Related Experiment Video

Updated: Jun 21, 2026

Multi-Gene Single Nucleotide Polymorphism Detection in Gastric Cancer Based on Ion Semiconductor Sequencing Platform
06:21

Multi-Gene Single Nucleotide Polymorphism Detection in Gastric Cancer Based on Ion Semiconductor Sequencing Platform

Published on: May 10, 2024

Methotrexate-induced apoptosis is enhanced by altered expression of methylenetetrahydrofolate reductase

Basak Celtikci1, Andrea K Lawrance, Qing Wu

  • 1Departments of Human Genetics and Pediatrics, McGill University, Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.

Anti-Cancer Drugs
|July 14, 2009
PubMed

Insights

Altering methylenetetrahydrofolate reductase (MTHFR) enzyme levels, either decreased or increased, significantly enhances methotrexate (MTX)-induced apoptosis and myelosuppression. MTHFR genotyping may inform MTX chemotherapy.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Genetics

Background:

  • Folates are crucial for DNA synthesis and methylation.
  • Methotrexate (MTX) is an antifolate chemotherapy drug inhibiting DNA synthesis and inducing apoptosis.
  • Methylenetetrahydrofolate reductase (MTHFR) activity is critical for folate metabolism, influencing nucleotide synthesis and homocysteine remethylation.

Purpose of the Study:

  • To investigate the impact of altered MTHFR expression on MTX-induced apoptosis in spleen.
  • To elucidate the mechanisms linking MTHFR levels to MTX chemosensitivity and myelosuppression.

Main Methods:

  • Evaluation of MTX-induced apoptosis in MTHFR-deficient and MTHFR-overexpressing mice using TUNEL staining and caspase-3/7 activity assays.
  • Correlation analysis of plasma homocysteine levels and dUTP/dTTP ratios with apoptotic index.

Main Results:

  • Both decreased and increased MTHFR expression significantly elevated MTX-induced apoptosis in the spleen, indicated by increased TUNEL-positive cells and caspase-3/7 activity.
  • Hyperhomocysteinemia correlated with apoptosis in MTHFR-deficient mice.
  • Deoxyribonucleotide pool imbalances (dUTP/dTTP ratios) correlated with apoptosis in MTHFR-overexpressing mice.

Conclusions:

  • MTHFR underexpression and overexpression exacerbate MTX-induced apoptosis and myelosuppression.
  • These findings suggest that MTHFR genetic variations could influence MTX treatment outcomes.
  • Genotyping for MTHFR polymorphisms may hold therapeutic implications for MTX-based chemotherapy.

Related Concept Videos

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase01:27

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
Phase II Reactions: Methylation Reactions01:17

Phase II Reactions: Methylation Reactions

Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
Therapeutic Drug Monitoring: Affecting Factors01:29

Therapeutic Drug Monitoring: Affecting Factors

Therapeutic Drug Monitoring (TDM) is the clinical practice of measuring specific drug levels in a patient's blood or body tissues to manage and optimize therapy. TDM is crucial for drugs with narrow therapeutic windows, like warfarin and phenytoin, where incorrect doses can lead to treatment failure or severe side effects. This monitoring ensures the dosage administered is within a safe and effective range. The factors affecting therapeutic drug monitoring include:Patient-Specific Factors:a.
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...