Journal of Neuro-Oncology

, 90:309

Valproic acid was well tolerated in heavily pretreated pediatric patients with high-grade glioma

  • Johannes E. A. Wolff
  • Christof Kramm
  • Rolf-Dieter Kortmann
  • Torsten Pietsch
  • Stefan Rutkowski
  • Norbert Jorch
  • Astrid Gnekow
  • Pablo Hernáiz Driever
Clinical Study - Patient Study

Abstract

Valproic acid (VPA) inhibits histone deacetylase and has been reported to induce apoptosis in glioma. We report 44 heavily pretreated pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma who received VPA as oral continues maintenance treatment with individual dose adaptation. The tumor status when starting the drug was: no measurable disease in 12, measurable but stable disease in 12, and measurable progressive disease in 22 patients. Average trough blood levels of VPA were 99 mg/l. The most frequent complaint was somnolence (three patients), but no severe toxicity was reported. One relapse patient responded, early progression of disease was observed in three frontline patients and in six relapsed patients. Median overall survival duration for all patients was 1.33 years, with large differences between first-line (5-year overall survival, 44%) and relapse therapy (5-year overall survival, 14%). This shows that valproate is safe in this patient population. The moderate tumor efficacy encourages studying the drug further as an element of multi-agent protocols.

Keywords

Valproic acid Glioblastoma Anaplastic astrocytomas Pontine glioma Child Adolescent 

References

  1. 1.
    Lance JW, Anthony M (1975) Sodium valproate in the management of intractable epilepsy: comparison with clonazepam. Proc Aust Assoc Neurol 12:55–60PubMedGoogle Scholar
  2. 2.
    Post RM, Uhde TW (1983) Treatment of mood disorders with antiepileptic medications: clinical and theoretical implications. Epilepsia 24(Suppl 2):S97–S108. doi:10.1111/j.1528-1157.1983.tb04652.x PubMedCrossRefGoogle Scholar
  3. 3.
    Anthony M, Hinterberger H, Lance JW (1977) Plasma sodium valproate levels and clinical response in epilepsy. Clin Exp Neurol 14:208–215PubMedGoogle Scholar
  4. 4.
    Limdi NA, Knowlton RK, Cofield SS, Ver Hoef LW, Paige AL, Dutta S et al (2007) Safety of rapid intravenous loading of valproate. Epilepsia 48:478–483. doi:10.1111/j.1528-1167.2007.00989.x PubMedCrossRefGoogle Scholar
  5. 5.
    Brown NA, Kao J, Fabro S (1980) Teratogenic potential of valproic acid. Lancet 1:660–661. doi:10.1016/S0140-6736(80)91159-9 PubMedCrossRefGoogle Scholar
  6. 6.
    Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV (1993) Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1383–1388. doi:10.1056/NEJM199311043291904 PubMedCrossRefGoogle Scholar
  7. 7.
    Regan CM (1985) Therapeutic levels of sodium valproate inhibit mitotic indices in cells of neural origin. Brain Res 347:394–398. doi:10.1016/0006-8993(85)90207-0 PubMedCrossRefGoogle Scholar
  8. 8.
    Selby R, Nisbet-Brown E, Basran RK, Chang L, Olivieri NF (1997) Valproic acid and augmentation of fetal hemoglobin in individuals with and without sickle cell disease. Blood 90:891–893PubMedGoogle Scholar
  9. 9.
    Kieslich M, Schwabe D, Cinatl J Jr, Driever PH (2003) Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Pediatr Hematol Oncol 20:15–22. doi:10.1080/713842215 PubMedCrossRefGoogle Scholar
  10. 10.
    Knupfer MM, Hernaiz-Driever P, Poppenborg H, Wolff JE, Cinatl J (1998) Valproic acid inhibits proliferation and changes expression of CD44 and CD56 of malignant glioma cells in vitro. Anticancer Res 18:3585–3589PubMedGoogle Scholar
  11. 11.
    Driever PH, Knupfer MM, Cinatl J, Wolff JE (1999) Valproic acid for the treatment of pediatric malignant glioma. Klin Padiatr 211:323–328PubMedGoogle Scholar
  12. 12.
    Witt O, Schweigerer L, Driever PH, Wolff J, Pekrun A (2004) Valproic acid treatment of glioblastoma multiforme in a child. Pediatr Blood Cancer 43:181. doi:10.1002/pbc.20083 PubMedCrossRefGoogle Scholar
  13. 13.
    Driever PH, Wagner S, Hofstadter F, Wolff JE (2004) Valproic acid induces differentiation of a supratentorial primitive neuroectodermal tumor. Pediatr Hematol Oncol 21:743–751. doi:10.1080/08880010490514985 PubMedCrossRefGoogle Scholar
  14. 14.
    Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741. doi:10.1074/jbc.M101287200 PubMedCrossRefGoogle Scholar
  15. 15.
    Das CM, Aguilera D, Vasquez H, Prasad P, Zhang M, Wolff JE et al (2007) Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol 85:159–170. doi:10.1007/s11060-007-9402-7 PubMedCrossRefGoogle Scholar
  16. 16.
    Blaheta RA, Michaelis M, Driever PH, Cinatl J Jr (2005) Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev 25:383–397. doi:10.1002/med.20027 PubMedCrossRefGoogle Scholar
  17. 17.
    Dong G, Wang L, Wang CY, Yang T, Kumar MV, Dong Z (2008) Induction of apoptosis in renal tubular cells by histone deacetylase inhibitors, a family of anticancer agents. J Pharmacol Exp Ther 325:978–984. doi:10.1124/jpet.108.137398 PubMedCrossRefGoogle Scholar
  18. 18.
    Johnson J, Pahuja A, Graham M, Hering B, Hancock WW, Bansal-Pakala P (2008) Effects of histone deacetylase inhibitor SAHA on effector and FOXP3+ regulatory T cells in rhesus macaques. Transplant Proc 40:459–461. doi:10.1016/j.transproceed.2008.01.039 PubMedCrossRefGoogle Scholar
  19. 19.
    Huang L, Sowa Y, Sakai T, Pardee AB (2000) Activation of the p21WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites. Oncogene 19:5712–5719. doi:10.1038/sj.onc.1203963 PubMedCrossRefGoogle Scholar
  20. 20.
    Yi X, Wei W, Wang SY, Du ZY, Xu YJ, Yu XD (2008) Histone deacetylase inhibitor SAHA induces ERalpha degradation in breast cancer MCF-7 cells by CHIP-mediated ubiquitin pathway and inhibits survival signaling. Biochem Pharmacol 75:1697–1705. doi:10.1016/j.bcp. 2007.10.035 PubMedCrossRefGoogle Scholar
  21. 21.
    Domingo-Domènech J, Pippa R, Tápia M, Gascón P, Bachs O, Bosch M (2008) Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells. Breast Cancer Res Treat (in press)Google Scholar
  22. 22.
    Carlisi D, Vassallo B, Lauricella M, Emanuele S, D’Anneo A, Di Leonardo E et al (2008) Histone deacetylase inhibitors induce in human hepatoma HepG2 cells acetylation of p53 and histones in correlation with apoptotic effects. Int J Oncol 32:177–184PubMedGoogle Scholar
  23. 23.
    Hassig CA, Symons KT, Guo X, Nguyen PM, Annable T, Wash PL et al (2008) KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 7:1054–1065. doi:10.1158/1535-7163.MCT-07-2347 PubMedCrossRefGoogle Scholar
  24. 24.
    Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A et al (2008) MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 7:759–768. doi:10.1158/1535-7163.MCT-07-2026 PubMedCrossRefGoogle Scholar
  25. 25.
    Petrella A, D’Acunto CW, Rodriquez M, Festa M, Tosco A, Bruno I et al (2008) Effects of FR235222, a novel HDAC inhibitor, in proliferation and apoptosis of human leukaemia cell lines: role of annexin A1. Eur J Cancer 44:740–749. doi:10.1016/j.ejca.2008.01.023 PubMedCrossRefGoogle Scholar
  26. 26.
    Spiller SE, Ditzler SH, Pullar BJ, Olson JM (2008) Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA). J Neurooncol 87:133–141. doi:10.1007/s11060-007-9505-1 PubMedCrossRefGoogle Scholar
  27. 27.
    Blumenschein GR Jr, Kies MS, Papadimitrakopoulou VA, Lu C, Kumar AJ, Ricker JL et al (2008) Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs 26:81–87. doi:10.1007/s10637-007-9075-2 PubMedCrossRefGoogle Scholar
  28. 28.
    Atmaca A, Al-Batran SE, Maurer A, Neumann A, Heinzel T, Hentsch B et al (2007) Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial. Br J Cancer 97:177–182. doi:10.1038/sj.bjc.6603851 PubMedCrossRefGoogle Scholar
  29. 29.
    Wolff JE, Boos J, Kuhl J (1996) HIT-GBM: multicenter study of treatment of children with malignant glioma. Klin Padiatr 208:193–196PubMedGoogle Scholar
  30. 30.
    Bouffet E, Khelfaoui F, Philip I, Biron P, Brunat-Mentigny M, Philip T (1997) High-dose carmustine for high-grade gliomas in childhood. Cancer Chemother Pharmacol 39:376–379. doi:10.1007/s002800050586 PubMedCrossRefGoogle Scholar
  31. 31.
    Estlin EJ, Lashford L, Ablett S, Price L, Gowing R, Gholkar A et al (1998) Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children’s Cancer Study Group. Br J Cancer 78:652–661PubMedGoogle Scholar
  32. 32.
    Liu L, Vapiwala N, Munoz LK, Winick NJ, Weitman S, Strauss LC et al (2001) A phase I study of cranial radiation therapy with concomitant continuous infusion paclitaxel in children with brain tumors. Med Pediatr Oncol 37:390–392. doi:10.1002/mpo.1215 PubMedCrossRefGoogle Scholar
  33. 33.
    Broniscer A, Gajjar A (2004) Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9:197–206. doi:10.1634/theoncologist.9-2-197 PubMedCrossRefGoogle Scholar
  34. 34.
    Donaldson SS, Laningham F, Fisher PG (2006) Advances toward an understanding of brainstem gliomas. J Clin Oncol 24:1266–1272. doi:10.1200/JCO.2005.04.6599 PubMedCrossRefGoogle Scholar
  35. 35.
    Sposto R, Ertel IJ, Jenkin RD, Boesel CP, Venes JL, Ortega JA et al (1989) The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. J Neurooncol 7:165–177. doi:10.1007/BF00165101 PubMedCrossRefGoogle Scholar
  36. 36.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330 PubMedCrossRefGoogle Scholar
  37. 37.
    Wolff JE, Boos J, Krahling KH, Jurgens H (1996) Second temporal remission in a malignant glioma with trofosfamide and etoposide: a case report. Klin Padiatr 208:190–192PubMedCrossRefGoogle Scholar
  38. 38.
    Wolff JE, Molenkamp G, Westphal S, Pietsch T, Gnekow A, Kortmann RD et al (2000) Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme. Cancer 89:2131–2137. doi :10.1002/1097-0142(20001115)89:10<2131::AID-CNCR14>3.0.CO;2-JPubMedCrossRefGoogle Scholar
  39. 39.
    Wolff JE, Westphal S, Molenkamp G, Gnekow A, Warmuth-Metz M, Rating D et al (2002) Treatment of paediatric pontine glioma with oral trophosphamide and etoposide. Br J Cancer 87:945–949. doi:10.1038/sj.bjc.6600552 PubMedCrossRefGoogle Scholar
  40. 40.
    Wolff JE, Wagner S, Sindichakis M, Pietsch T, Gnekow A, Kortmann RD et al (2002) Simultaneous radiochemotherapy in pediatric patients with high-grade glioma: a phase I study. Anticancer Res 22:3569–3572PubMedGoogle Scholar
  41. 41.
    Wolff JE, Wagner S, Reinert C, Gnekow A, Kortmann RD, Kuhl J et al (2006) Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma. J Neurooncol 79:315–321. doi:10.1007/s11060-006-9147-8 PubMedCrossRefGoogle Scholar
  42. 42.
    Wolff JE, Classen CF, Wagner S, Kortmann RD, Palla SL, Pietsch T, Kühl J, Gnekow A, Kramm CM (2008) Subpopulations of malignant gliomas in pediatric patients: analysis of the HIT-GBM database. J Neurooncol 87(2):155–164CrossRefGoogle Scholar
  43. 43.
    Kramm CM, Wagner S, Van Gool S, Schmid H, Strater R, Gnekow A et al (2006) Improved survival after gross total resection of malignant gliomas in pediatric patients from the HIT-GBM studies. Anticancer Res 26:3773–3779PubMedGoogle Scholar
  44. 44.
    Benesch M, Wagner S, Berthold F, Wolff JE (2005) Primary dissemination of high-grade gliomas in children: experiences from four studies of the Pediatric Oncology and Hematology Society of the German Language Group (GPOH). J Neurooncol 72:179–183. doi:10.1007/s11060-004-3546-5 PubMedCrossRefGoogle Scholar
  45. 45.
    Spiller HA, Krenzelok EP, Klein-Schwartz W, Winter ML, Weber JA, Sollee DR et al (2000) Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol 38:755–760Google Scholar
  46. 46.
    Koenig SA, Buesing D, Longin E, Oehring R, Haussermann P, Kluger G et al (2006) Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003. Epilepsia 47:2027–2031. doi:10.1111/j.1528-1167.2006.00846.x PubMedCrossRefGoogle Scholar
  47. 47.
    Bohan TP, Helton E, McDonald I, Konig S, Gazitt S, Sugimoto T et al (2001) Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 56:1405–1409PubMedGoogle Scholar
  48. 48.
    Wagner S, Warmuth-Metz M, Emser A, Gnekow AK, Strater R, Rutkowski S et al (2006) Treatment options in childhood pontine gliomas. J Neurooncol 79:281–287. doi:10.1007/s11060-006-9133-1 PubMedCrossRefGoogle Scholar
  49. 49.
    Camphausen K, Cerna D, Scott T, Sproull M, Burgan WE, Cerra MA et al (2005) Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int J Cancer 114:380–386. doi:10.1002/ijc.20774 PubMedCrossRefGoogle Scholar
  50. 50.
    Zaskodova D, Rezacova M, Vavrova J, Vokurkova D, Tichy A (2006) Effect of valproic acid, a histone deacetylase inhibitor, on cell death and molecular changes caused by low-dose irradiation. Ann N Y Acad Sci 1091:385–398. doi:10.1196/annals.1378.082 PubMedCrossRefGoogle Scholar
  51. 51.
    Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN (2005) In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates. Mol Cancer Ther 4:1993–2000. doi:10.1158/1535-7163.MCT-05-0194 PubMedCrossRefGoogle Scholar
  52. 52.
    Masoudi A, Elopre M, Amini E, Nagel ME, Ater JL, Gopalakrishnan V, Wolff JEA (2008) Influence of Valproic acid on outcome of high-grade gliomas in children. AntiCancer Res (accepted)Google Scholar
  53. 53.
    Wagner S, Reinert C, Schmid HJ, Liebeskind AK, Jorch N, Langler A et al (2005) High-dose methotrexate prior to simultaneous radiochemotherapy in children with malignant high-grade gliomas. Anticancer Res 25:2583–2587PubMedGoogle Scholar
  54. 54.
    Wagner S, Csatary CM, Gosztonyi G, Koch HC, Hartmann C, Peters O et al (2006) Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid. APMIS 114:731–743. doi:10.1111/j.1600-0463.2006.apm_516.x PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Johannes E. A. Wolff
    • 1
    • 2
    • 3
  • Christof Kramm
    • 4
  • Rolf-Dieter Kortmann
    • 5
  • Torsten Pietsch
    • 6
  • Stefan Rutkowski
    • 7
  • Norbert Jorch
    • 8
  • Astrid Gnekow
    • 9
  • Pablo Hernáiz Driever
    • 10
  1. 1.Children’s Cancer Hospital, Department of Pediatrics, Unit 87The University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of BiostatisticsThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  3. 3.Pediatric Hematology and OncologyUniversity of RegensburgRegensburgGermany
  4. 4.Department of Pediatric OncologyMartin-Luther University Halle-WittenbergHalleGermany
  5. 5.Department of Radiation OncologyUniversity of LeipzigLeipzigGermany
  6. 6.Department of NeuropathologyUniversity of BonnBonnGermany
  7. 7.Children’s University HospitalUniversity of WuerzburgWuerzburgGermany
  8. 8.Department of PediatricsKrankenanstalten GileadBielefeldGermany
  9. 9.Department of PediatricsKlinik für Kinder und JugendlicheAugsburgGermany
  10. 10.Department of Pediatric Oncology and HematologyCharité-Universitätsmedizin BerlinBerlinGermany

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