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The enzyme that recycles folate so cells can build DNA. Methotrexate blocks it, which is why folinic acid rescue after high-dose methotrexate matters.
Dihydrofolate reductase regenerates tetrahydrofolate, the carrier of one-carbon units needed for thymidylate and purine synthesis. Methotrexate is a tight-binding folate analogue that shuts the enzyme down and, as polyglutamates, also inhibits thymidylate synthase; leucovorin bypasses the block in normal tissues, allowing high-dose regimens in acute lymphoblastic leukaemia, osteosarcoma and primary CNS lymphoma. DHFR gene amplification is a classic mechanism of acquired methotrexate resistance, and pemetrexed inhibits DHFR among its folate targets.
In plain words · The enzyme that recycles folate so cells can build DNA. Methotrexate blocks it, which is why folinic acid rescue after high-dose methotrexate matters.
The enzyme that recycles folate so cells can build DNA. Methotrexate blocks it, which is why folinic acid rescue after high-dose methotrexate matters.
NADPH-dependent reductase maintaining the tetrahydrofolate pool; amplified in methotrexate-resistant cells.
2 products aim at Dihydrofolate reductase (DHFR): small molecules and other agents. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Broadly expressed or essential: HPA lists DHFR among essential proteins and finds the RNA at low tissue specificity; the 4 medicines aimed at it (Methotrexate, Pemetrexed, Aminopterin and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA DHFR: RNA low tissue specificity; no normal tissue stained high; highest cancer staining prostate cancer (1 of 12 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Leukaemia, Sarcomas (soft tissue, bone, GIST), Lymphoma); Open Targets associates it with 11 specific cancer types at or above 0.5 (non-small cell lung carcinoma, acute lymphoblastic leukemia, breast cancer, mesothelioma, malignant pleural mesothelioma, hereditary neoplastic syndrome and more). (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas DHFR tissue; Open Targets ENSG00000228716 associations
First described 1983. Earliest sequence paper UniProt cites for the protein: Masters J.N. et al, Gene, 1983, "The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase". Source.
NADPH-dependent reductase maintaining the tetrahydrofolate pool; amplified in methotrexate-resistant cells.
RNA: low tissue specificity, detected in all normal tissues.
No normal tissue stained high.
Medium only: breast cancer, carcinoid, cervical cancer, colorectal cancer.
HPA DHFR tissue · HPA DHFR pathology · HPA protein class: Essential proteins, FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Metastatic cancer | all% | Housekeeping enzyme present in every dividing cell (folate recycling); not a selection marker, which is why these drugs are given by cancer type rather than by test. |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Aminopterin was the first drug to send childhood leukaemia into remission. In 1948 Sidney Farber reported temporary remissions in children with acute leukaemia, the birth of cancer chemotherapy; its safer cousin methotrexate replaced it within a decade.
Leucovorin is not a cancer drug in itself: it rescues normal tissue after high-dose methotrexate and, given with fluorouracil, makes that chemotherapy work better, which is why it appears in FOLFOX, FOLFIRI and FOLFIRINOX.
Query for this target: (TITLE:"Dihydrofolate reductase" OR ABSTRACT:"Dihydrofolate reductase" OR TITLE:"DHFR" OR ABSTRACT:"DHFR") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Dihydrofolate reductase (DHFR), not a curated reading list.
Shares Leucovorin (folinic acid), Osteosarcoma, Methotrexate.
Shares GART (trifunctional purine synthesis enzyme), Leucovorin (folinic acid), Pemetrexed.
Shares Leucovorin (folinic acid), Osteosarcoma.
Shares Leucovorin (folinic acid), Methotrexate, Acute lymphoblastic leukaemia.
Shares Primary CNS lymphoma, Methotrexate.
Shares Leucovorin (folinic acid), Methotrexate, Acute lymphoblastic leukaemia.