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Concurrent allopurinol and 5-fluorouracil: 5-fluoro-2′-deoxyuridylate formation and thymidylate synthase inhibition in rat colon carcinoma and in regenerating rat liver

  • Original Articles
  • 5-FU, Allopurinol, Thymidylate Synthase, Colon Carcinoma
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Summary

The formation of FdUMP and the inhibition of TS were studied in a subcutaneously growing transplantable rat colon carcinoma and in regenerating rat liver following bolus administration of 5-FU, with or without HPP pretreatment.

In tumor, peak levels of FdUMP at 30 min following bolus 5-FU, 100 mg/kg, averaged 4931±587 pmol/g. Pretreatment with HPP, 50 mg/kg, 24 h and 1 h before 5-FU, reduced the peak FdUMP level to 2085±387 pmol/g. The inhibition of TS by 5-FU treatment was greater than 95% by 30 min, and after 48 h residual enzyme inhibition averaged 40%. No effect on TS inhibition by 5-FU treatment could be observed as a result of HPP pretreatment. The levels of TStot increased linearly after 5-FU treatment and doubled within 48 h.

In regenerating rat liver, neither FdUMP levels nor TS inhibition, studied at 1 h after bolus 5-FU, were affected by HPP pretreatment.

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Abbreviations

BSA:

bovine serum albumin

DMH:

dimethylhydrazine

5-FU:

5-fluorouracil

HPP:

allopurinol (4-hydroxypyrazolopyrimidine)

CH2FH4 :

5, 10-methylenepteroylmonoglutamic acid

FUMP:

5-fluorouridine-5′-monophosphate

FUTP:

5-fluorouridine-5′-triphosphate

FdUMP:

5-fluoro-2′-deoxyuridylate

TS:

thymidylate synthase (EC 2.1.1.45, dTMP synthase)

TSf :

free, non-FdUMP-bound TS

TSb :

ternary complex-bound TS

TStot :

total TS TSf+TSb

PRPP:

phosphoribosylpyrophosphate

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Authors and Affiliations

  1. Department of Surgery, Östra Sjukhuset, University of Gothenburg, S-41685, Gothenburg, Sweden

    M. Berne, B. Gustavsson & O. Almersjö

  2. Comprehensive-Cancer Center, University of Southern California, Los Angeles, California, USA

    C. P. Spears

  3. Department of Clinical Chemistry, Sahlgrenska sjukhuset, Gothenburg, Sweden

    J. Waldenström

Authors
  1. M. Berne
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  2. B. Gustavsson
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  3. O. Almersjö
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  4. C. P. Spears
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  5. J. Waldenström
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Additional information

This study was supported by grants from the Swedish Cancer Society, The Medical Society of Göteborg, the University of Göteborg, the Wellcome Foundation, and NCI Grant 39629.

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Berne, M., Gustavsson, B., Almersjö, O. et al. Concurrent allopurinol and 5-fluorouracil: 5-fluoro-2′-deoxyuridylate formation and thymidylate synthase inhibition in rat colon carcinoma and in regenerating rat liver. Cancer Chemother. Pharmacol. 20, 193–197 (1987). https://doi.org/10.1007/BF00570483

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  • DOI: https://doi.org/10.1007/BF00570483

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