Potentiation of 5-fluorouracil efficacy by the dihydrouracil dehydrogenase inhibitor, 5-benzyloxybenzyluracil.

Paper

Potentiation of 5-fluorouracil efficacy by the dihydrouracil dehydrogenase inhibitor, 5-benzyloxybenzyluracil.

Published Oct 1, 1994 · F. Naguib, S. Hao, M. H. el Kouni

Cancer research

Q1 SJR score

20

Citations

0

Influential Citations

Semantic Scholar

Abstract

5-Benzyloxybenzyluracil (BBU) is the most potent inhibitor (Ki approximately 30 nM) of dihydrouracil dehydrogenase (EC 1.3.1.2), the first enzyme in the catabolic pathway of pyrimidine bases and their analogues, including 5-fluorouracil (FUra). The effect of BBU on modulating the chemotherapeutic efficacy and host toxicity of FUra was evaluated using human colon carcinoma DLD-1 grown in culture and as xenografts in anti-thymocyte serum (ATS)-immunosuppressed mice. The effect of BBU on FUra-induced host toxicity was also studied in nontumor-bearing-ATS-immunosuppressed and immunocompetent mice. At 0.2 microM, BBU potentiated growth inhibition by FUra of DLD-1 cells in culture (the concentration that produces 50% inhibition of cell growth was 0.48 microM at 3 h) by 1.3-fold (from 45 to 28% growth). BBU also enhanced the cytocidal effect of FUra (0.48 microM, 3 h) against DLD-1 grown in soft agar by 3-fold (from 45 to 15% growth). In ATS-immunosuppressed mice bearing DLD-1 xenografts, coadministration of BBU with FUra enhanced not only the efficacy of FUra in killing the tumor but also protected the host from FUra-induced host toxicity. This was particularly evident at low doses of FUra. Coadministration of BBU (10 mg/kg/day x 2) with FUra at 30 mg/kg/day x 2 reduced tumor weight by 16-fold (from 799 to 49 mg) and increased host survival from 83 to 100%. The enhancement of tumor kill and protection from host toxicity induced by FUra was also evident at higher doses of FUra, albeit to a lesser degree. At 120 mg/kg/day x 2 FUra, coadministration of BBU (10 mg/kg/day x 2) reduced tumor weight from 44 to 10 mg and increased survival of the animals from 33 to 50%. Host protection from FUra-induced toxicity was corroborated further by the protective effect of BBU, inferred from the increase in the dose that produces 50% mortality in ATS-immunosuppressed (from 135 to 195 mg/kg/day x 2) and immunocompetent (from 250 to 300 mg/kg/day x 2) mice. Therefore, coadministration of BBU improved the therapeutic index of FUra by 5.5-fold (from 2.3 to 12.6) as a result of potentiating the antitumor efficacy of FUra and reducing its induced host toxicity. This protection by BBU sharply contrasts with the effect of most other dihydrouracil dehydrogenase inhibitors, which at therapeutic doses increase host toxicity by FUra. These findings may lead to a more successful use of FUra in cancer chemotherapy.

Non-RCT

Animal Study

Study Snapshot

Coadministration of 5-fluorouracil with 5-benzyloxybenzyluracil (BBU) significantly enhances tumor kill and protects the host from FUra-induced host toxicity in cancer treatment.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Potentiation of 5-fluorouracil efficacy by the dihydrouracil dehydrogenase inhibitor, 5-benzyloxybenzyluracil.

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References

5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma.

EU significantly improves the efficacy and therapeutic index of 5-fluorouracil in rats with advanced colorectal carcinoma, resulting in 100% complete and sustained tumor regression.

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5-EU effectively modulates 5-fluorouracil catabolism, increasing its pharmacokinetics and antitumor efficacy, potentially increasing its therapeutic index by 2- to 4-fold.

Clinical Cardiotoxicity of 5‐Fluorouracil

5'-fluorouracil can cause life-threatening cardiac toxicity, leading to increased coronary vasomotor tone and spasm in susceptible individuals.

Circadian rhythm of orotate phosphoribosyltransferase, pyrimidine nucleoside phosphorylases and dihydrouracil dehydrogenase in mouse liver. Possible relevance to chemotherapy with 5-fluoropyrimidines.

The circadian rhythm of key enzymes in pyrimidine metabolism may impact therapeutic regimens with 5-fluorinated pyrimidines, potentially affecting uridine bioavailability.

Inhibition of fluoropyrimidine catabolism by benzyloxybenzyluracil. Possible relevance to regional chemotherapy.

Benzyloxybenzyluracil (BBU) effectively inhibits fluoropyrimidine catabolism in the liver, potentially improving regional chemotherapy effectiveness for hepatic metastases.

Citations

Potent combination therapy for human breast tumors with high doses of 5-fluorouracil: remission and lack of host toxicity

Oral PTAU and uridine effectively reduce 5-fluorouracil toxicity and enhance its chemotherapeutic efficacy against human breast tumors, with all mice surviving and tumor weights reduced by 97% and total remission, respectively.

Modulation of 5-fluorouracil host-toxicity and chemotherapeutic efficacy against human colon tumors by 5-(Phenylthio)acyclouridine, a uridine phosphorylase inhibitor

PTAU, a uridine phosphorylase inhibitor, can reduce 5-fluorouracil's host-toxicity and enhance its chemotherapeutic efficacy against human colon tumors.

Significance of dihydropyrimidine dehydrogenase activity in renal cell carcinoma.

Low DPD activity in renal cell carcinoma is associated with malignant potential and may be overcome by using DPD inhibitors in 5-FU-based chemotherapy treatment protocols.

The significance of dihydropyrimidine dehydrogenase (DPD) activity in bladder cancer.

Elevated DPD activity in bladder cancer correlates with progression and increased grade, suggesting it may be linked to malignant potential and could be overcome using DPD inhibitors in 5-FU-based chemotherapy.

Risk Factors Determining Chemotherapeutic Toxicity in Patients with Advanced Colorectal Cancer

Dose adjustment based on risk factors can potentially decrease toxicity and improve therapeutic index in advanced colorectal cancer patients.