Comparison of 5-fluoro-2'-deoxyuridine and 5-fluorouracil in the treatment of murine colon cancer; effects on thymidylate synthase.

doi:10.1007/978-1-4615-2584-4_25

Paper

Comparison of 5-fluoro-2'-deoxyuridine and 5-fluorouracil in the treatment of murine colon cancer; effects on thymidylate synthase.

Published 1994 · C. L. van der Wilt, J. V. van Laar, K. Smid

Advances in experimental medicine and biology

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2

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Abstract

The fluoropyrimidines 5-fluoro-2’-deoxyuridine (FdUrd) and 5-fluorouracil (FUra) are both applied in the treatment of patients with colorectal cancer. These agents exert their action after metabolization to the nucleotide level (Fig. 1). The nucleotides 5-fluorouridine triphosphate (FUTP) and 5-fluoro-2’-deoxyuridine triphosphate (FdUTP) may mediate antiproliferative effects by their incorporation into cellular RNA and DNA, respectively. Anabolism to 5-fluorodeoxyuridine monophosphate (FdUMP) causes an inhibition of the key-enzyme of the pyrimidine de novo synthesis, thymidylate synthase (TS)1, 2. FdUrd’s main mechanism of action is thought to be inhibition of TS3, while the action of FUra is incorporation into RNA and TS inhibition in different magnitudes, depending on the schedule4, 5.

Study Snapshot

Both 5-fluorouracil and 5-fluoro-2'-deoxyuridine show antiproliferative effects in colorectal cancer, with 5-fluorouracil showing more TS inhibition and 5-fluorouracil showing more RNA incorporation and TS inhibition.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Comparison of 5-fluoro-2'-deoxyuridine and 5-fluorouracil in the treatment of murine colon cancer; effects on thymidylate synthase.

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References

Novel approaches to selective treatments of human solid tumors: laboratory and clinical correlation.

Selective treatments of human solid tumors with fluoropyrimidines show promise for advanced colorectal, head and neck, and breast cancers.

Antitumor activity of the weekly intravenous push schedule of 5-fluoro-2'-deoxyuridine +/- N-phosphonacetyl-L-aspartate in mice bearing advanced colon carcinoma 26.

The weekly intravenous push schedule of 5-fluorouracil and 5-fluorouridine is superior to daily or i.v. push schedules, with PALA pretreatment enhancing antitumor activity and achieving long-term survivors.

Regulation of thymidylate synthase in human colon cancer cells treated with 5-fluorouracil and interferon-gamma.

The increase in thymidylate synthase protein after 5-fluorouracil exposure and the inhibitory effect of interferon-gamma on thymidylate synthase protein expression are both regulated at the post-transcriptional level in human colon cancer cells.

Elevation of thymidylate synthase following 5-fluorouracil treatment is prevented by the addition of leucovorin in murine colon tumors.

Leucovorin enhances the antitumor effect of 5-fluorouracil in murine colon tumors by increasing the inhibition of thymidylate synthase, potentially explaining its potentiating effect in vivo.

Modulation of fluoropyrimidines: role of dose and schedule of leucovorin administration.

Optimal leucovorin dose and schedule for modulating 5-fluorouracil in cancer therapy varies between cell lines, with higher doses (200 to 500 mg/m2) potentially offering the best chance to improve antitumor activity.

Citations

ALPPL2 Aptamer-Mediated Targeted Delivery of 5-Fluoro-2'-Deoxyuridine to Pancreatic Cancer.

SQ2 aptamer effectively targets pancreatic cancer cells, minimizing toxic side effects and maximizing effectiveness while reducing uptake into normal cells.

Cellular pharmacology of multi- and duplex drugsconsisting of ethynylcytidine and 5-fluoro-2′-deoxyuridine

Liposomal formulations of ETC-L-FdUrd and ETC-L-FdUrd can reduce resistance due to thymidine kinase deficiency, potentially improving their cytotoxic activity and cellular uptake in cancer cells.