What is the mechanism of action of NUC-1031 when combined with cisplatin in treating biliary tract and ovarian cancer?

Label:chem

Topic
NUC-1031 is a phosphorylated form of gemcitabine designed to overcome limitations associated with gemcitabine, such as resistance and metabolic breakdown. Cisplatin is a platinum-based chemotherapy agent that forms DNA crosslinks, causing cell cycle arrest and apoptosis. The combination of these drugs is hypothesized to enhance DNA damage and cell cycle arrest, leading to greater cellular apoptosis.
Answer
NUC-1031 is metabolized to dFdCTP, which is incorporated into DNA, causing cell cycle arrest in the S phase and eliciting a DNA damage response. When combined with cisplatin, the DNA damage is increased and occurs earlier compared to monotherapy. The combination also affects nucleotide pools by binding to the RRM1 subunit of ribonucleotide reductase, potentially enhancing the DNA damage response. This mechanism suggests that the combination of NUC-1031 and cisplatin can lead to synergistic effects, enhancing the efficacy of treatment in biliary tract and ovarian cancer.
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