Last updated: July 12, 2019
Topic: HealthDrugs
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MTX ChemistryMTX is a solidodorless, yellow or orange-brown crystallite compound. Chemically MTX is4-amino-4-deoxy-N-methyl- Pteroylglutamic acid. It shows the molecular structural difference from folic acidonly in that folic acid has a hydroxyl group (OH-) in place of the 4-amino groupon the pteridine ring and there is no methyl group at the N10 position (W. Bleyer, 1978).

Methotrexate, (previously amethopterin), differsfrom aminopterin in that the latter is also not methylated at the N10 position. Therefore the activesite of the molecule appears to involve the pteridine ring portion. MTX is aweak organic acid in nature and lipid insoluble at physiological pH.

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Itssolubility in human urine is directly proportional to its increasing pH. It issoluble in dilute solutions of alkali hydroxides and carbonates, slightlysoluble in dilute hydrochloric acid whereas practically insoluble in water andalcohol (Lewis, R.J., Sr (Ed.). Hawley’sCondensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons,Inc.

1997., p. 722)    Its molecularstructure differs from folic acid only in that folic acid has a hydroxyl group in place ofthe 4- amino group on the pteridine ringand there isno methyl group at the N’Oposition. Methotrexate- ate, alsoknown as amethopterin, differs fromaminopterin in thatthe latter is also not methyl- rated at the N’O  position.  Hence the active site of the moleculeappears to involve the pteridinering portion. Its molecularstructure differs from folic acid only in that folic acid has a hydroxyl group in place ofthe 4- amino group on the pteridine ringand there isno methyl group at the position.

 Methotrexate- ate, alsoknown as amethopterin, differs fromaminopterin in thatthe latter is also not methyl- rated at the N’O  position.  Hence the active site of the moleculeappears to involve the pteridine ring portion. A)    Fig1.A) Pteridine, just to compare the common ring all the structures mentioned. B) Methotrexate molecular structure, C) Folic acid Molecular structure, D) Aminopterin Molecular structure E) Comparison between B, C and D showing the structural difference in terms of functional group.

P.C: “All structural image taken from Wikipedia the free encyclopedia”. Wikipedia the fee encyclopedia D) Aminopterin D) E) C) Folic Acid B) Methotrexate             Molecularweight is 454.

44 g/mol and empirical formula is C20H22N8O5with biological half-life 3-10 hours (lower doses, <20mg/m2)and 8-15 hours (higher doses, >30mg/m2). The bioavailability atlower doses is approximately 60% and comparatively less at higher doses. (Trexall, Rheumatrex (methotrexate) dosing,indications, interactions, adverse effects, and more”. Medscape Reference.WebMD. Archived from the original on 8 February 2014. Retrieved 12 April 2014.)    Mechanismof action Methotrexate isknown to inhibit Dihydrofolate reductase (DHFR) competitively having 1000-foldmore affinity than folate.

DHFR is a key enzyme functionally associated toconvert dihydrofolate to active tetrahydrofolate (reduced folate factors)  (Rajagopalan et al., 2002). Tetrahydrofolate (reduced folate factors) plays animportant role in transferring one carbon unit in biochemical reactionsspecific for the synthesis of thymidylic acid and ionosinic acid. The former is an important component of DNA,whereas latter is the precursor of purines involved in the synthesis of bothDNA and RNA (W.

Bleyer, 1978). In humans,MTX inhibits DNA synthesis to a greater degree as compared to RNA synthesissignifying that thymidylate synthesis is a mostcrucial mechanism for MTX cytotoxicity. This makes it cell cycle-dependent thereby acting primarily on DNAsynthesis (S-phase) (Hoffbrand and Tripp, 1972).

Hence the cells undergoing rapid proliferation in thecell cycle are more liable to the cytotoxic effect of MTX. Chemotherapy affectsin cell division by damaging DNA or RNA. If the cancer cells cannot divide, thetumor will shrink. Chemotherapy drugs could be effective in dividing cells, (cell-cycle specific); or tocells that are at rest, (cell-cycle non-specific) (“Methotrexate.” ScottHamilton CARES Initiative 21 Nov 2012.

com/chemotherapy/drug-info/Methotrexate.aspx).However,chemotherapy drugs cannot distinguish between the cancerous cells and thenormal cells, which leads to the side effects.

The normal cells most commonlyaffected by chemotherapy are the blood cells, the cells in the mouth, stomach,and the hair follicles; resulting in low blood counts, mouth sores, nausea,diarrhea, and/or hair loss. (Brigitte C.Widemanna, Peter C. Adamson b. Understanding and Managing MethotrexateNephrotoxicity Pediatric Oncology 2006;11;694-703)    Fig.2 Schematic diagram showing the mechanism of action of MTX in DNA and RNA. MTX: Methotrexate, PM: Plasma membrane, FH2: Dihydrofolate, FH4: Tetrahydrofolate, CH3FH4: Tetrahydrofolate methylated, TMP: Thymidylate monophosphate, TTP:Thymidylate Triphosphate, dUMP: Deoxyuridine Monophosphate                            MTXand Drosophila hematopoietic pathways Hematopoiesis inDrosophila melanogaster is quite simple and less complex as compared to othermammalian blood systems.

Blood cell development in Drosophila shares homologywith other vertebrates to an extent such as hematopoietic cell fatedetermination, signaling pathways and transcription factors which make it apart of an intense research (Evans,Hartenstein, & Amp; Banerjee, 2003). Vertebrate blood derives fromcommon progenitor stem cell but in caseof Drosophila, it is thought to bederived from a set of hematopoieticprecursors called prohemocytes. (Kondoet al., 2003), M. Letourneau et al., 2016).

Drosophila wandering thirdinstar larva has blood cells in three compartments I) a paired lymph glandlobes, II) circulating hemocytes and III) sessile hemocytes under the cuticle (Lanot, Zachary, Holder, & Meister,2001).Three types of distinguishable matured blood cell populations namely Plasmatocytes, Crystal cells, and Lamellocytes are present in bloodcirculation. (Crozatier and Meister,2007; Lemaitre and Hoffmann, 2007; Márkus et al., 2009.)  MTX is an FDAapproved antimetabolite agent used in neoplastic conditions, psoriasis andrheumatoid arthritis. Methotrexate is an anti-cancer drug and considered to bean immunosuppressant (The AmericanSociety of Health-System Pharmacists, Retrieved 22 Aug 2016). Ithas immense usage in pharmacological industries.

Now day’s young adults andpatients with an old age of leukemia aremore responsive to present day chemotherapy. In addition, “clinical remissionis more difficult to obtain and early relapse is more common.Methotrexate alone or in combination with steroids was usedinitially for induction of remission in acute lymphoblastic leukemia’s”. (Methotrexate Tablets, USP reference id3879293). Recent publications haveestablished the fact that MTX inhibits the JAK-STAT pathway through dephosphorylationof STAT 1 and STAT5 (Thomas et al., 2015).In most of thehigher animals, MTX is a known teratogenbut its effect on invertebrate’s project very limited information. Previousliterature provides some studies showing that MTX treated flies have an effect on their survival, oviposition, and eggmorphologies.

In spite of MTX treatment rare survived flies showed somedevelopmental aberrations such as larval tumors, bristle, wing, and leg and eyedefects. Developmental abnormalities due to toxic effects of MTX are alsostudied in another vertebrate model systemsuch as rats, rabbits, and mice (DeSasso and Goeringer, 1992; Pellizzer etal., 2004; Scmid, 1984).  Zeidlar showedin his paper that MTX inhibits JAK/STAT pathway by inhibiting the STAT92e transcriptionalfactor in drosophila and by reducing phosphorylation in STAT5 in the cellsexpressing mutation associated most human myeloproliferative neoplasms (MPNs)respectively.

(Thomas et al., 2015).  MTX is able to hold down and stopshematopoiesis and as result it can causeno. of hematological sicknesses/problems such as leukopenia, pancytopenia,blood disorder (that causes weakness), neutropenia, thrombocytopenia etc.

Thedrug should be used carefully to the patients suffering from such hematologicalcancer growths/harmful things and damage/weakness. The MTX treatment of drosophila blood cells will be a new andinteresting work figuring out the how it is targeting the blood cells at the individual level. By which the knowledge can bepredicted (numbers, based on what’s known) to human cancer cells treated withMTX.