Genetic determinants for activated fluoropyrimidine chemotherapy

Abstract

Fluoropyrimidines (FPs) remain widely used for the treatment of diverse malignancies more than four decades following the initial report of 5-fluorouracil (5FU), the archetypal FP, as a novel compound with potential anti-neoplastic activity. Subsequent decades of research have enriched our understanding of the biochemical mechanisms that are important for FP activation as well as the genetic determinants that are predictive of the likely success, or failure, of FP chemotherapy for a particular individual. The concept that chemotherapy should be customized to complement the genetic profiles of cancer patients has become increasingly important as genotyping of tumor samples has become possible and as the number of available anticancer drugs has increased. Significant progress has been made in identifying the gene expression profiles for cancer patients who are likely to benefit from treatment with FPs. In this review, we will summarize the results of retrospective clinical studies correlating response to FP chemotherapy with the expression of specific genes, such as TS and DPD. We will also present a summary of FPs in current clinical use, including orally bioavailable FPs such as capecitabine, as well as FPs that are in pre-clinical development, such as FdUMP [10]. Refinement of a target population through pharmacogenetic analysis and development of novel FPs that evoke very high response rates in this target population will likely result in the use of FP regimens in the coming era when cancer becomes a largely manageable disease. Drug Dev.

Genome-Wide mRNA and microRNA Profiling of the NCI 60 Cell-Line Screen and Comparison of FdUMP[10] with Fluorouracil, Floxuridine, and Topoisomerase 1 Poisons

“…A potential advantage of FdUMP[10] relative to currently used FP drugs, such as 5FU, is that fewer steps of metabolic activation are required to produce FdUMP and FdUTP, the DNA-directed FP metabolites that are responsible for antitumor activity (9,22). A summary of correlation of expression of genes important for nucleotide metabolism with drug sensitivity is included in Table 3.…”

Zn2+ selectively stabilizes FdU-substituted DNA through a unique major groove binding motif

“…Zn 2+ binding is energetically favored under conditions where half of the FdU are deprotonated, or slightly above physiological pH (the pK A of FdU is ∼7.6). As both Zn 2+ and FdU-containing DNA are cytotoxic toward prostate cancer cells, it is of interest whether Zn 2+ might be complexed with FdU-containing DNA for therapeutic purposes ( 16 ). In the present study, we have demonstrated that lipofectamine enhances the cytotoxicity of Zn 2+ –DNA complexes towards PCa cells.…”

Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway

“…The general cytotoxic process that cancer cells undergo in response to TS inhibitors is referred to as “thymineless death” [2, 3]. Few studies have investigated thymineless death in leukemia cells because drugs that target TS are not presently used for this indication.…”