Cancer Chemotherapy and Pharmacology

, Volume 31, Issue 4, pp 269–276 | Cite as

Prolonged retention of high concentrations of 5-fluorouracil in human and murine tumors as compared with plasma

  • G. J. Peters
  • J. Lankelma
  • R. M. Kok
  • P. Noordhuis
  • C. J. van Groeningen
  • C. L. van der Wilt
  • S. Meyer
  • H. M. Pinedo
Original Articles 5-Fluorouracil, 5-Fluoro-2′-Deoxy-5′-Monophosphate, Tissue Pharmacokinetics, Plasma Pharmacokinetics

Summary

Concentrations of 5-fluorouracil (5-FU) and its active metabolite 5-fluoro-2′-deoxy-5′-monophosphate (FdUMP) were measured in biopsy specimens of tumor tissue, normal mucosa, metastatic liver nodules, and normal liver tissue obtained from 39 patients and in two murine colon tumors (colon 26 and colon 38) after a single injection of 5FU at a therapeutic dose (500 mg/m2 and 100 mg/kg, respectively). These data were compared with plasma concentrations. Peak plasma concentrations (300–500 μm) of 5FU were comparable in human and murine plasma. The half-life of plasma elimination (during the period from 15 to 120 min) in both mouse and man ranged from 10 to 20 min, whereas at between 2 and 8 h, plasma concentrations varied from 0.1 to 1 μm, the half-life being about 100 min. In both species, 5FU could be measured in plasma at concentrations ranging from 0.01 to 1 μm for several days after 5FU treatment. 5FU concentrations in tissue samples obtained from 14 patients were measured during the time range of 1–6 h, those in samples taken from 7 patients, during the interval of 19–27 h; and those in samples obtained from 18 patients, within the interval of 40–48 h after injection. 5FU tumor concentrations varied between 0.78–21.6, 0.44–6.1, and 0.17–10.8 μmol/kg wet wt., respectively. Some of the 48-h samples were obtained from patients who had received leucovorin plus 5FU; coadministration of leucovorin did not alter 5FU tissue concentrations. At between 4 and 48 h, the tissue concentration/plasma concentration ratio was at least 10. 5FU concentrations in murine tumors were measured for up to 10 days after 5FU administration, with plateau 5FU tumor concentrations being about 50 μmol/kg wet wt. in colon 38 and about 200 μmol/kg wet wt. in colon 26 at 2 h after treatment; after 4 days, values of 0.5 and 4.8 μmol/kg, respectively, were obtained and after 10 days, respective concentrations of 0.1 and 0.07 μmol/kg were detected. The FdUMP concentrations measured in colon 26 and colon 38 tumors were 214 and 46 pmol/g, respectively, at 2 h after 5FU administration, and these values subsequently decreased to about 15 pmol/g in both tumors. In human tumors the initial FdUMP concentration ranged from 10 to 1000 pmol/g; at later time points the level of FdUMP was just above the detection limit of the assay. In liver metastases, high 5FU concentrations seemed to be related to high levels of FdUMP, which was likely of importance for the antitumor effect. The prolonged retention of 5FU should be taken into consideration in the design of biochemical modulation studies.

Keywords

Plasma Concentration Leucovorin Peak Plasma Concentration Normal Mucosa Metastatic Liver 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bates CD, Watson DG, Willmott N, Logan H, Golberg J (1991) The analysis of 5-fluorouracil in human plasma by gas chromatography-negative ion chemical ionization mass spectrometry (GC-NICIMS) with stable isotope dilution. J Pharm Biomed Anal 9: 19–21Google Scholar
  2. 2.
    Byfield JE (1988) 5-Fluorouracil radiation sensitization—a brief review. Invest New Drugs 7: 111–116Google Scholar
  3. 3.
    Collins JM (1985) Pharmacokinetics of 5-fluorouracil infusion in the rat: comparison with man and other species. Cancer Chemother Pharmacol 14: 108–111Google Scholar
  4. 4.
    Danenberg PV (1977) Thymidylate synthetase—a target enzyme in cancer chemotherapy. Biochim Biophys Acta 473: 73–92Google Scholar
  5. 5.
    De Bruijn EA, Remeyer L, Tjaden UR, Erkelens C, De Brauw LM, Van de Velde CJH (1986) Non-linear pharmacokinetics of 5-fluorouracil. Biochem Pharmacol 35: 2461–2465Google Scholar
  6. 6.
    Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16: 215–237Google Scholar
  7. 7.
    Domin BA, Mahony WB (1990) 5-Fluorouracil transport into human erythrocytes (abstract 59). Proc Am Assoc Cancer Res 31: 10Google Scholar
  8. 8.
    Donelli MG, D'Incalci M, Garattini S (1984) Pharmacokinetics studies of anticancer drugs in tumor-bearing animals. Cancer Treat Rep 68: 381–400Google Scholar
  9. 9.
    Doong SL, Dolnick BJ (1988) 5-Fluorouracil substitution alters pre-mRNA splicing in vitro. J Biol Chem 263: 4467–4473Google Scholar
  10. 10.
    El Hag IA, Jakobsson B, Christensson PI, Ericksen C, Joensson PE, Stenram U (1987) Modulation of 5-fluorouracil toxicity by uridine, deoxyuridine, orotate and dipyridamole in normal tissues of rats with liver adenocarcinoma. In Vivo 1: 309–312Google Scholar
  11. 11.
    Finan PJ, Chisholm EM, Woodhouse L, Giles GR (1987) The relationship between plasma pharmacokinetics and tissue metabolites of 5-fluorouracil (5-FU) in patients with colorectal cancer. Eur J Surg Oncol 13: 349–353Google Scholar
  12. 12.
    Finn C, Sadée W (1975) Determination of 5-fluorouracil (NSC-19893) plasma levels in rats and man by isotope dilution-mass fragmentography. Cancer Chemother Rep 59: 279–286Google Scholar
  13. 13.
    Guerquin-Kern JL Leteurtre F, Croisy A, Lloste J-M (1991) pH Dependence of 5-fluorouracil uptake observed by in vivo31P and19F nuclear magnetic resonance spectroscopy. Cancer Res 51: 5770–5773Google Scholar
  14. 14.
    Hull WE, Port RE, Herrmann R, Britsch B, Kund W (1988) Metabolites of 5-fluorouracil in plasma and urine, as monitored by19F nuclear magnetic resonance spectroscopy, for patients receiving chemotherapy with or without methotrexate pretreatment. Cancer Res 48: 1680–1688Google Scholar
  15. 15.
    Kok RM, De Jong APJM, Van Groeningen CJ, Peters GJ, Lankelma J (1985) Highly sensitive determination of 5-fluorouracil in human plasma by capillary gas chromatography and negative ion chemical ionization mass spectrometry. J Chromatogr 343: 59–66Google Scholar
  16. 16.
    Liss RH, Chadwick M (1974) Correlation of 5-fluorouracil (NSC-19893) distribution in rodents with toxicity and chemotherapy in man. Cancer Chemother Rep 58: 777–786Google Scholar
  17. 17.
    Lönn U, Lönn S (1988) Increased levels of DNA lesions induced by leucovorin-5-fluoropyrimidine in human colon adenocarcinoma. Cancer Res 48: 4153–4157Google Scholar
  18. 18.
    Malet-Martino MC, Martino R (1989) The application of nuclear magnetic resonance spectroscopy to drug metabolism studies. Xenobiotica 19: 583–607Google Scholar
  19. 19.
    Marsh JC, Bertino JR, Katz KH (1991) The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer. J Clin Oncol 9: 371–380Google Scholar
  20. 20.
    McSheehy PMJ, Prior MJW, Griffiths JR (1989) Prediction of 5-fluorouracil cytotoxicity towards the Walker carcinosarcoma using peak integrals of fluoronucleotides measured by MRS in vivo. Br J Cancer 60: 303–309Google Scholar
  21. 21.
    Moran RG, Scanlon KL (1991) Schedule dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. Cancer Res 51: 4618–4623Google Scholar
  22. 22.
    Peters GJ, Van Groeningen CJ (1991) Clinical relevance of biochemical modulation of 5-fluorouracil. Ann Oncol 2: 469–480Google Scholar
  23. 23.
    Peters GJ, Laurensse E, Leyva A, Pinedo HM (1986) Tissue homogenization using a microdismembrator for the measurement of enzyme activities. Clin Chim Acta 158:1983–1986Google Scholar
  24. 24.
    Peters GJ, Van Groeningen CJ, Laurensse E, Lankelma J, Leyva A, Pinedo HM (1987) Uridine-induced hypothermia in mice and rats in relation to plasma and tissue levels of uridine and its metabolites. Cancer Chemother Pharmacol 20: 101–108Google Scholar
  25. 25.
    Peters GJ, Van Dijk J, Nadal J, Van Groeningen CJ, Lankelma J, Pinedo HM (1987) Diurnal variation in the therapeutic efficacy of 5-fluorouracil against murine colon cancer. In Vivo 1: 113–118Google Scholar
  26. 26.
    Peters GJ, Van Dijk J, Laurensse E, Van Groeningen CJ, Lankelma J, Leyva A, Nadal JC, Pinedo HM (1988) In vitro biochemical and in vivo biological studies of the uridine “rescue” of 5-fluorouracil. Br J Cancer 57: 259–265Google Scholar
  27. 27.
    Peters GJ, Van Groeningen CJ, Laurensse E, Pinedo HM (1991) A comparison of 5-fluorouracil metabolism in human colorectal cancer and colon mucosa. Cancer 68:1903–1909Google Scholar
  28. 28.
    Peters GJ, Van Groeningen CJ, Van der Wilt CL, Smid K, Meijer S, Pinedo HM (1991) Effect of leucovorin on 5-fluorouracil induced inhibition of thymidylate synthase in patients with colorectal cancer. Adv Exp Med Biol 309A: 131–134Google Scholar
  29. 29.
    Pinedo HM, Peters GJ (1988) 5-Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6: 1653–1664Google Scholar
  30. 30.
    Port RE, Bachert P, Semmler W (1991) Kinetic modeling of in vivo nuclear magnetic resonance spectroscopy data: 5-fluorouracil in liver and liver tumors. Clin Pharmacol Ther 49: 497–505Google Scholar
  31. 31.
    Semmler W, Bachert-Baumann P, Gückel F, Ermark F, Schlag P, Lorenz WJ, Van Kaick G (1990) Real-time follow-up of 5-fluorouracil metabolism in the liver of tumor patients by means of F-19 MR spectroscopy. Radiology 174: 141–145Google Scholar
  32. 32.
    Shani J, Wolf W, Schlesinger T (1978) Distribution of [18F]-5-fluorouracil in tumor-bearing mice and rats. Int J Nucl Med Biol 5: 19–28Google Scholar
  33. 33.
    Smith, P, Mirabelli C, Fondacaro J, Ryan F, Dent J (1988) Intestinal 5-fluorouracil absorption: use of ussing chambers to assess transport and metabolism. Pharm Res 5: 598–603Google Scholar
  34. 34.
    Spoelstra EC, Pinedo HM, Dekker H, Peters GJ, Lankelma J (1991) Measurement of in vitro cellular pharmacokinetics of 5-fluorouracil in human and rat cancer cell lines and rat hepatocytes using a flow-through system. Cancer Chemother Pharmacol 27: 320–325Google Scholar
  35. 35.
    Stevens AN, Morris PG, Iles RA, Sheldon PW, Griffiths JR (1984) 5-Fluorouracil metabolism monitored in vivo by19F NMR. Br J Cancer 50: 113–117Google Scholar
  36. 36.
    Van der Wilt CL, Pinedo HM, Smid K, Peters GJ (1992) Elevation of thymidylate synthase following 5-fluorouracil treatment is prevented by the addition of leucovorin in murine colon cancers. Cancer Res 52: 4922–4929Google Scholar
  37. 37.
    Van Groeningen CJ, Pinedo HM, Heddes J, Kok RM, De Jong APJM, Wattel E, Peters GJ, Lankelma J (1988) Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients during a dose escalation schedule. Cancer Res 48: 6956–6961Google Scholar
  38. 38.
    Visser GWM, Gorrée GCM, Peters GJ, Herscheid JDM (1990) On parameters that may influence the tissue distribution of 5-fluorouracil in mice. Cancer Chemother Pharmacol 26: 205–209Google Scholar
  39. 39.
    Wohlhueter RM, McIvor RS, Plagemann PGW (1980) Facilitated transport of uracil and 5-fluorouracil and permeation of orotic acid into cultured cells. J Cell Physiol 104: 309–319Google Scholar
  40. 40.
    Wolf W, Presant CA, Servis KL, El-Tahlawy A, Albright MJ, Barker PB, Ring, R III, Atkinson D, Ong R, King M, Singh M, Ray M, Wiseman C, Blaney D, Shani J (1990) Tumor trapping of 5-fluorouracil: in vivo19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits. Proc Natl Acad Sci USA 87: 492–496Google Scholar
  41. 41.
    Yamamoto S, Kawasaki T (1981) Active transport of 5-fluorouracil and its energy coupling in Ehrlich ascites tumor cells. J Biochem 90: 635–642Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • G. J. Peters
    • 1
  • J. Lankelma
    • 1
  • R. M. Kok
    • 2
  • P. Noordhuis
    • 1
  • C. J. van Groeningen
    • 1
  • C. L. van der Wilt
    • 1
  • S. Meyer
    • 3
  • H. M. Pinedo
    • 1
    • 4
  1. 1.Department of OncologyFree University HospitalAmsterdamThe Netherlands
  2. 2.Dept of PediatricsFree University HospitalAmsterdamThe Netherlands
  3. 3.Dept of SurgeryFree University HospitalAmsterdamThe Netherlands
  4. 4.Netherlands Cancer InstituteAmsterdamThe Netherlands

Personalised recommendations