Methotrexate (MTX) is widely used in different types of cancers and in autoimmune diseases.
It is an FDA approved chemotherapeutic agent and anti-cancer drug formerly known as amethopterin. In spite of the fact that it is considered an immunosuppressant, it has severe side effects which could be life-threatening such as nausea, vomiting, liver disease, lung disease and even low blood cell count synthesized by the bone marrow. MTX is recommended in low doses as high dose often leads to severe side effects. MTX synthetically resembles folate compound and competitively inhibit Dihydrofolate reductase (DHFR). DHFR, key enzyme, plays a crucial role in the biosynthesis of purines and pyrimidines as well as in several amino acids. Here we have used the Drosophila model system to assess the anti-cancerous activity of MTX. Previous literature has shown the effect of MTX on the survival of adult flies, female fecundity, egg morphology, larval tumors, and wing, eye, and leg defects. Also, MTX activity interferes with the JAK/STAT pathway leading to the dysregulation of the hemocytes (blood cells in Drosophila). The action of a mechanism still remains enigmatic. Our effort here is to see the targets of MTX in the hematopoietic pathways such as VEGFR, Toll/Cactus, Notch signaling. These pathways also contribute to the development, differentiation, and migration of the hemocytes. Relapse is being witnessed in most of the cancer cases. To eradicate it completely there is still a lot to understand the targets and mechanism of MTX in Drosophila blood cells.
Keywords: MTX, hemocytes, cancer, tumor, chemotherapy
A brief information of chemotherapy status till date.
Yellapragada Subba Rao, an eminent biochemist, who unraveled anti-cancer activity of MTX for the treatment of cancer which revolutionized that era. Prior 1950, the 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 an 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 the 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).
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 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 the 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.