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MTX Chemistry

Methotrexate IUPAC
derived name is 4-amino-4-deoxy-N-methyl- Pteroylglutamic acid.It shows themolecular structural difference from folic acid
only in that folic acid has a hydroxyl group (OH-) in place of the 4-amino group
on the pteridine ring and there is no methyl group at the N’Oposition. 
Methotrexate, (previously amethopterin), differs from aminopterin in
that the latter is also not methylated at the N’Oposition.  Hence the active site of the molecule appears
to involve the pteridine ring portion.

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Its
molecular

structure differs from folic acid
only in that folic

acid has ahydroxyl group inplace of the4-

amino
groupon the pteridine ring
andthere
is

no methyl group
at the N’Oposition. 
Methotrexate-

ate, also known as amethopterin,
differs from

aminopterin in that the latter
is also not methyl-

ratedat
the N’Oposition.  Hence the
active site of

the molecule appearsto
involvethe pteridine

ring
portion.

Its
molecular

structure differs from folic acid
only in that folic

acid has ahydroxyl group inplace of the4-

amino
groupon the pteridine ring
andthere
is

no methyl group
at the position. 
Methotrexate-

ate, also known as amethopterin,
differs from

aminopterin in that the latter
is also not methyl-

ratedat
the N’Oposition.  Hence the
active site of

the molecule appearsto
involve thepteridine

ring  portion.

 

 

Fig1. A) Methotrexate
molecular structure, B) Folic acid Molecular structure, C) Aminopterin
Molecular structure D) Comparison between A, B and C showing the structural
difference in terms of functional group.P.C:
“All structural image taken from Wikipedia the free encyclopedia”.

D)

Wikipedia the fee encyclopedia

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Molecular weight
is 454.44 g/mol and empirical formula is C20H22N8O5
with biological half-life 3-10 hours (lower doses, 30mg/m2). The bioavailability at
lower 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.)

 

 

 

 

 

 

 

 

 

Mechanism of action

 

Methotrexate is known
to inhibit Dihydrofolate reductase (DHFR) competitively having 1000-fold more
affinity than folate. DHFR is a key enzyme functionally associated to convert
dihydrofolate to active tetrahydrofolate (reduced folate factors)(Rajagopalan et al., 2002). Tetrahydrofolate (reduced folate factors) plays an
important role in transferring one carbon unit in biochemical reactions
specific 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 both
DNA and RNA(W. Bleyer,1978).In humans,
MTX inhibits DNA synthesis to a greater degree as compared to RNA synthesis
signifying that thymidylate synthesis is amost
crucial mechanism for MTX cytotoxicity. This makes it cell cycle-dependent thereby acting primarily on DNA
synthesis (S-phase)(Hoffbrand and Tripp, 1972).Hence the cells undergoing rapid
proliferation in thecell cycle are more
liable to thecytotoxic effect of MTX.

 

 

 

 

 

MTX and Drosophila hematopoietic pathways

 

Hematopoiesis
in Drosophila melanogaster is quite simple and less complex as compared to
other mammalian blood systems. Blood cell development in Drosophila shares homology
with other vertebrates to an extent such as hematopoietic cell fate
determination, signaling pathways and transcription factors which make it a
part of an intense research (Evans,
Hartenstein, & Amp;Banerjee, 2003).Vertebrate blood derives from common
progenitor stem cell but incase of Drosophila, it is thought to be derived from aset of hematopoietic precursors called prohemocytes.
(Kondo et al., 2003), M. Letourneau et
al., 2016). Drosophila wandering third instar larva has blood cells in
three compartments I) a paired lymph gland lobes, 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 blood circulation. (Crozatier and
Meister, 2007; Lemaitre and Hoffmann, 2007; Márkus et al., 2009.)

 

MTX is an FDA approved
antimetabolite agent used in neoplastic conditions, psoriasis and rheumatoid
arthritis. Methotrexate is an anti-cancer drug and considered to be an
immunosuppressant (The American Society
of Health-System Pharmacists, Retrieved 22 Aug 2016). It has
immense usage in pharmacological industries. Now day’s young adults and
patients with anold age of leukemia are
more responsive to present day chemotherapy. In addition, “clinical remission
is more difficult to obtain and early relapse is more common.Methotrexate alone or in combination with steroids was used
initially for induction of remission in acute lymphoblastic leukemia’s”. (Methotrexate Tablets, USP reference id
3879293).Recent publications have established
the fact that MTX inhibits the JAK-STAT pathway through dephosphorylation of
STAT 1 and STAT5(Thomas et al., 2015).

In most of the higher animals, MTX is a known teratogen but its
effect on invertebrate’s project very limited information. Previous literature
provides some studies showing that MTX treated flies have aneffect on their survival, oviposition, and egg
morphologies. In spite of MTX treatment rare survived flies showed some
developmental aberrations such as larval tumors, bristle, wing, and leg and eye
defects. Developmental abnormalities due to toxic effects of MTX are also
studied in another vertebrate model system
such as rats, rabbits,and mice (DeSasso and Goeringer, 1992; Pellizzer et
al., 2004; Scmid, 1984).  Zeidlar showed
in his paper that MTX inhibits JAK/STAT pathway by inhibiting the STAT92e transcriptional
factor in drosophila and by reducing phosphorylation in STAT5 in the cells
expressing mutation associated most human myeloproliferative neoplasms (MPNs)
respectively.(Thomas et al., 2015).

 

 

 

Combination Therapy

 

MTX was witnessed
clinically to be effective but certain side effects were reported which were
taken into consideration such as bone marrow suppression, lung or liver
toxicity, post-treatment fatigue,
headaches, dizziness, nausea, therisk of
infection etc. Then the concept of combination therapy came into picture due to
the effective experience in leukemia and lymphoma. Several combinations were
recruited to visualize the best combination. The most successful came out to be
till now is Cyclosporine(Tugwell et al., 1995). It is also known that MTX in combination with
ara-C (Arabinofuranosylcytosine, nucleoside analogue, a chemotherapy agent
which requires phosphorylation by deoxycytidine kinase (dCK) before getting
incorporated into chromosomes) has effective role in curing leukemia and
lymphoma such as non-Hodgkin’s lymphoma including Burkitt’s leukemia/lymphoma (Thomas et al., 1999; Lee et al., 2001).
MTX with few anti-TNF agents has been shown to have curative effect on
ulcerative colitis(Herfarth et al., 2016)

 

Apart from Cyclosporine, MTX with hydroxychloroquine and MTX with sulfasalazine
were also reported to have abetter result
as compared to monotherapy.Some negative combinations (with low dose) were also
conveyed.(Willkens
et al., 1992)

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