID   11818492. Archived from the original on 13 August 2024. Retrieved 21 January 2024.
  34. Ivachtchenko, Alexandre; Kiselyov, Alex; Tkachenko, Sergey; Ivanenkov, Yan; Balakin, Konstantin (2007). "Novel Mitotic Targets and Their Small-Molecule Inhibitors". Current Cancer Drug Targets. 7 (8): 766–84. doi:10.2174/156800907783220499. PMID   18220536.
  35. 1 2 3 Attard, Gerhardt; Greystoke, Alastair; Kaye, Stan; De Bono, Johann (2006). "Update on tubulin-binding agents". Pathologie Biologie. 54 (2): 72–84. doi:10.1016/j.patbio.2005.03.003. PMID   16545633.
  36. 1 2 Terwogt, Jetske M.Meerum; Schellens, Jan H.M.; Huinink, Wim W.ten Bokkel; Beijnen, Jos H. (1999). "Clinical pharmacology of anticancer agents in relation to formulations and administration routes". Cancer Treatment Reviews. 25 (2): 83–101. doi:10.1053/ctrv.1998.0107. PMID   10395834.
  37. Gordaliza, M. (2008). "Natural products as leads to anticancer drugs". Clinical and Translational Oncology. 9 (12): 767–76. doi:10.1007/s12094-007-0138-9. PMID   18158980. S2CID   19282719.