Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Jun 15;83(2):219–224. doi: 10.1054/bjoc.2000.1230

Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha

J P Braybrooke 1, D J Propper 1, K J O’Byrne 1, M I Koukourakis 2, A V Patterson 1, S Houlbrook 1, S D Love 1, S Varcoe 1, M Taylor 1, T S Ganesan 1, D C Talbot 1, A L Harris 1
PMCID: PMC2363491  PMID: 10901374

Abstract

Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNα), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m–2, 9 MIU m–2and 18 MIUm–2. IFNα was administered on day 0 cycle two, day –1 and day 0 cycle three and day –2, day –1 and day 0 cycle four. A fourth cohort was treated with IFNα 9 MIU m–2three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNα. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNα led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P = 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNα. A single dose of IFNα as low as 3 MIU m–2can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNα for biomodulation of 5-FU. © 2000 Cancer Research Campaign

Keywords: thymidine phosphorylase, interferon alpha, 5-fluorouracil, folinic acid

Full Text

The Full Text of this article is available as a PDF (72.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. De Gramont A., Krulik M., Cady J., Lagadec B., Maisani J. E., Loiseau J. P., Grange J. D., Gonzalez-Canali G., Demuynck B., Louvet C. High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer. Eur J Cancer Clin Oncol. 1988 Sep;24(9):1499–1503. doi: 10.1016/0277-5379(88)90341-0. [DOI] [PubMed] [Google Scholar]
  2. Fox S. B., Moghaddam A., Westwood M., Turley H., Bicknell R., Gatter K. C., Harris A. L. Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: an immunohistochemical study. J Pathol. 1995 Jun;176(2):183–190. doi: 10.1002/path.1711760212. [DOI] [PubMed] [Google Scholar]
  3. Fox S. B., Westwood M., Moghaddam A., Comley M., Turley H., Whitehouse R. M., Bicknell R., Gatter K. C., Harris A. L. The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium. Br J Cancer. 1996 Feb;73(3):275–280. doi: 10.1038/bjc.1996.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Giatromanolaki A., Koukourakis M. I., Comley M., Kaklamanis L., Turley H., O'Byrne K., Harris A. L., Gatter K. C. Platelet-derived endothelial cell growth factor (thymidine phosphorylase) expression in lung cancer. J Pathol. 1997 Feb;181(2):196–199. doi: 10.1002/(SICI)1096-9896(199702)181:2<196::AID-PATH763>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  5. Houghton J. A., Morton C. L., Adkins D. A., Rahman A. Locus of the interaction among 5-fluorouracil, leucovorin, and interferon-alpha 2a in colon carcinoma cells. Cancer Res. 1993 Sep 15;53(18):4243–4250. [PubMed] [Google Scholar]
  6. Kosmidis P. A., Tsavaris N., Skarlos D., Theocharis D., Samantas E., Pavlidis N., Briassoulis E., Fountzilas G. Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group. J Clin Oncol. 1996 Oct;14(10):2682–2687. doi: 10.1200/JCO.1996.14.10.2682. [DOI] [PubMed] [Google Scholar]
  7. Makower D., Wadler S., Haynes H., Schwartz E. L. Interferon induces thymidine phosphorylase/platelet-derived endothelial cell growth factor expression in vivo. Clin Cancer Res. 1997 Jun;3(6):923–929. [PubMed] [Google Scholar]
  8. Matthews J. N., Altman D. G., Campbell M. J., Royston P. Analysis of serial measurements in medical research. BMJ. 1990 Jan 27;300(6719):230–235. doi: 10.1136/bmj.300.6719.230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Moghaddam A., Bicknell R. Expression of platelet-derived endothelial cell growth factor in Escherichia coli and confirmation of its thymidine phosphorylase activity. Biochemistry. 1992 Dec 8;31(48):12141–12146. doi: 10.1021/bi00163a024. [DOI] [PubMed] [Google Scholar]
  10. Moghaddam A., Zhang H. T., Fan T. P., Hu D. E., Lees V. C., Turley H., Fox S. B., Gatter K. C., Harris A. L., Bicknell R. Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):998–1002. doi: 10.1073/pnas.92.4.998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Moran R. G., Scanlon K. L. Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. Cancer Res. 1991 Sep 1;51(17):4618–4623. [PubMed] [Google Scholar]
  12. O'Brien T. S., Fox S. B., Dickinson A. J., Turley H., Westwood M., Moghaddam A., Gatter K. C., Bicknell R., Harris A. L. Expression of the angiogenic factor thymidine phosphorylase/platelet-derived endothelial cell growth factor in primary bladder cancers. Cancer Res. 1996 Oct 15;56(20):4799–4804. [PubMed] [Google Scholar]
  13. Patterson A. V., Zhang H., Moghaddam A., Bicknell R., Talbot D. C., Stratford I. J., Harris A. L. Increased sensitivity to the prodrug 5'-deoxy-5-fluorouridine and modulation of 5-fluoro-2'-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. Br J Cancer. 1995 Sep;72(3):669–675. doi: 10.1038/bjc.1995.392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ragnhammar P., Blomgren H., Edler D., Lundell G., Magnusson I., Sonnenfeld T. Different dose regimens of 5-fluorouracil and interferon-alpha in patients with metastatic colorectal carcinoma. Eur J Cancer. 1995;31A(3):315–320. doi: 10.1016/0959-8049(94)00510-c. [DOI] [PubMed] [Google Scholar]
  15. Schwartz E. L., Baptiste N., O'Connor C. J., Wadler S., Otter B. A. Potentiation of the antitumor activity of 5-fluorouracil in colon carcinoma cells by the combination of interferon and deoxyribonucleosides results from complementary effects on thymidine phosphorylase. Cancer Res. 1994 Mar 15;54(6):1472–1478. [PubMed] [Google Scholar]
  16. Schwartz E. L., Baptiste N., Wadler S., Makower D. Thymidine phosphorylase mediates the sensitivity of human colon carcinoma cells to 5-fluorouracil. J Biol Chem. 1995 Aug 11;270(32):19073–19077. doi: 10.1074/jbc.270.32.19073. [DOI] [PubMed] [Google Scholar]
  17. Seymour M. T., Johnson P. W., Hall M. R., Wrigley P. F., Slevin M. L. Double modulation of 5-fluorouracil with interferon alpha 2a and high-dose leucovorin: a phase I and II study. Br J Cancer. 1994 Oct;70(4):719–723. doi: 10.1038/bjc.1994.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Seymour M. T., Patel N., Johnston A., Joel S. P., Slevin M. L. Lack of effect of interferon alpha 2a upon fluorouracil pharmacokinetics. Br J Cancer. 1994 Oct;70(4):724–728. doi: 10.1038/bjc.1994.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Seymour M. T., Slevin M. L., Kerr D. J., Cunningham D., James R. D., Ledermann J. A., Perren T. J., McAdam W. A., Harper P. G., Neoptolemos J. P. Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council. J Clin Oncol. 1996 Aug;14(8):2280–2288. doi: 10.1200/JCO.1996.14.8.2280. [DOI] [PubMed] [Google Scholar]
  20. Takahashi Y., Bucana C. D., Akagi Y., Liu W., Cleary K. R., Mai M., Ellis L. M. Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. Clin Cancer Res. 1998 Feb;4(2):429–434. [PubMed] [Google Scholar]
  21. Takebayashi Y., Yamada K., Miyadera K., Sumizawa T., Furukawa T., Kinoshita F., Aoki D., Okumura H., Yamada Y., Akiyama S. The activity and expression of thymidine phosphorylase in human solid tumours. Eur J Cancer. 1996 Jun;32A(7):1227–1232. doi: 10.1016/0959-8049(96)00061-5. [DOI] [PubMed] [Google Scholar]
  22. Wadler S., Goldman M., Lyver A., Wiernik P. H. Phase I trial of 5-fluorouracil and recombinant alpha 2a-interferon in patients with advanced colorectal carcinoma. Cancer Res. 1990 Apr 1;50(7):2056–2059. [PubMed] [Google Scholar]
  23. Wadler S., Horowitz R., Mao X., Schwartz E. L. Effect of interferon on 5-fluorouracil-induced perturbations in pools of deoxynucleotide triphosphates and DNA strand breaks. Cancer Chemother Pharmacol. 1996;38(6):529–535. doi: 10.1007/s002800050522. [DOI] [PubMed] [Google Scholar]
  24. Wadler S., Lembersky B., Atkins M., Kirkwood J., Petrelli N. Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1991 Oct;9(10):1806–1810. doi: 10.1200/JCO.1991.9.10.1806. [DOI] [PubMed] [Google Scholar]
  25. Wadler S., Wersto R., Weinberg V., Thompson D., Schwartz E. L. Interaction of fluorouracil and interferon in human colon cancer cell lines: cytotoxic and cytokinetic effects. Cancer Res. 1990 Sep 15;50(18):5735–5739. [PubMed] [Google Scholar]
  26. Wolmark N., Bryant J., Smith R., Grem J., Allegra C., Hyams D., Atkins J., Dimitrov N., Oishi R., Prager D. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst. 1998 Dec 2;90(23):1810–1816. doi: 10.1093/jnci/90.23.1810. [DOI] [PubMed] [Google Scholar]
  27. Yoshikawa T., Suzuki K., Kobayashi O., Sairenji M., Motohashi H., Tsuburaya A., Nakamura Y., Shimizu A., Yanoma S., Noguchi Y. Thymidine phosphorylase/platelet-derived endothelial cell growth factor is upregulated in advanced solid types of gastric cancer. Br J Cancer. 1999 Mar;79(7-8):1145–1150. doi: 10.1038/sj.bjc.6690182. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES