Molecular mechanisms of resistance to antifolates, a review.

D. Banerjee, E. Ercikan-Abali, M. Waltham, B. Schnieders, D. Hochhauser, W. W. Li, J. Fan, R. Gorlick, E. Goker, J. R. Bertino

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Methotrexate (MTX) is a clinically important antifolate that has been used in combination with other chemotherapeutic agents in the treatment of malignancies including acute lymphocytic leukemia, osteosarcoma, carcinomas of the breast, head and neck, choriocarcinoma and non-Hodgkin's lymphoma. The primary target of MTX is the enzyme dihydrofolate reductase (DHFR) which catalyzes the reduction of folate and 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. Understanding of MTX action has revealed how cells acquire resistance to this drug. The four known mechanisms of MTX resistance are a decrease in the uptake of the drug, a decrease in the retention of the drug due to defective polyglutamylation or an increase in polyglutamate breakdown, an increase in the enzyme activity and a decrease in the binding of MTX to DHFR. The molecular basis for some of these mechanisms has been elucidated in MTX resistant cell lines; in particular the occurrence of gene amplification resulting in increased DHFR and point mutations resulting in altered DHFR with reduced affinity for MTX. Cloning of the human folylpolyglutamate synthase gene and the reduced folate transport gene have been reported recently and should facilitate the identification of the molecular basis of these resistant phenotypes. DHFR protein has been shown to regulate its synthesis by exerting an inhibitory influence on its own translation. Addition of MTX relieves this inhibition thus providing a possible molecular explanation for the rapid rise in DHFR activity noted in some cells after MTX administration. Alterations in genes involved in regulating the cell cycle such as cyclin D1 and the retinoblastoma (Rb) gene have also been shown to influence cellular response to MTX. Overexpression of cyclin D1 in HT1080, a human fibrosarcoma cell line, results in decreased MTX sensitivity. The molecular basis of this observation is under investigation. Abnormalities in the Rb gene may also have profound effects on MTX sensitivity. Rb interacts with the family of transcription factors called E2F reducing transcription of genes that contain E2F binding sites in the promoter regions e.g. DHFR. When Rb is deleted or rendered nonfunctional levels of "free" or unbound E2F are high resulting in enhanced transcription of genes such as DHFR. This results in increased DHFR protein and may lead to MTX resistance. As the knowledge regarding mechanisms of resistance increases newer approaches to circumvent such resistance or to target resistant cells can be undertaken.

Original languageEnglish (US)
Pages (from-to)457-464
Number of pages8
JournalActa Biochimica Polonica
Volume42
Issue number4
StatePublished - 1995
Externally publishedYes

Fingerprint

Folic Acid Antagonists
Methotrexate
Tetrahydrofolate Dehydrogenase
Genes
Retinoblastoma Genes
Retinoblastoma
Cyclin D1
Cells
Transcription
Folic Acid
bcl-1 Genes
E2F Transcription Factors
Pharmaceutical Preparations
Polyglutamic Acid
Cell Line
Choriocarcinoma
Gene Amplification
Fibrosarcoma
Cloning
Enzyme activity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Banerjee, D., Ercikan-Abali, E., Waltham, M., Schnieders, B., Hochhauser, D., Li, W. W., ... Bertino, J. R. (1995). Molecular mechanisms of resistance to antifolates, a review. Acta Biochimica Polonica, 42(4), 457-464.

Molecular mechanisms of resistance to antifolates, a review. / Banerjee, D.; Ercikan-Abali, E.; Waltham, M.; Schnieders, B.; Hochhauser, D.; Li, W. W.; Fan, J.; Gorlick, R.; Goker, E.; Bertino, J. R.

In: Acta Biochimica Polonica, Vol. 42, No. 4, 1995, p. 457-464.

Research output: Contribution to journalArticle

Banerjee, D, Ercikan-Abali, E, Waltham, M, Schnieders, B, Hochhauser, D, Li, WW, Fan, J, Gorlick, R, Goker, E & Bertino, JR 1995, 'Molecular mechanisms of resistance to antifolates, a review.', Acta Biochimica Polonica, vol. 42, no. 4, pp. 457-464.
Banerjee D, Ercikan-Abali E, Waltham M, Schnieders B, Hochhauser D, Li WW et al. Molecular mechanisms of resistance to antifolates, a review. Acta Biochimica Polonica. 1995;42(4):457-464.
Banerjee, D. ; Ercikan-Abali, E. ; Waltham, M. ; Schnieders, B. ; Hochhauser, D. ; Li, W. W. ; Fan, J. ; Gorlick, R. ; Goker, E. ; Bertino, J. R. / Molecular mechanisms of resistance to antifolates, a review. In: Acta Biochimica Polonica. 1995 ; Vol. 42, No. 4. pp. 457-464.
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