Retroviral transduction of human dihydropyrimidine dehydrogenase cDNA confers resistance to 5-fluorouracil in murine hematopoietic progenitor cells and human CD34+-enriched peripheral blood progenitor cells

Abstract

Severe 5 -fluorouracil ( 5 -FU ) toxicity has been reported among patients lacking dihydropyrimidine dehydrogenase ( DPD ) enzymatic activity. DPD is the principal enzyme involved in the degradation of 5 -FU to 5 0 -6 0 -dihydrofluorouracil, which is further metabolized to fluoro --alanine. We demonstrate here that overexpression of human DPD confers resistance to 5 -FU in

Pharmacologic resistance in colorectal cancer: a review

“…5-FUH 2 is then converted into the soluble molecule 5-fluoro-β-alanine and eliminated in urine. Intrinsic overexpression of DPD by malignant cells has been shown in vitro to extend resistance to 5-FU [Longley and Johnston, 2005;Takebe et al 2001]. High levels of DPD mRNA expression in CRC cells have also been associated with 5-FU resistance [Salonga et al 2000].…”

Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy

“…DPD, an initial and rate-limiting enzyme in 5-FU catabolism, has significance for the pharmacokinetics and toxicity of 5-FU (Harris et al, 1990). Overexpression of DPD in tumor cell lines is associated with resistance to 5-FU (Takebe et al, 2001). Degradation of 5-FU by induction of DPD expression may also inhibit 5-FU-induced apoptosis.…”

Protection of hematopoietic stem cells from pemetrexed toxicity by retroviral gene transfer with a mutant dihydrofolate reductase-mutant thymidylate synthase fusion gene

“…5 Our laboratory has previously generated a variety of drug resistance genes, and combinations thereof, conferring resistance to antimetabolites such as MTX, trimetrexate, 5FU, raltitrexed, thymitaq, and cytosine arabinoside. 14,[20][21][22][23][24] In this study, we show that the transfer of a DHFR F/S-TS G52S fusion gene into hematopoietic progenitor cells results in resistance to a promising new antifolate, pemetrexed.…”