Yellapragada acid on female urogenital system (reproductive plus

Yellapragada Subba Rao, an eminent biochemist, who unraveled anti-cancer activity of MTX for the treatment of cancer which revolutionized that era. Prior 1950, majority of the cancers were treated either by surgery or radiation most of which was not successful at times (US Department of human health and services, National Cancer Institute, NCI). In the course of 1949, Sidney Farber conjectured that cancerous cells proliferate rapidly and so require folate for their continuous maintenance of cell growth (Farber et al., 1948). Folate, being one of the nutrients of the B group vitamins, mark a vital role in the production and maintenance of early developing cells particularly in infants and in pregnant women (National Cancer Institute, NCI).  This made him think that if anti-folate drug, such as MTX, administered to the suffering patients probably would have some inhibitory effect on the growth rate of these cancerous cells. Furthermore, children with acute lymphoblastic leukemia (ALL), rapid developing blood cancer, fed with MTX showed remarkable improvement in their symptomatic behavior (Farber, 2016). Nevertheless, the success of improvement was of short term, due to relapse. Roy Hertz, another scientist working in the field of medical oncology, studied the effects of folic acid on female urogenital system (reproductive plus urinary system) specifically urogenital tract. His early research work sheds light on the effect of the anti-folate treatments, such as MTX, on actively proliferating cells of the female urogenital tract (Hertz et al., 1958).

 

Meanwhile, Min C. Li, Ph.D., endeavored anti-folate treatment in patients with metastatic melanoma leading to an intangible success. However, it had an intense reducing effect in urinary human chorionic gonadotropin (?-HCG) which went unnoticeable at that time. Since healthy pregnant women are (?-HCG) positive and (?-HCG) is also associated with multiple tumors, carcinomas, and melanomas (Hertz et al., 1956).

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Li’s result intrigued Hertz and he speculated that MTX could be a beneficial tool to treat cancer specific to the female reproductive tract called gestational carcinoma (GC). GC occurs due to the abnormal growth of cells which are specific to the placental origin. Hertz and Li together showed that metastatic GC tumors were inhibited drastically against MTX use. The case was remarkable as for the first time the solid tumor has ever responded to the chemotherapy treatment. The treatment was breakthrough since its perseverance was for the first time. In 1958, Hertz group came up with another publication, Hertz et al. showing how 27 patients who suffered from choriocarcinoma and related diseases responded to treatment. Five patients were reported to achieve a complete cure.

 

Alan Rabson, M.D., Deputy Director of NCI, praised Dr. Hertz for his outstanding work which had had an immense impact on cancer therapy and was not only limited to leukemia. New challenges were being by the scientist in cancer biology which paved the new pathway in the field of medical oncology (treatment of cancer with chemotherapy). Previous perceptions about cancer being fatal were getting remolded and revised. Early results published by Farber et al, showed the success of an antifolate (Aminopterin) treatment to childhood leukemia. This attracted the scientist for the use of an anti-metabolite in the treatment of childhood leukemia.(Farber et al., 1948). Aminopterin, an anti-metabolite compound structurally show resemblance to MTX, interferes with the connective tissue and this observation was extrapolated, by Gubner research group in 1951 in, rheumatoid arthritis (RA) (Gubner et al., 1951). Several patients with RA, psoriasis and psoriatic arthritis were treated with aminopterin routinely. They showed a rapid recovery in RA signs and symptoms but drug discontinuation lead to the emergence of RA back. Due to struggle in manufacturing aminopterin, the compound was synthetically modified in structure for the easier production (Weinblatt, 2013). The modified version was MTX. Over past 25 years, MTX has become an emerging standard and popular drug in the treatment of adult rheumatoid arthritis.

 

 

Key points in discovery of MTX
 
1. In 1949, Sidney Farber conjectured that taking anti-folate drug such as MTX would slow the growth rate of cancer cells.
 
2. Gubner published stating that aminopterin taken as part of rheumatoid infection could also be beneficial to treat psoriasis.
 
3. 1958, Edmundsun and Guy reported that aminopterin can be replaced by its structural analogue MTX as it has lower lethality rate.
 
4. In 1950 MTX effectiveness against psoriasis was proved.
 
5. Finally, in 1970 MTX was approved by FDA for psoriasis.
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

MTX Chemistry

MTX is a solid odorless, yellow or orange-brown crystallite compound. Chemically MTX is 4-amino-4-deoxy-N-methyl- Pteroylglutamic acid. It shows the molecular 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 N10 position (W. Bleyer, 1978). Methotrexate, (previously amethopterin), differs from aminopterin in that the latter is also not methylated at the N10 position. Therefore the active site of the molecule appears to involve the pteridine ring portion. MTX is a weak organic acid in nature and lipid insoluble at physiological pH. Its solubility in human urine is directly proportional to its increasing pH. It is soluble in dilute solutions of alkali hydroxides and carbonates, slightly soluble in dilute hydrochloric acid whereas practically insoluble in water and alcohol (Lewis, R.J., Sr (Ed.). Hawley’s Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley & Sons, Inc. 1997., p. 722)

 

 

 

Its molecular

structure differs from folic acid only in that folic

acid has a hydroxyl group in place of the 4-

amino group on the pteridine ring and there 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-

rated at the N’O  position.  Hence the active site of

the molecule appears to involve the pteridine

ring portion.

Its molecular

structure differs from folic acid only in that folic

acid has a hydroxyl group in place of the 4-

amino group on the pteridine ring and there is

no methyl group at the position.  Methotrexate-

ate, also known as amethopterin, differs from

aminopterin in that the latter is also not methyl-

rated at the N’O  position.  Hence the active site of

the molecule appears 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

 

 

 

 

 

 

 

 

 

 

 

 

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 a most 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 the cell cycle are more liable to the cytotoxic effect of MTX. Chemotherapy affects in cell division by damaging DNA or RNA. If the cancer cells cannot divide, the tumor will shrink. Chemotherapy drugs could be effective to dividing cells, (cell-cycle specific); or to cells that are at rest, (cell-cycle non-specific) (“Methotrexate.”Scott Hamilton CARES Initiative 21 Nov 2012.

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