A mitotic inhibitor is a drug that inhibits mitosis, or cell division. These drugs disrupt microtubules, which are structures that pull the cell apart when it divides, mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow and eventually spread through the body through continuous mitotic division. Thus, cancer cells are sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are used in cytogenetics, where they stop cell division at a stage where chromosomes can be easily examined. Mitotic inhibitors are derived from substances such as plant alkaloids. Microtubules are long, ropelike proteins that extend through the cell, microtubules are long polymers made of smaller units of the protein tubulin. Microtubules are created during normal cell functions by assembling tubulin components, one of the important functions of microtubules is to move and separate chromosomes and other components of the cell for cell division. Mitotic inhibitors interfere with the assembly and disassembly of tubulin into microtubule polymers and this interrupts cell division, usually during the mitosis phase of the cell cycle when two sets of fully formed chromosomes are supposed to separate into daughter cells.
Examples of mitotic inhibitors used in the treatment of cancer include paclitaxel, vinblastine, vincristine. Colchicine and griseofulvin are mitotic inhibitors used in the treatment of gout and toenail fungus, the study of chromosomal material by analysis of G-Banded chromosomes, uses mitotic inhibitors extensively. In order to prepare a slide for cytogenetic study, an 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 and this experiment is crucial to many forms of cancer research. Taxanes are complex terpenes produced by the plants of the genus Taxus, originally derived from the Pacific yew tree, they are now synthesized artificially. Their principal mechanism is the disruption of the microtubule function by stabilizing microtubule formation.
Microtubules are essential to mitotic reproduction, so through the inactivation of the function of a cell. Paclitaxel—used to treat cancer, ovarian cancer, breast cancer. Docetaxel—used to treat breast and non-small cell lung cancer, vinca alkaloids are amines produced by the hallucinogenic plant Catharanthus roseus
Dihydrofolate reductase inhibitor
A dihydrofolate reductase inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate. Since folate is needed by rapidly dividing cells to make thymine, for example, methotrexate is used as cancer chemotherapy because it can prevent neoplastic cells from dividing. Bacteria need DHFR to grow and multiply and hence inhibitors selective for bacterial vs. host DHFR have found application as antibacterial agents, classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline & diaminopyrroloquinazoline, diaminopyrimidine and diaminotriazines. The examples provided below are specific molecules belonging to one of the above-mentioned classes, a variety of drugs act as inhibitors of dihydrofolate reductase, the experimental antimalarial and anti-toxoplasmosis compound JPC-2056 Oral piritrexim, a treatment for metastatic urothelial cancer
Purine analogues are antimetabolites that mimic the structure of metabolic purines. Azathioprine is the main immunosuppressive cytotoxic substance and it is widely used in transplantations to control rejection reactions. It is nonenzymatically cleaved to 6-mercaptopurine that acts as a purine analogue, by preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. Pentostatin and cladribine are adenosine analogs that are used primarily to treat hairy cell leukemia, purine antimetabolites are commonly used to treat cancer by interfering with DNA replication
These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and assign numbers of atoms of the other elements in the compound, as ratios to the key element.
For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula.
For example, ethanol may be represented by the chemical formula CH3CH2OH
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. This process occurs in all living organisms and is the basis for biological inheritance, DNA is made up of a double helix of two complementary strands. During replication, these strands are separated, each strand of the original DNA molecule serves as a template for the production of its counterpart, a process referred to as semiconservative replication. Cellular proofreading and error-checking mechanisms ensure near perfect fidelity for DNA replication, in a cell, DNA replication begins at specific locations, or origins of replication, in the genome. Unwinding of DNA at the origin and synthesis of new results in replication forks growing bi-directionally from the origin. A number of proteins are associated with the fork to help in the initiation and continuation of DNA synthesis. Most prominently, DNA polymerase synthesizes the new strands by adding nucleotides that complement each strand, DNA replication occurs during the S-stage of interphase. DNA replication can be performed in vitro, DNA polymerases isolated from cells and artificial DNA primers can be used to initiate DNA synthesis at known sequences in a template DNA molecule.
The polymerase chain reaction, a laboratory technique, cyclically applies such artificial synthesis to amplify a specific target DNA fragment from a pool of DNA. DNA usually exists as a structure, with both strands coiled together to form the characteristic double-helix. Each single strand of DNA is a chain of four types of nucleotides, nucleotides in DNA contain a deoxyribose sugar, a phosphate, and a nucleobase. These nucleotides form phosphodiester bonds, creating the phosphate-deoxyribose backbone of the DNA double helix with the bases pointing inward. Nucleotides are matched between strands through hydrogen bonds to form base pairs, adenine pairs with thymine, and guanine pairs with cytosine. DNA strands have a directionality, and the different ends of a single strand are called the 3 end and the 5 end. By convention, if the sequence of a single strand of DNA is given. The strands of the helix are anti-parallel with one being 5 to 3. These terms refer to the atom in deoxyribose to which the next phosphate in the chain attaches.
Directionality has consequences in DNA synthesis, because DNA polymerase can synthesize DNA in only one direction by adding nucleotides to the 3 end of a DNA strand, the pairing of complementary bases in DNA means that the information contained within each strand is redundant
Taxanes are a class of diterpenes. They were originally identified from plants of the genus Taxus and docetaxel are widely used as chemotherapy agents. Cabazitaxel was FDA approved to treat prostate cancer. Taxanes present difficulties in formulation as medicines because they are soluble in water. As their name suggests, taxanes were first derived from natural sources, paclitaxel was originally derived from the Pacific yew tree. Taxanes are difficult to synthesize because of their numerous chiral centres — taxol has 11 of these, the presence of taxanes in the shells and leaves of Corylus avellana has been reported. The principal mechanism of action of the class of drugs is the disruption of microtubule function. Microtubules are essential to cell division, and taxanes stabilize GDP-bound tubulin in the microtubule, thus, in essence, taxanes are mitotic inhibitors. In contrast to the taxanes, the vinca alkaloids prevent mitotic spindle formation through inhibition of tubulin polymerization, both taxanes and vinca alkaloids are, named spindle poisons or mitosis poisons, but they act in different ways.
Taxanes are thought to be radiosensitizing, hongdoushans A-C are oxygenated taxane diterpenes, isolated from the wood of Taxus wallichiana. Hongdoushan A, hongdoushan B, and hongdoushan C are reported to have activity in vitro. Taxanes are usually treated as synonymous with taxoids, the name taxol began as a common noun, but it was capitalized as a trade name, and the international nonproprietary name of the compound is paclitaxel. Taxine Media related to taxanes at Wikimedia Commons
The epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, as of September 2008, epothilones A to F have been identified and characterised. Early studies in cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar, but their structure is simpler. Due to their water solubility, cremophors are not needed. Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines, epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. The structure of epothilone A was determined in 1996 using x-ray crystallography, the principal mechanism of the epothilone class is inhibition of microtubule function. Microtubules are essential to cell division, and epothilones therefore stop cells from properly dividing, epothilone B possess the same biological effects as paclitaxel both in vitro and in cultured cells.
This is because they share the same binding site, as well as binding affinity to the microtubule, like paclitaxel, epothilone B binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules, epothilone B has been shown to induce tubulin polymerization into microtubules without the presence of GTP. This is caused by formation of microtubule bundles throughout the cytoplasm, epothilone B causes cell cycle arrest at the G2-M transition phase, thus leading to cytotoxicity and eventually cell apoptosis. At the higher concentrations, paclitaxel appears to act by suppressing microtubule detachment from centrosomes. It is quite possible that epothilone can act though similar mechanism, in November 2008, the EMEA refused a marketing authorisation for Ixabepilone. Several synthetic epothilone analogs are currently undergoing clinical development for treatment of various cancers, epothilone B has proven to contain potent in vivo anticancer activities at tolerate dose levels in several human xenograft models.
As a result, epothilone B and its various analogues are As of 2001 undergoing various clinical phases, results of a phase III trial with ixabepilone in combination with capecitabine in metastatic breast cancer have been announced. Patupilone failed a phase III trial for ovarian cancer in 2010, utidelone is a genetically engineered epothilone analog that has shown benefits in a phase III breast cancer trial when added to capecitabine. Due to the potency and clinical need for cancer treatments. The first group to publish the total synthesis of epothilones was S. J. Danishefsky et al. in 1996 and this total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation
Pemetrexed is a chemotherapy drug manufactured and marketed by Eli Lilly and Company. Its indications are the treatment of mesothelioma and non-small cell lung cancer. A Phase III study showed benefits of maintenance use of pemetrexed for non-squamous NSCLC, activity has been shown in malignant peritoneal mesothelioma. Trials are currently testing it against esophagus and other cancers, Pemetrexed is recommended in combination with carboplatin for the first-line treatment of advanced non-small cell lung cancer. It is recommended for patients to be on a steroid on the day prior, day of, whether used alone or in combination with cisplatin, has these side effects, Low blood cell counts, as measured by a complete blood count. Fatigue can be reduced through a prescription of Provigil. Pemetrexeds emetogenic effects are managed with prophylactic antiemetics, oral ulcers can be mitigated by proper oral hygiene, including rinsing of the mouth with salt water following consumption of food or drink. Physician-prescribed steroids administered on the day prior, day of, constipation Pemetrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites.
It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, the molecular structure of pemetrexed was developed by Edward C. Taylor at Princeton University and clinically developed by Indianapolis-based drug maker, Eli Lilly and Company in 2004. It has been researched in the PARAMOUNT trial, in addition to the brand name Alimta, this drug is marketed in India by Abbott Healthcare as Pleumet and by Cadila Healthcare as Pemecad. In the United States as of 2015 each vial of medicine costs between 2,623 and 3,100 USD, Alimta website NCI Drug Information Summary on Pemetrexed Disodium
The cell cycle or cell-division cycle is the series of events that take place in a cell leading to its division and duplication of its DNA to produce two daughter cells. In bacteria, which lack a nucleus, the cell cycle is divided into the B, C. The B period extends from the end of cell division to the beginning of DNA replication, DNA replication occurs during the C period. The D period refers to the stage between the end of DNA replication and the splitting of the cell into two daughter cells. In cells with a nucleus, as in eukaryotes, the cycle is divided into three periods, the mitotic phase, and cytokinesis. During interphase, the cell grows, accumulating nutrients needed for mitosis, preparing it for cell division, during the mitotic phase, the chromosomes separate. During the final stage, the chromosomes and cytoplasm separate into two new daughter cells, to ensure the proper division of the cell, there are control mechanisms known as cell cycle checkpoints. After cell division, each of the cells begin the interphase of a new cycle.
The cell cycle consists of four phases, G1 phase, S phase, G2 phase. Activation of each phase is dependent on the progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase, after cell division, each of the daughter cells begin the interphase of a new cycle. G0 is a phase where the cell has left the cycle and has stopped dividing. The cell cycle starts with this phase, the word post-mitotic is sometimes used to refer to both quiescent and senescent cells. Non proliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time and this is very common for cells that are fully differentiated. Cellular senescence occurs in response to DNA damage and external stress, some cells enter the G0 phase semi-permanently, and are considered post-mitotic e. g. some liver, stomach cells. Many cells do not enter G0 and continue to divide throughout an organisms life, before a cell can enter cell division, it needs to take in nutrients.
All of the preparations are done during interphase, interphase is a series of changes that takes place in a newly formed cell and its nucleus, before it becomes capable of division again. It is called preparatory phase or intermitosis, previously it was called resting stage because there is no apparent activity related to cell division. Typically interphase lasts for at least 90% of the total time required for the cell cycle