Resistance Mechanisms to Methotrexate in Tumors

Abstract

The mechanisms of intrinsic and acquired resistance to methotrexate (MTX) in human tumors are reviewed herein. In blasts from patients with acute lymphocytic leukemia, resistance mechanisms found are decreased uptake and increased dihydrofolate reductase (DHFR) activity. A major cause of intrinsic resistance to MTX in soft tissue sarcoma cells and in acute myelocytic leukemia appears to be a lack of drug retention, due mainly to low levels of polyglutamylation. A novel association between lack of the retinoblastoma protein and intrinsic MTX resistance has been found. This has been attributed to an increase in DHFR activity, due to an increased rate of transcription of this gene, stimulated by an increase in levels of free E2F, not sequestered by hypophosphorylated retinoblastoma protein.

Combined antitumoral effects of pretubulysin and methotrexate

“…18 However, acquired resistance to MTX represents a common problem of monotherapy approaches. [19][20][21] This hurdle can possibly be overcome by combining MTX with a second antitumoral agent.…”

High Content Phenotypic Profiling in Oesophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery

“…Aminopterin was removed from further analysis due to its toxicity profile in the clinic 27 , however, it showed potent activity in an initial dose response in the OAC lines, validating it as a hit our screen (results not shown).…”

Simple surface functionalization of magnetic nanoparticles with methotrexate‐conjugated bovine serum albumin as a biocompatible drug delivery vehicle

“…[4] However, its therapeutic application has been restricted owing to its toxicity in different parts of the body [5] and drug resistance. [6] Therefore, the discovery and development of precise diagnostic methods and carriers for effective drug delivery have been known as two areas of interesting research in cancer therapy over the past few decades. [7,8] Magnetic nanoparticles (MNPs), as an intelligent nanomagnetic substance, [9] are applicable in a variety of fields including biomedical science for diagnosis, [10] carrier of drugs, [11,12] magnetic hyperthermia, [13] etc., due to their unique properties.…”

“…Methotrexate (MTX), an analog of folic acid, is an effective cytotoxic drug in numerous types of neoplasms . However, its therapeutic application has been restricted owing to its toxicity in different parts of the body and drug resistance . Therefore, the discovery and development of precise diagnostic methods and carriers for effective drug delivery have been known as two areas of interesting research in cancer therapy over the past few decades …”