Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 6, pp 1125–1130 | Cite as

Clinical potency of methotrexate, aminopterin, talotrexin and pemetrexed in childhood leukemias

  • Robin E. Norris
  • Peter C. Adamson
Original Article

Abstract

Purpose

Renewed interest in antifols for the treatment of childhood cancers has resulted from identification of novel antifols with broad spectrums of anti-cancer activity and from re-evaluation of the original clinical antifol, aminopterin. In this pre-clinical study we evaluated the in vitro activity of both traditional antifols (methotrexate, aminopterin) and novel antifols (pemetrexed, talotrexin) in childhood acute leukemias and lymphomas.

Methods

We compared the in vitro cytotoxicity of methotrexate, aminopterin, pemetrexed, and talotrexin in a panel of six pediatric leukemia and lymphoma cell lines using the sulforhodamine B assay. In addition to defining a 50% growth inhibitory concentration (IC50) for a 120-h drug exposure, we contrasted the activity of the drugs in the context of clinically achievable (tolerable) drug exposures using the area under the plasma concentration–time curve (AUC). We defined each agent’s clinical potency index (CPI) as the AUC achieved with standard pediatric dosing regimens divided by the in vitro IC50.

Results

Across all cell lines, talotrexin (median IC50 7 nM) and aminopterin (median IC50 17 nM) had lower IC50’s than methotrexate (median IC50 78 nM) and pemetrexed (median IC50 155 nM). However, the CPI for methotrexate (median 0.9) was significantly greater than that for aminopterin (median 0.4). In contrast, pemetrexed had a significantly better CPI (median 13) than the traditional antifols.

Conclusions

Aminopterin does not appear to offer any advantage over methotrexate for the treatment of childhood ALL. Further study of pemetrexed in childhood leukemias is warranted.

Keywords

Antifol Methotrexate Aminopterin Pemetrexed Talotrexin In vitro 

Notes

Acknowledgments

This work was supported by the T32-CA09615 grant from the National Institute of Health and the Alex’s Lemonade Stand Young Investigator Grant.

References

  1. 1.
    Adamson PC, Balis FM, Miser J, Arndt C, Wells RJ, Gillespie A, Aronson L, Penta JS, Clendeninn NJ, Poplack DG (1992) Pediatric phase I trial, pharmacokinetic study, and limited sampling strategy for piritrexim administered on a low-dose, intermittent schedule. Cancer Res 52:521–524PubMedGoogle Scholar
  2. 2.
    Balis FM, Patel R, Luks E, Doherty KM, Holcenberg JS, Tan C, Reaman GH, Belasco J, Ettinger LJ, Zimm S et al (1987) Pediatric phase I trial and pharmacokinetic study of trimetrexate. Cancer Res 47:4973–4976PubMedGoogle Scholar
  3. 3.
    Balis FM, Savitch JL, Bleyer WA (1983) Pharmacokinetics of oral methotrexate in children. Cancer Res 43:2342–2345PubMedGoogle Scholar
  4. 4.
    Burchenal JH, Karnofsky DA, Kingsley-Pillers EM, Southam CM, Myers WP, Escher GC, Craver LF, Dargeon HW, Rhoads CP (1951) The effects of the folic acid antagonists and 2, 6-diaminopurine on neoplastic disease, with special reference to acute leukemia. Cancer 4:549–569CrossRefPubMedGoogle Scholar
  5. 5.
    Cao S, McGuire JJ, Rustum YM (1999) Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine. Clin Cancer Res 5:1925–1934PubMedGoogle Scholar
  6. 6.
    Cohen MH, Johnson JR, Wang YC, Sridhara R, Pazdur R (2005) FDA drug approval summary: pemetrexed for injection (Alimta) for the treatment of non-small cell lung cancer. Oncologist 10:363–368CrossRefPubMedGoogle Scholar
  7. 7.
    Cole PD, Drachtman RA, Masterson M, Smith AK, Glod J, Zebala JA, Lisi S, Drapala DA, Kamen BA (2008) Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia. Cancer Chemother Pharmacol 62:65–75CrossRefPubMedGoogle Scholar
  8. 8.
    Cole PD, Drachtman RA, Smith AK, Cate S, Larson RA, Hawkins DS, Holcenberg J, Kelly K, Kamen BA (2005) Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clin Cancer Res 11:8089–8096CrossRefPubMedGoogle Scholar
  9. 9.
    Estlin EJ, Pinkerton CR, Lewis IJ, Lashford L, McDowell H, Morland B, Kohler J, Newell DR, Boddy AV, Taylor GA, Price L, Ablett S, Hobson R, Pitsiladis M, Brampton M, Clendeninn N, Johnston A, Pearson AD (2001) A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children’s Cancer Study Group Investigation. Br J Cancer 84:11–18CrossRefPubMedGoogle Scholar
  10. 10.
    Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 238:787–793PubMedCrossRefGoogle Scholar
  11. 11.
    Giles F, Rizzieri DA, George S, Stock W, Fontanilla J, Choy GS, Berk GI (2006) A phase I study of Talvesta(R) (Talotrexin) in relapsed or refractory leukemia or myelodysplastic syndrome. Blood (ASH Annual Meeting Abstracts) 108: 1968Google Scholar
  12. 12.
    Hazarika M, White RM Jr, Booth BP, Wang YC, Ham DY, Liang CY, Rahman A, Gobburu JV, Li N, Sridhara R, Morse DE, Lostritto R, Garvey P, Johnson JR, Pazdur R (2005) Pemetrexed in malignant pleural mesothelioma. Clin Cancer Res 11:982–992PubMedGoogle Scholar
  13. 13.
    Holford NHG (2007) Pharmacokinetics & Pharmacodynamics: rational dosing & the time course of drug action. In: Katzung BG (ed) Basic and Clinical Pharmacology. McGraw-Hill, New York, pp 34–49Google Scholar
  14. 14.
    Horton TM, Blaney SM, Langevin AM, Kuhn J, Kamen B, Berg SL, Bernstein M, Weitman S (2005) Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a Pediatric Oncology Group study. Clin Cancer Res 11:1884–1889CrossRefPubMedGoogle Scholar
  15. 15.
    Jackman AL, Taylor GA, Calvert AH, Harrap KR (1984) Modulation of anti-metabolite effects. Effects of thymidine on the efficacy of the quinazoline-based thymidylate synthetase inhibitor, CB3717. Biochem Pharmacol 33:3269–3275CrossRefPubMedGoogle Scholar
  16. 16.
    Johnson JM, Meiering EM, Wright JE, Pardo J, Rosowsky A, Wagner G (1997) NMR solution structure of the antitumor compound PT523 and NADPH in the ternary complex with human dihydrofolate reductase. Biochemistry 36:4399–4411CrossRefPubMedGoogle Scholar
  17. 17.
    Jonsson OG, Kamen BA (1991) Methotrexate and childhood leukemia. Cancer Invest 9:53–60CrossRefPubMedGoogle Scholar
  18. 18.
    Kim HM, Han SB, Kim MS, Kang JS, Oh GT, Hong DH (1996) Efficient fixation procedure of human leukemia cells in sulforhodamine B cytotoxicity assay. J Pharmacol Toxicol Methods 36:163–169CrossRefPubMedGoogle Scholar
  19. 19.
    Malempati S, Nicholson HS, Reid JM, Blaney SM, Ingle AM, Krailo M, Stork LC, Melemed AS, McGovern R, Safgren S, Ames MM, Adamson PC (2007) Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: the Children’s Oncology Group. J Clin Oncol 25:1505–1511CrossRefPubMedGoogle Scholar
  20. 20.
    Matloub Y, Bostrom BC, Hunger SP, Angiolillo AL, Cole C, Thomson B, Devidas M, Heerema NA, La MK, Buckley PJ, Carroll WL, Winick N, Sather H, Nachman JB, Gaynon PS (2008) Escalating dose intravenous methotrexate without leucovorin rescue during interim maintenance is superior to oral methotrexate for children with standard risk acute lymphoblastic leukemia (SR-ALL): Children’s Oncology Group study 1991. ASH annual meeting abstracts 112: 9Google Scholar
  21. 21.
    Messmann RA, Allegra CJ (2001) Antifolates. In: Chabner BA, Longo DL (eds) Cancer Chemotherapy & Biotherapy. Lippincott Williams & Wilkins, Philadephia, pp 139–184Google Scholar
  22. 22.
    Monahan BP, Allegra CJ (2006) Antifolates. In: Chabner BA, Longo DL (eds) Cancer Chemotherapy & Biotherapy: Principles and Practice. Lippincott Williams & Wilkins, Philadelphia, pp 91–124Google Scholar
  23. 23.
    Oettgen HF, Burkitt D, Burchenal JH (1963) Malignant lymphoma involving the jaw in African children: treatment with methotrexate. Cancer 16:616–623CrossRefPubMedGoogle Scholar
  24. 24.
    Ratliff AF, Wilson J, Hum M, Marling-Cason M, Rose K, Winick N, Kamen BA (1998) Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies. J Clin Oncol 16:1458–1464PubMedGoogle Scholar
  25. 25.
    Rosowsky A, Bader H, Cucchi CA, Moran RG, Kohler W, Freisheim JH (1988) Methotrexate analogues. 33. N delta-acyl-N alpha-(4-amino-4-deoxypteroyl)-l-ornithine derivatives: synthesis and in vitro antitumor activity. J Med Chem 31:1332–1337CrossRefPubMedGoogle Scholar
  26. 26.
    Rosowsky A, Bader H, Wright JE, Keyomarsi K, Matherly LH (1994) Synthesis and biological activity of N-omega-hemiphthaloyl-alpha, omega- diaminoalkanoic acid analogues of aminopterin and 3′, 5-dichloroaminopterin. J Med Chem 37:2167–2174CrossRefPubMedGoogle Scholar
  27. 27.
    Rosowsky A, Forsch RA, Wright JE (2004) Synthesis and in vitro antifolate activity of rotationally restricted aminopterin and methotrexate analogues. J Med Chem 47:6958–6963CrossRefPubMedGoogle Scholar
  28. 28.
    Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF, Andis SL, Bewley JR, Rayl EA, Moroson BA, Beardsley GP, Kohler W, Ratnam M, Schultz RM (1997) LY231514, a pyrrolo[2, 3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57:1116–1123PubMedGoogle Scholar
  29. 29.
    Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM (1998) Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul 38:135–152CrossRefPubMedGoogle Scholar
  30. 30.
    Skeel RT, Cashmore AR, Sawicki WL, Bertino JR (1976) Clinical and pharmacological evaluation of triazinate in humans. Cancer Res 36:48–54PubMedGoogle Scholar
  31. 31.
    Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112CrossRefPubMedGoogle Scholar
  32. 32.
    Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG (1992) A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3, 4-dihydro-4-oxo-7H-pyrrolo[2, 3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 35:4450–4454CrossRefPubMedGoogle Scholar
  33. 33.
    Tickoo V, Dey E (2007) UPDATE 2-Hana product development faces setback; shares tank. http://www.reuters.com. Thomson Reuters, Bangalore
  34. 34.
    Westerhof GR, Schornagel JH, Kathmann I, Jackman AL, Rosowsky A, Forsch RA, Hynes JB, Boyle FT, Peters GJ, Pinedo HM et al (1995) Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity. Mol Pharmacol 48:459–471PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Division of Clinical Pharmacology and Therapeutics, Children’s Hospital of PhiladelphiaAbramson Research CenterPhiladelphiaUSA
  2. 2.Division of Oncology, Division of Clinical Pharmacology and TherapeuticsChildren’s Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations