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A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid

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Summary

Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities.

Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation.

Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance.

The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

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References

  1. Taylor EC, Harrington PJ, Fletcher SR, Beardley GP, Moran RG: Synthesis of the antileukemic agents 5,10-dideazaaminop-terin and 5,10-dideaza-5,6,7,8-tetra-hydroaminopterin. J Med Chem 28:914–921, 1985

    Article  PubMed  CAS  Google Scholar 

  2. Beardsley GP, Moroson BA, Taylor EC, Moran RG: A new folate antimetabolite, 5,10-Dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis. J Biol Chem 264:328–333, 1989

    PubMed  CAS  Google Scholar 

  3. Jansen G, Westerhof GR, Kathmann I, Rijksen G, Schornagel JH: Growth-inhibitory effects of 5,10-dideazatetrahydrofolic acid on variant murine L1210 and human CCRF-CEM leukemia cells with different membrane transport characteristics for (anti)folate compounds. Cancer Chemother Pharmacol 28:115–117, 1991

    Article  PubMed  CAS  Google Scholar 

  4. Shih C, Grindey GB, Houghton PJ, Houghton JA: In vivo antitumour activity of 5,10-Dideazatetrahydrofolic acid (DDATHF) and its diastereomeric isomers. Proc Amer Assoc Cancer Res 29:283, 1988

    Google Scholar 

  5. Nelson R, Butler F, Dugan W Jr, Davisland C, Stone M, Dyke R: Phase I clinical trial of LY264618 (dideazatetrahydrofolic acid; DDATHF). Proc Amer Soc Clin Oncol 9:76, 1990

    Google Scholar 

  6. Ray MS, Muggia FM, Leichman CG, Grunberg SM, Nelson RL, Dyke RW: Phase I study of (6R)-5,10-Dideazatetrahydrofolate: a folate antimetabolite inhibitory to de novo purine synthesis. J Natl Cancer Inst 85:1154–1159, 1993

    PubMed  CAS  Google Scholar 

  7. Pagani O, Sessa C, Dejong J, Kem H, Hatty H, Schmit H, Cavalli F: Phase I study of lometrexol (DDATHF) given in combination with leucovorin. Proc Amer Soc Clin Oncol 11:109, 1992

    Google Scholar 

  8. Lometrexol LY 264618 Clinical Investigation Brochure: Sub-chronic studies, mice 3.30; 3.2, 1992

  9. Young C, Currie V, Baltzer L, Trochanowski B, Eton O, Dyke R, Bowsher R: Phase I and clinical pharmacologic study of LY264618, 5,10-dideazatetrahydrofolate. Proc Amer Assoc Cancer Res 31:177, 1990

    Google Scholar 

  10. Grindey GB, Alati T, Shih C: Reversal of the toxicity but not the antitumour activity of lometrexol by folic acid. Proc Amer Assoc Cancer Res 32:324, 1991

    Google Scholar 

  11. Alati T, Shih C, Pohland RC, Lantz RJ, Grindy GB: Evaluation of the mechanism(s) of inhibition of the toxicity, but not the antitumor activity of lometrexol (DDATHF) by folic aci. Proc Am Assoc Cancer Res 33: 407, 1992

    Google Scholar 

  12. Wedge SR, Laohavinij S, Taylor GA, Boddy A, Calvert AH, Newell DR: Clinical pharmacokinetics of the antipurine antifolate (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) administration with an oral folic acid supplement. Clin Cancer Res 1:1479–1486, 1995

    PubMed  CAS  Google Scholar 

  13. Moran RG, Baldwin SW, Taylor EC, Shih C: The 6S- and 6R- diastereomers of 5,10–5,6,7,8-tetrahydrofolate are equiactive inhibitors de novo purine synthesis. J Biol Chem 264:21047–21051, 1989

    PubMed  CAS  Google Scholar 

  14. Pizzorno G, Cashmore AR, Moroson BA, Beardsley GP: Leucovorin (LV): a “rescue” agent for 6(R)-5,10-dideazatetrahydrofolic acid (DDATHF). Proc AACR 31:339, 1990

    Google Scholar 

  15. Herbert V: Folic acid. Annu Rev Med 16:359–370, 1965

    Article  PubMed  CAS  Google Scholar 

  16. Rossi E, Ferraccioli GF, Cavalieri F, Menta R, Dall'Aglio PP, Migone L: Diclofenac-associated acute renal failure. Nephron 40:491–493, 1985

    Article  PubMed  CAS  Google Scholar 

  17. Clive DM, Stoff JS: Renal syndromes associated with nonsteroidal anti-inflammatory drugs. New Engl J Med 310:563–572, 1984

    Article  PubMed  CAS  Google Scholar 

  18. Zipser RD, Hoefs JC, Speckart PF, Zia PK, Horton R: Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab 48:895–900, 1979

    Article  PubMed  CAS  Google Scholar 

  19. Thyss A, Milano G, Kubar J, Namer M: Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet 256–258, 1986

  20. Ellison NM, Servi RJ: Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration. Cancer Treat Rep 69:342–343, 1985

    PubMed  CAS  Google Scholar 

  21. Fox RM: Methotrexate nephrotoxicity. Clin Exp Pharmacol Physiol 5:43–45, 1979

    PubMed  CAS  Google Scholar 

  22. Jacobs SA, Stoller RG, Chabner BA, Johns DG: 7-Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate. J Clin Invest 57:534–538, 1976

    Article  PubMed  CAS  Google Scholar 

  23. Pitman SW, Parker LM, Tattersall MHN et al.: Clinical trial of high dose methotrexate (NSC-740) with citrovorum factor (NSC-3590)-toxicology and therapeutic observations. Cancer Chemother Rep 6(1):43–49, 1975

    Google Scholar 

  24. Newell DR, Siddik ZH, Calvert AH, Jackman AL, Alison DL, McGhee KG, Harrap KR: Pharmacokinetics and toxicity studies with CB 3717. Proc Amer Assoc Cancer Res 23:181, 1982

    Google Scholar 

  25. Alison DL, Newell DR, Sessa C, Harland SJ, Hart LI, Harrap KR, Calvert AH: The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717). Cancer Chemother Pharmacol 14:265–271, 1985

    Article  PubMed  CAS  Google Scholar 

  26. Pitman SW, Miller D, Weichselbaum R, Frei E: Weekly high dose methotrexate with leucovorin rescue as initial adjuvant therapy in advanced squamous cell carcinoma of the head and neck: a pilot study. In: Salmon SE, Jones SE (eds) Adjuvant Therapy of Cancer. Elsevier/North-Holland Biomedical Press, Amsterdam, 1977, pp 467–473

    Google Scholar 

  27. Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA: Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. New Engl J Med 297:630–634, 1977

    Article  PubMed  CAS  Google Scholar 

  28. Boarman DM, Allegra CJ: Intracellular metabolism of 5-formyl tetrahydrofolate in human breast and colon cell lines. Cancer Res 52:36–44, 1992

    PubMed  CAS  Google Scholar 

  29. Bunni BA, Sirotnak FM, Otter GM, Priest DG: Disposition of leucovorin and its metabolites in the plasma, intestinal epithelium and intraperitoneal L1210 cells of methotrexate-pretreated mice. Cancer Chemother Pharmacol 34:455–458, 1994

    Article  PubMed  CAS  Google Scholar 

  30. Saugstad OD: Hypoxanthine as a measurement of hypoxia. Pediat Res 9:158–161, 1975

    PubMed  CAS  Google Scholar 

  31. Zakaria M, Brown PR, Farnes MP, Barker BE: HPLC analysis of aromatic amino acids, nucleosides and bases in plasma of acute lymphocytic leukemics on chemotherapy. Clin Chim Acta 126:69–80, 1982

    Article  PubMed  CAS  Google Scholar 

  32. Wung WE, Howell SB: Hypoxanthine concentrations in normal subjects and patients with solid tumors and leukemia. Cancer Res 44:3144–3148, 1984

    PubMed  CAS  Google Scholar 

  33. Alati T, Lantz RJ, Grindey GB: Whole-body autoradiographic disposition and plasma pharmacokinetics of 5,10-dideazatetrahydrofolic acid in mice fed folic acid-deficient or regular diets. J Pharm Sci 83:1396–1399, 1994

    PubMed  Google Scholar 

  34. Schmitz JC, Grindey GB, Schultz RM, Priest DG: Impact of dietary folic acid on reduced folates in mouse plasma and tissues. Biochem Pharmacol 48:319–325, 1994

    Article  PubMed  CAS  Google Scholar 

  35. Farber S, Diamond LK, Mercer RD et al.: Temporary remissions in acute leukaemia in children produced by folic acid antagonist 4-amethopteroylglutamic acid (aminopterin). New Engl J Med 238:787–793, 1948

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cancer Research Unit, The Medical School, University of Newcastle-upon-Tyne, NE2 4HH, Framlington Place, Newcastle-upon-Tyne, UK

    Sudsawat Laohavinij, Stephen R. Wedge, Micheal J. Lind, Nigel Bailey, Alison Humphreys, Madeleine Proctor, Fiona Chapman, Dorothy Simmons, Avril Oakley, Lesley Robson, Lyndsey Gumbrell, Gordon A. Taylor, Huw D. Thomas, Alan V. Boddy, David R. Newell & A. Hilary Calvert

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  1. Sudsawat Laohavinij
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  2. Stephen R. Wedge
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  3. Micheal J. Lind
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  4. Nigel Bailey
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  5. Alison Humphreys
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  6. Madeleine Proctor
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  7. Fiona Chapman
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  8. Dorothy Simmons
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  14. Alan V. Boddy
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  15. David R. Newell
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  16. A. Hilary Calvert
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Additional information

Supported by Eli Lilly and Company, Indianapolis, IN, USA. Financial support was also provided by the North of England Cancer Research Campaign.

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Laohavinij, S., Wedge, S.R., Lind, M.J. et al. A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid. Invest New Drugs 14, 325–335 (1996). https://doi.org/10.1007/BF00194536

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