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Mechanisms of Resistance to Antineoplastic Drugs
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
Philip J. Vickers, Alan J. Townsend, Kenneth H. Cowan
The transformation of the pyrimidine analog 5-fluorouracil (5-FU) to its various active metabolites is a complex process, involving a number of biochemical pathways (Figure 2). The active metabolites generated in these reactions are potentially cytotoxic by inhibition of thymidylate synthase or through incorporation into RNA or DNA.25-28 Decreased activation of 5-FU resulting from decreased levels of uridine kinase,16 orotic acid phosphoribosyl transferase,17,18 and uridine phosphorylase19 have all been reported in cells resistant to 5-FU.
Colon Carcinogenesis: Biochemical Changes
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Young S. Kim, Laurence J. Mcintyre
The study of enzyme changes in colon carcinogenesis, in addition to investigating individual enzymes in detail, has also been concerned with the patterns of key enzyme levels in the control of intermediary metabolism. Shonk et al.19 measured the levels of the enzymes involved in glycolysis in normal human colon and colonic cancer tissue. They found that all the enzymes in glycolysis were elevated in the tumor tissue. This is in agreement with the common finding in malignant tissues that the respiratory enzyme activities are at the bottom of the range present in normal tissue, while the glycolytic enzyme activities are at the top end of the normal range.20 These studies were extended using a transplantable colon adenocarcinoma compared with normal colonic mucosa in the mouse.21 When the enzymes of pyrimidine metabolism were measured in normal colon, CTP synthetase activity was an order of magnitude lower than the other enzymes, suggesting that it was rate-limiting. It is interesting to note that in the cancer tissue this enzyme showed a higher increase than any of the others — 927% of the normal mucosa activity. This study also demonstrated that the colonic tumor cells displayed reciprocal regulation. This type of regulation is based on the fact that one way of increasing the supply of metabolic intermediates is not only to increase the synthetic enzyme activity but also to concomitantly reduce the level of the corresponding catabolic enzyme. This is seen in the increase in uridine kinase and the decrease in uridine Phosphorylase as well as in the increase in thymidine kinase and the decrease in dihydrothymine dehydrogenase. The most striking example of reciprocal regulation is in glutamine PRPP amidotransferase and xanthine oxidase where the ratio of synthetic to catabolic enzymes is increased 81-fold by the changes.
An overview of ProTide technology and its implications to drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Michaela Serpi, Fabrizio Pertusati
A significant breakthrough was the application of the ProTide technology to 5-fluoro-2ʹ-deoxyuridine (FUdR), which led to substantial increases in in vitro cancer cell cytotoxic in comparison to the parent drug [29]. Among several FUdR ProTides the naphthyloxy L-alanine benzyl ester derivatives (NUC3373, 9) (Figure 3) was identified as lead candidate by NuCana plc. Whereas FUdR substantially lost its cytostatic potential in thymidine kinase (TK)-deficient cell cultures, NUC3373 markedly kept its antiproliferative activity in TK-deficient tumor cells. The prodrug is largely independent from the intracellular TK activity to exert its cytostatic action. NUC3373 was found to inhibit TS in the TK-deficient and wild-type cell lines at drug concentrations that correlated well with its cytostatic activity in these cells. NUC3373 does not seem to be susceptible to inactivation by catabolic enzymes such as thymidine phosphorylase (TP) and uridine phosphorylase (UP). NUC3373 is currently evaluated in a phase I study in patients with advanced solid tumors and in a phase Ib in combination with other agents typically administered with fluorouracil (5-FU; drug used as standard therapy) in patients with advanced colorectal cancer [97]. The preliminary results of phase I study showed that NUC3373 has a favorable pharmacokinetic and safety profiles with respect to 5-FU [98].
Proteomic investigations into resistance in colorectal cancer
Published in Expert Review of Proteomics, 2020
David I. Cantor, Harish R. Cheruku, Jack Westacott, Joo-Shik Shin, Abidali Mohamedali, Seong Boem Ahn
Another source of resistance to fluoropyrimidines is the presence of microsatellite instability (MSI), which involves the insertion or deletion of repetitive genetic sequences (typically 1-5bp in length, repeated 15–30 times) into susceptible regions, resulting in alteration to DNA replication processes [5]. However, as a key example of the challenges posed by CRC resistance, TS is only one of several enzymes involved in 5-FU metabolism. These compounding enzymes include thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT) and uridine phosphorylase (UP); each with demonstrated relationships between their respective activities and sensitivity to 5-FU. Positive correlations have been observed between TP, OPRT, and UP expression and increased susceptibility to 5-FU therapy [34,35], whilst DPD expression inversely corresponded with sensitivity, likely due to its contribution to 5-FU degradation [36].
Uridine triacetate - an antidote in the treatment of 5-fluorouracil or capecitabine poisoning
Published in Expert Opinion on Orphan Drugs, 2019
We concluded that there is a threshold 5-FU dose after which the efficacy is dramatically improved – in mice, that threshold is a dose of >150 mg/kg/week (i.e. 175 and 200 mg/kg/week), and the increased efficacy correlates with about a fourfold increase in the AUC of 5-FU. This finding is consistent with previous studies including the use of injected uridine, uridine diphosphoglucose (UDPG) and vistogard in combination with 5-(benzyloxybenzyl) barbituric acid acyclonucleoside (BBBA), an inhibitor of uridine phosphorylase (UrdPase) indicating that these agents can allow the escalation of 5-FU doses for better chemotherapeutic efficacy. This was the first report that delayed administration of vistogard alone is sufficient for enabling dose escalation of 5-FU to a degree sufficient to induce regressions of the Colon 26 adenocarcinoma.