Improved potency of F10 relative to 5-fluorouracil in colorectal cancer cells with p53 mutations

Abstract

Results: Significant resistance to 5-FU resulted from p53-loss or from gain-of-function (GOF) mutation (R248W) and was greatest when GOF mutation was coupled with loss of wild-type p53. F10 is much more potent than 5-FU (137-314-fold depending on TP53 mutational status). F10 and 5-FU induce apoptosis by DNA-and RNA-directed mechanisms,respectively, and only F10 shows a modest enhancement in cytotoxicity upon co-treatment with leucovorin.Conclusion: TP53 mutational status affects inherent sensitivity to FPs, with p53 GOF mutations most deleterious. F10 is much more effective than 5-FU regardless of TP53 mutations and has potential to be effective to CRC that is resistant to 5-FU due, in part, to TP53 mutations.

Fluoropyrimidine Modulation of the Anti-Tumor Immune Response―Prospects for Improved Colorectal Cancer Treatment

“…The extent of the mechanistic difference between F10 and 5-FU was demonstrated by COMPARE analysis of data from the NCI60 cell line screen, which showed low correlation between these drugs consistent with dissimilar mechanisms [ 52 ]. Further, we showed 5-FU-induced apoptosis in CRC cells was p53-dependent and rescued by Uridine while F10’s effects were p53-indepedendent and not reversed by Uridine [ 150 ]. Apart from distinguishing polymeric FPs from 5-FU mechanistically, these findings have potential implications for anti-tumor immunity since mode of cell death affects DAMP secretion, DC cell maturation and ultimately the recognition of malignant cells as foreign by effector T-cells.…”

Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs

“…5-FU is inefficiently converted to the TS inhibitory metabolite FdUMP with ~85% of the dose administered to humans degraded or excreted intact [43] . Among anabolic metabolites, ribonucleotides that contribute primarily to systemic toxicities are produced at higher levels than deoxynucleotides [44] . The Gmeiner lab developed FP polymers (e.g., F10) to efficiently generate FdUMP [45] .…”

Cancer drug resistance: a new perspective

“…When a drug manages to be taken up into a cancer cell, the drug will encounter more hurdles leading to resistance, such as defective activation, or extensive degradation. The paper by Dominijanni and Gmeiner [7] describes a dual approach to bypass resistance. By using a prodrug complex, the drug can bypass the usual transporters, does not need activation and can immediately hit its target, thymidylate synthase (TS).…”

“…When a drug, in this case FdUMP, the active metabolite of 5FU, hits its target TS, the cell can respond by modifying the target, e.g., by increasing the gene expression or the (1) at oral administration gut uptake can be poor; (2) i.v. administration can be associated with extensive renal clearance or liver metabolic clearance by phase I and II enzymes; (3) from the tumor blood capillaries the drug can be taken up by either diffusion (single arrow), facilitated transport (tube) or active transport (cross); (4) in the cell the drug can be activated or inactivated; (5) these metabolites can be effluxed; (6) the drug can be sequestered (e.g., in the lysosome, where it can be protonated); (7) the drug can hit a protein kinase; (8) or DNA; (9) or other targets. The cell can respond to changes in any of these processes (either increase or decrease), activate alternative signaling pathways, modify the target, or repair the damage activity of the target, modify the drug binding or enabling the cell to increase the concentration of its target [8] , making it less sensitive.…”