Mechanisms of action of ProTide NUC-1031 and cisplatin combination chemotherapy

Abstract

Biliary tract cancers and advanced ovarian cancers are associated with a high mortality rate. Treatment for ovarian cancers have previously consisted of a regimen of intravenous gemcitabine and cisplatin, administered over a number of weeks. This remains the current treatment option for biliary tract cancers. Gemcitabine is associated with drug resistance via a number of resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, was developed to circumvent these mechanisms. NUC-1031, is the first anti-cancer ProTide to enter the clinic and was investigated in a Phase III trial for biliary tract cancer in combination with cisplatin. Understanding its mode of action may help to improve treatment options and determine a suitable use in patients. It is hypothesised that synergistic effects may occur in combination with cisplatin, where NUC-1031 may sensitise cells to cisplatin lesions via incorporation into DNA. The kinetics of activation of NUC-1031 and mode of action, both as a single agent and in combination with cisplatin were assessed. NUC-1031 displayed slower activation kinetics than gemcitabine, however remained detectable and continued to exert an effect for a prolonged period after treatment. NUC-1031 was found to generate the active metabolites dFdCDP and dFdCTP in cells. The nucleotide analogue dFDCTP is incorporated into DNA which prevents elongation of growing strands in S phase, leading to replication fork collapse and formation of cytotoxic double strand breaks. Combinations of NUC-1031 and cisplatin were also investigated by measuring the DNA damage response and cell cycle distribution over time. NUC-1031 may inhibit cisplatin repair through its incorporation during DNA repair. The slow activation and the prolonged effects of NUC-1031 may be a favourable trait when included in drug combinations, as the active metabolite of NUC-1031 may be available to interact with additional agents in the drug treatment.