Use of Topoisomeraze in Cancer

Use of Topoisomerse inhibitors for treatment of Cancer

Use of Topoisomerase inhibitors for treatment of CancerByShahzada Khurram Syed

Cancer is basically a disease of cells characterized by a shift in the control mechanisms that govern cell proliferation and differentiation.Neoplastic cells proliferate excessively and form local tumors that can compress or invade adjacent normal structures.

IntroductionLymphomasOriginate from lymphatic system SarcomasThey originate in the connective tissues like ligaments, cartilageCarcinomasThey originate from the epithelial tissues which are lining of organs like the lungs and liver Classes of cancerLeukimias:is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Hodgkin: Is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes.When doctors detect the presence of a specific type of abnormal cell called a Reed-Sternberg cells, the lymphocyte is called Hodgkin. Genetic predisposition exposure to environmental carcinogens. Chemical carcinogens (particularly those in tobacco smoke) as well as azo dyes, aflatoxins, asbestos, and benzeneRadiations ultra violet radiationsCoal tars

Causes of Cancer Tumor suppressor genes, may be deleted or damaged, with resulting neoplastic change. A single gene in this class, the p53 gene, has been shown to have mutated from a tumor suppressor gene to an oncogene in a high percentage of cases of several human tumors,Certain herpes and papilloma group DNA viruses and type C RNA viruses have also been implicated as causative agents in animal cancers and are responsible for some human cancers as well.

Causes

The Cell Cycle G0 phase (resting stage): The cell has not yet started to divide. Cells spend much of their lives in this phase. Depending on the type of cell, G0 can last from a few hours to a few years. When the cell gets a signal to reproduce, it moves into the G1 phase. G1 phase: During this phase, the cell starts making more proteins and growing larger, so the new cells will be of normal size. This phase lasts about 18 to 30 hours Cell cycleCell cycleS phase: In the S phase, the chromosomes containing the genetic code (DNA) are copied so that both of the new cells formed will have matching strands of DNA. The S phase lasts about 18 to 20 hours.

G2 phase: In the G2 phase, the cell checks the DNA and gets ready to start splitting into 2 cells. This phase lasts from 2 to 10 hours

M phase (mitosis): In this phase, which lasts only 30 to 60 minutes, the cell actually splits into 2 new cells. This cell cycle is important because many chemotherapy drugs work only on cells that are actively reproducing (not cells that are in the resting phase, G0). Some drugs specifically attack cells in a particular phase of the cell cycle (the M or S phases

Topoisomerase inhibitors are agents designed to interfere with the action of topoisomerase enzymes (topoisomerase I and II), which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.In recent years, topoisomerases have become popular targets for cancer chemotherapy treatments. It is thought that topoisomerase inhibitors block the ligation step of the cell cycle, generating single and double stranded breaks that harm the integrity of the genome. Introduction of these breaks subsequently leads to apoptosis and cell death.TOPOISOMERASE INHIBITORTopoisomerase inhibitors are often divided according to which type of enzyme it inhibits.

Topoisomerase I inhibitors: irinotecan, topotecan, camptothecin and lamellarin D all target type IB topoisomerases,

Topoisomerase II inhibitors: etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, and HU-331, a quinolone synthesized from cannabidiol.

CLASSIFICATIONThese inhibitors are split into two main classes: topoisomerase poisons, which target the topoisomerase-DNA complex, and topoisomerase inhibitors, which disrupt catalytic turnover.Topo II poisonsExamples of topoisomerase poisons include the following:eukaryotic type II topoisomerase inhibitors (topo II): amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin. These drugs are anti-cancer therapies.bacterial type II topoisomerase inhibitors (gyrase and topo IV): fluoroquinolones. These are antibacterials and include such fluoroquinolones as ciprofloxacin.

TOPOISOMERASE II INHIBITORSSome of these poisons encourage the forward cleavage reaction (fluoroquinolones), while other poisons prevent the re-ligation of DNA (etoposide and teniposide).Interestingly, poisons of type IIA topoisomerases can target prokaryotic and eukaryotic enzymes preferentially, making them attractive drug candidates. Ciprofloxacin targets prokaryotes in excess of a thousandfold more than it targets eukaryotic topo IIs. The mechanism for this specificity is unknown, but drug-resistant mutants cluster in regions around the active site.

The topoisomerases are essential nuclear enzymes for DNA replication. They control DNA structure by maintaining the correct super helical state within the cell, as well as by resolving intertwined DNA strands. This requires the formation of transient breaks in DNA. Topoisomerase I generates single-stranded breaks, and topoisomerase II introduces double-stranded breaks.

All cells require topoisomerases, but fast-growing cancer cells need more of them. By inhibiting the enzymes, the drugs selectively inflict more damage on cancer cells than on normal cells.

Mechanism of actions of Topoisomerase enzymeThe nuclear enzymes topoisomerase I and II are critical for DNA function and cell survival, and recent studies have identified these enzymes as cellular targets for several clinically active anticancer drugs.

Importance of Topoisomerase enzymes

Podophyllotoxins ( Etoposide and teniposide )

Mechanism of action:

Block cell cycle: in late S-G2 phase inhibition of topoisomerase II -- which results in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme.

Topoisomerase II inhibitorsTopoisomerase inhibitors are cell cycle specific , that is, they only kill cells that are in a particular phase of cell division and generally do not have any effect on other cells. Examples of Topoisomerase inhibitors are Etoposide and Topotecan

Topoisomerase InhibitorsNausea vomiting alopecia significant hematopoietic toxicity lymphoid toxicityAdverse Effects of Topoisomerase II InhibitorsThe drugs are water-insoluble and need to beformulated in a Cremophor vehicle for clinical use. These agents are administered via the intravenous route and are rapidly and widely distributed throughout the body except for the brain. Up to 9095% of drug is protein-bound, mainly to albumin. Dose reduction is required in the setting of renal dysfunction. Etoposide has clinical activity in germ cell cancerPharmacokinetics of Topoisomerase II inhibitors Etoposide has clinical activity in germ cell cancer, lung cancer, Hodgkin's and non-Hodgkin's lymphomas, and gastric cancer High-dose therapy in the transplant setting for breast cancer and lymphomas. Teniposide's use is limited to acute lymphoblastic leukemiaTherapeutic useCamptothecinsThe Camptothecins are natural products that are derived from the Camptotheca acuminate treeMechanism of actionThey inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and relegating single DNA strands. Inhibition of the enzyme results in DNA damage. Topoisomerase I inhibitorsTopotecan is indicated in the treatment of patients of

Advanced ovarian cancer

approved as second-line therapy lung cancer.

Topoisomerase I Inhibitor drugsThe main route of elimination is renal excretion, and for this reason caution must be exercised in patients with abnormal renal function, with dosage reduction being required.

Pharmacokinetics Primary neutropenia

thrombocytopenia

anemiaAdverse effectsTable. Topoisomerase Inhibitor-Based Cancer DrugsProductTargetIndicationClinical StatusManufacturerHycamtinTopoisomerase ISmall cell lung cancerMarketGlaxoSmithKlineIrinotecan (Campto, Camptosar)Topoisomerase IColorectal cancerMarketAventis, Pfizer, and MerckLucanthoneTopoisomerase IIBrain tumorPhase IISuperGenMLN576Topoisomerase I and IIVarious tumorsPhase IMillenniumNovantroneTopoisomerase IILeukemia and prostate cancerMarketOSIPegamotecanTopoisomerase IGastroesopheagal cancerPhase IIEnzonRubitecanTopoisomerase IProstate cancerPhase IIISuperGenTopoisomerase II inhibitors (anthracyclines, epipodophyllotoxins, etc.) are active against several types of tumours. However, treatment with these drugs often results in the development of the multi-drug resistance. Because topoisomerase II-active drugs have several different modes of action, different mechanisms of resistance, including decreased activation and increased detoxification by glutathione-dependent enzymes, have also been implicated.Resistance to Topoisomerase II inhibitorsCertain clinical limitations of the camptothecin derivatives are.These include: 1) spontaneous inactivation to a lactone form in blood, 2) rapid reversal of the trapped cleavable complex after drug removal, requiring prolonged infusions, 3) resistance of cancer cells overexpressing membrane transporters, and 4) dose-limiting side effects of diarrhea and neutropenia.

Resistance to Topoisomerase I inhibitors To circumvent these limitations, Dr. Mark Cushman at Purdue University and Dr. Yves Pommier at the National Cancer Institute developed the non-camptothecin family of indenoisoquinoline inhibitors of Top1. In contrast to the camptothecins, the indenoisoquinolines are: 1) chemically stable in blood, 2) inhibitors of Top1 cleavable complexes at distinct sites, 3) not substrates of membrane transporters, and 4) more effective as anti-tumor agents in animal models.REFERENCES^ a b Champoux JJ (2001). "DNA topoisomerases: structure, function, and mechanism". Annu. Rev. Biochem. 70: 369413. doi:10.1146/annurev.biochem.70.1.369. PMID 11395412.^ "National Academy of Sciences: NAS Award in Molecular Biology". National Academy of Science. http://www.nasonline.org/site/PageServer?pagename=AWARDS_molbio. Retrieved 2009-01-07.^ C.Michael Hogan. 2010. Deoxyribonucleic acid. Encyclopedia of Earth. National Council for Science and the Environment. eds. S.Draggan and C.Cleveland. Washington DC^ Wang JC (April 1991). "DNA topoisomerases: why so many?". J. Biol. Chem. 266 (11): 665962. PMID 1849888. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1849888.Pommier, Yves (May 28, 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chemistry & Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20534341. Retrieved May 28, 2010.

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