Skip to main content
SpringerLink
Log in

Does Leucovorin Alter the Intratumoral Pharmacokinetics of 5-Fluorouracil (5-FU)? A Southwest Oncology Group Study

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Abstract

Purpose and design: We previouslydocumented that there was an associationbetween the intra-tumoral pharmacokinetics(TPK) of 5-FU and response to therapy with5-FU and leucovorin (p < .0001). Since wehave shown that other modulators of 5-FU,such as methotrexate, interferon andneutrexin alter its TPK, it was of interestto determine if the modulating effect ofleucovorin would also alter the tumoral PKof 5-FU. In order to determine the effectof leucovorin on intratumoral 5-FUpharmacokinetics, 23 patients (21evaluable) underwent 19F magneticresonance spectroscopy 19F-MRS)twice. The first 19F-MRS was following5-FU 600 mg/m2 alone, and the second19F-MRS was following by leucovorin500 mg/m2 and then 5-FU 600 mg/m2.

Results: A comparison of theintratumoral 5-FU pharmacokineticsindicated that there was no general effectof leucovorin on the intratumoral half-lifeof 5-FU. In only two of these 21 patientswas the half-life of 5-FU altered, and inboth cases it was decreased by more than20%. Partial responses to 5-FU plusleucovorin therapy were seen only inpatients with a long intratumoral half-life(trapping) of 5-FU (3 PR in 11 patientswith T1/2 ≥ 20 minutes, comparedto 0 PR in 11 patients with T1/2 <20 minutes). There was a statisticallysignificant correlation between tumorresponse and the intratumoral T1/2 of5-FU, consistent with our prior results ina larger number of patients. However, therewas no statistically significantcorrelation of time-to-progression orsurvival with classification of thepatients into trappers or non-trappers,probably due to the small sample size inthis current study.

Conclusion: The data reported hereare compatible with the hypothesis thatleucovorin enhancement of 5-fluorouracilantitumor responses is not mediated by thelevels of 5-FU in tumors, but rather, isdue to the modulation by leucovorin ofcellular metabolic processes that followthe uptake of free 5-FU into the tumorcell. The MRS technique may be useful inselected instances for elucidating thepossible metabolic interactions of drugsin vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Duschinsky R, Pleven E, Heidelberger C: The synthesis of 5-Fluoropyrimidines. J Am Chem Soc 79:4559–4560, 1957

    Google Scholar 

  2. Smith IC, Hutcheon AW, Heys SD: Current and potential chemotherapeutic agents used for induction chemotherapy in the treatment of breast cancer. Curr Pharm Des 6:327–343, 2000

    Google Scholar 

  3. Kamm YJ, Wagener DJ, Rietjens IM, Punt CJ: 5-Fluorouracil in colorectal cancer: rationale and clinical results of frequently used schedules. Anti-Cancer Drugs 9:371–380, 1998

    Google Scholar 

  4. Clayman GL, Lippman SM, Laramore GE, Hong WK: Head and neck cancer. In: Bast RC, Kufe DW, Pollock RE, Weichselbaum RR, Holland JF, Frei E, III, DeVita VT (eds) Holland-Frei Cancer Medicine, 5th Edition. BC Decker, Inc, Hamilton, Ontario, Canada, 2000, 1985, pp 407–505

    Google Scholar 

  5. Chaudhuri NK, Mukherjee KL, Heidelberger C: Biochem studies on fluorinated pyrimidines. VII. The degradative pathway. Biochem Pharmacol 1:328–341, 1958

    Google Scholar 

  6. Ardalan B, Glazer R: An update on the biochemistry of 5-fluorouracil. Cancer Treat Rev 8:157–167, 1981

    Google Scholar 

  7. Danenberg PV: Thymidylate synthethase - a target enzyme in cancer chemotherapy. Biochem Biophys Acta 473:73–79, 1977

    Google Scholar 

  8. Spiegelman S, Sawyer R, Nayak R, Ritzi E, Stolfi R, Martin D: Improving anti-tumor activity of 5-fluorouracil by increasing its incorporation into RNA via metabolic modulation. Proc Natl Acad Sci 77:4966–4970, 1980

    Google Scholar 

  9. Parker WB, Cheng YC: Metabolism and mechanims of action of 5-Fluorouracol. Pharmacol Therap 48:381–395, 1990

    Google Scholar 

  10. Stevens AN, Morris PG, Iles RA, Sheldon PW, Griffiths JR: 5-Fluorouracil metabolism monitored in vivo by 19F NMR. Br J Canc 50:113–117, 1984

    Google Scholar 

  11. Wolf W, Griffiths JR, Silver M, Bruckner H: Can NMR contribute to the radiopharmacokinetics of 5-fluorouracil in man? J Nucl Med 27:737, 1986 (abstract)

    Google Scholar 

  12. Wolf W, Albright MJ, Silver MS, Weber H, Reichardt U, Sauer R: Fluorine-19 NMR spectroscopic studies of the metabolism of 5-fluorouracil in the liver of patients undergoing chemotherapy. Mag Reson Imaging 5:165–169, 1987

    Google Scholar 

  13. Findlay MPN, Leach MO, Cunningham D, Collins DJ, Paynes GS, Glaholm MJ, Mansi JL, McCready VR: The noninvasive monitoring of low-dose, infusional 5-fluorouracil and its modulation by interferon-alpha using in vivo F-19 magnetic resonance spectroscopy in patients with colorectal cancer. A pilot study. Ann Oncol 4:597–602, 1993

    Google Scholar 

  14. Wolf W, Presant CA, Servis KL, El-Tahtawy A, Albright MJ, Barker PB, Ring R III, Atkinson D, Ong RL, King M, Singh M, Ray M, Wiseman C, Blayney D, Shani J: Tumor trapping of 5-fluorouracil: in vivo 19F-NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits. Proc Natl Acad Sci 87:492–496, 1990

    Google Scholar 

  15. Presant CA, Wolf W, Albright MJ, Servis KL, Ring III, Robert, Atkinson D, Ong RL, Wiseman C, King M, Blayney D, Kennedy P, El-Tahtawy A, Singh M, Shani J: Human tumor 5-fluorouracil trapping: clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy harmacokinetics. J Clin Oncol 8:1868–1873, 1990

    Google Scholar 

  16. Presant CA, Wolf W, Waluch V, Wiseman CL, Kennedy P, Blayney D, Brechner RR: Association of the intratumoral pharmacokinetics of 5-fluorouracil with clinical response: an in vivo 19F nuclear magnetic resonance study. Lancet 343:1184–1187, 1994

    Google Scholar 

  17. Wolf W, Waluch V, Presant CA: Non-invasive 19F-NMRS of fluorouracil in pharmacokinetics and pharmacodynamic studies. NMR in Biomedicine 11:380–387, 1998

    Google Scholar 

  18. Wolf W, Presant CA, Waluch V: 19F-MRS studies of fluorinated drugs in humans. Adv Drug Del Revs 41:55–74, 2000

    Google Scholar 

  19. Presant CA, Wolf W, Waluch V, Wiseman CL, Weitz I, Shani J: Enhancement of 5-fluorouracil uptake in human colorectal and gastric cancers, by interferon or by high-dose methotrexate - An in vivo human study using noninvasive 19F-magnetic resonance spectroscopy. J Clin Oncol 18:255–261, 2000

    Google Scholar 

  20. Findlay MP, Raynaud F, Cunningham D, Iveson A, Collins DJ, and Leach MO: Measurement of plasma 5-fluorouracil by high-performance liquid chromatography with comparison of results to tissue drug levels observed using in vivo 19F magnetic resonance spectroscopy in patients on a protracted venous infusion with or without interferon-alpha. Ann Oncol 7:47–53, 1996

    Google Scholar 

  21. El-Tahtawy A, Wolf W: In vivo measurements of intratumoral metabolism, modulation and pharmacokinetics of 5-fluorouracil using 19F nuclear magnetic resonance spectroscopy. Canc Res 51:5806–5812, 1991

    Google Scholar 

  22. McSheehy PM, Prior MJ, Griffiths JR: Methotrexate increases the activation and cytotoxicity of 5-fluorouracil detected by 19F n.m.r. in vivo. Biochem Soc Trans 17:1050, 1989

    Google Scholar 

  23. McSheehy PM, Prior MJ, Griffiths JR: Enhanced 5-fluorouracil cytotoxicity and elevated 5-fluoronucleotides in the rat Walker carcinosarcoma following methotrexate pretreatment: a 19F-MRS study in vivo. Br J Canc 65:369–375, 1992

    Google Scholar 

  24. Van Triest B, Pinedo HM, Giaccone G, Peters GJ: Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors. Ann Oncol 11:385–391, 2000

    Google Scholar 

  25. Raghunathan K, Priest DG: Modulation of fluorouracil antitumor activity by folic acid in a murine model system. Biochem Pharmacol 58:835–839, 1999

    Google Scholar 

  26. Drake JC, Voeller DM, Allegra CJ, Johnston PG: The effect of dose and interval between 5-fluorouracil and leucovorin on the formation of thymidylate synthase ternary complex in human cancer cells. Br J Canc 71:1145–1150, 1995

    Google Scholar 

  27. Zhang ZG, Rustum YM: Pharmacologic rationale for fluoropyrimidine-leucovorin combination: biochemical mechanisms. Semin Oncol 19(Suppl 4):46–50, 1992

    Google Scholar 

  28. Presant CA, Wolf W, Waluch V, Ardalan B, Brechner R, Wiseman C, Blayney DW, Kennedy P, Southwest Oncology Group (SWOG): Modulation of Intratumoral (IT) 5FU Pharmacokinetics (PK) by Leucovorin (LV) and Methotrexate (M) documented by 19F-magnetic resonance spectroscopy (MRS) - Initial results of Southwest Oncology Group (SWOG) Studies 9006 and 9118. Proc Am Soc Clin Oncol 12:201, 1993

    Google Scholar 

  29. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958

    Google Scholar 

  30. Ojugo AS, McSheehy PM, Stubbs M, Alder G, Bashford CL, Maxwell RJ, Leach MO, Judson IR, Griffiths JR: Influence of pH on the uptake of 5-fluorouracil into isolated tumour cells. Br J Canc 77:873–879, 1998

    Google Scholar 

  31. Ikonte C, Wolf W: The transport of 5-fluorouracil (5-FU) into tumor cells as an active process: studies with Walker 256 tumor cells. Proc Am Assoc Cancer Research 41: #3139, 492, 2000

    Google Scholar 

  32. Wolf W, Ikonte C: Mechanism of the active transport of 5-fluorouracil (5-FU) into Walker 256 tumor cells. Proc Am Assoc Cancer Research 92: #1585, 294, 2001

    Google Scholar 

  33. Blanke CD, Kasimis B, Schein P, Capizzi R, Kurman M: Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer. J Clin Oncol 15:915–920, 1997

    Google Scholar 

  34. Richardet E, Pedraza C, Mickiewicz E, Lerzo G, Bonamasa M, Coppola F, Elli A, Uranga G, Jovtis S, Bruno M, Ventriglia M, Cuevas MA, Alvarez AM, Suarez LA, Fein L: Uracil/tegafur plus oral calcium folinate in advanced breast cancer. Oncology 13(Suppl. 3):96–97, 1999

    Google Scholar 

  35. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485–493, 1999

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Southwest Oncology Group Statistical Center, Seattle, WA

    Cary A. Presant & Joth Jacobson

  2. California Cancer Medical Center, West Covina, CA

    Cary A. Presant

  3. St. Vincent's CCC, New York, NY, USA

    Cary A. Presant

  4. Los Angeles Oncologic Institute, St. Vincent Medical Center, Los Angeles, CA

    Walter Wolf & Victor Waluch

  5. Pharmacokinetic Imaging Program, University of Southern California, Los Angeles, CA, USA

    Walter Wolf & Victor Waluch

  6. California Cancer Medical Center, West Covina, CA, USA

    Ilene C. Weitz

  7. St. Vincent's CCC, New York, NY, USA

    John S. Macdonald

Authors
  1. Cary A. Presant
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joth Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Walter Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Victor Waluch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ilene C. Weitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John S. Macdonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Presant, C.A., Jacobson, J., Wolf, W. et al. Does Leucovorin Alter the Intratumoral Pharmacokinetics of 5-Fluorouracil (5-FU)? A Southwest Oncology Group Study. Invest New Drugs 20, 369–376 (2002). https://doi.org/10.1023/A:1020651311866

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020651311866

Search

Navigation