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Ribonucleotide reductase; DNA polymerase (RRM1 (for ribonucleotide reductase), null for DNA synthesis inhibition as a whole)

Target
RRM1 (for ribonucleotide reductase), null for DNA synthesis inhibition as a whole
Molecular classification
Enzyme (Ribonucleotide reductase, DNA polymerase), Other (Nucleoside analog incorporation into DNA)
01

Overview

Gemcitabine, a pyrimidine nucleoside analog, inhibits DNA synthesis in proliferating cells by two main mechanisms: it inhibits ribonucleotide reductase (via its diphosphate metabolite), lowering the pool of deoxynucleotides required for DNA replication, and it is incorporated into DNA (as its triphosphate metabolite), leading to masked chain termination and apoptosis. This mechanism is highly effective in cancer therapy, targeting rapidly dividing tumor cells, but can also affect healthy proliferating cells, leading to adverse effects such as myelosuppression and, in rare cases, liver toxicity

Other names
Gemcitabine targetdFdC targetDNA synthesis target of gemcitabineAntimetabolite target
02

Mechanism of action

Inhibition of ribonucleotide reductase, depleting deoxynucleotide pools needed for DNA synthesis (via gemcitabine diphosphate); Incorporation of gemcitabine triphosphate into DNA, causing masked chain termination and apoptosis; Self-potentiation: lowering dCTP levels, enhancing gemcitabine incorporation

03

Biological functions

Cell cycle progression (S-phase arrest)DNA replication and synthesisCell death/apoptosisNucleotide metabolism
04

Disease associations

Cancer (including: pancreatic, lung, breast, bladder, ovarian, cervical, lymphoma, mesothelioma, etc.)
05

Safety considerations

Myelosuppression (anemia, leukopenia, neutropenia, thrombocytopenia)Hepatic toxicity (elevated ALT, AST, alkaline phosphatase)Fertility reductionMutagenicity/clastogenicity
06

Interacting drugs

Gemcitabine
07

Biomarkers

Deoxycytidine kinase (DCK) expression (correlates with gemcitabine sensitivity)SLC29A1, SLC28A1, SLC28A3 (membrane transporters impacting drug uptake)RRM1 expression

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