Skip to main content

Advertisement

Log in

Safety and efficacy of convection-enhanced delivery of ACNU, a hydrophilic nitrosourea, in intracranial brain tumor models

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Convection-enhanced delivery (CED) is a local infusion technique, which delivers chemotherapeutic agents directly to the central nervous system, circumventing the blood–brain barrier and reducing systemic side effects. CED distribution is significantly increased if the infusate is hydrophilic. This study evaluated the safety and efficacy of CED of nimustine hydrochloride: 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), a hydrophilic nitrosourea, in rat 9 l brain tumor models. The local neurotoxicity of ACNU delivered via CED was examined in normal rat brains, and the maximum tolerated dose (MTD) was estimated at 0.02 mg/rat. CED of ACNU at the MTD produced significantly longer survival time than systemic administration (P < 0.05, log-rank test). Long-term survival (80 days) and eradication of the tumor occurred only in the CED-treated rats. The tissue concentration of ACNU was measured by high-performance liquid chromatography, which revealed that CED of ACNU at the dose of 100-fold less total drug than intravenous injection carried almost equivalent concentrations of ACNU into rat brain tissue. CED of hydrophilic ACNU is a promising strategy for treating brain tumors.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ACNU:

3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride

BBB:

Blood-brain barrier

BCNU:

1,3-bis-chlorethyl-1-nitrosourea

CED:

Convection-enhanced delivery

CNS:

Central nervous system

HBSS:

Hanks balanced salt solution

H&E:

Hematoxylin and eosin

i.v.:

Intravenous

MTD:

Maximum tolerated dose

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research, Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  PubMed  CAS  Google Scholar 

  2. Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018

    Article  PubMed  CAS  Google Scholar 

  3. Groothuis DR (2000) The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro-oncol 2:45–59

    Article  PubMed  CAS  Google Scholar 

  4. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91:2076–2080

    Article  PubMed  CAS  Google Scholar 

  5. Vogelbaum MA (2005) Convection enhanced delivery for the treatment of malignant gliomas: symposium review. J Neurooncol 73:57–69

    Article  PubMed  Google Scholar 

  6. Mahaley MS Jr (1991) Neuro-oncology index and review (adult primary brain tumors). Radiotherapy, chemotherapy, immunotherapy, photodynamic therapy. J Neurooncol 11:85–147

    Article  PubMed  Google Scholar 

  7. Gilmann AG, Goodman LS, Rall TW, Murad TW (eds) (1985) Goodman and Gilman’s the pharmacological basis of therapeutics, 7th edn. Macmillan, New York, pp 1260–1261

    Google Scholar 

  8. Walter KA, Tamargo RJ, Olivi A, Burger PC, Brem H (1995) Intratumoral chemotherapy. Neurosurgery 37:1128–1145

    PubMed  CAS  Google Scholar 

  9. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G, Muller P, Morawetz R, Schold SC (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345:1008–1012

    Article  PubMed  CAS  Google Scholar 

  10. Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jaaskelainen J, Ram Z (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncol 5:79–88

    Article  PubMed  CAS  Google Scholar 

  11. Saito R, Krauze MT, Noble CO, Tamas M, Drummond DC, Kirpotin DB, Berger MS, Park JW, Bankiewicz KS (2006) Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: Implications for local drug delivery. J Neurosci Methods 9:S0165–S0270

    Google Scholar 

  12. Buahin KG, Brem H (1995) Interstitial chemotherapy of experimental brain tumors: comparison of intratumoral injection versus polymeric controlled release. J Neurooncol 26:103–110

    Article  PubMed  CAS  Google Scholar 

  13. Fleming AB, Saltzman WM (2002) Pharmacokinetics of the carmustine implant. Clin Pharmacokinet 41:403–419

    Article  PubMed  CAS  Google Scholar 

  14. Bruce JN, Falavigna A, Johnson JP, Hall JS, Birch BD, Yoon JT, Wu EX, Fine RL, Parsa AT (2000) Intracerebral clysis in a rat glioma model. Neurosurgery 46:683–691

    Article  PubMed  CAS  Google Scholar 

  15. Walker MD, Hilton J (1976) Nitrosourea pharmacodynamics in relation to the central nervous system. Cancer Treat Rep 60:725–728

    PubMed  CAS  Google Scholar 

  16. Hansch C, Smith N, Engle R, Wood H (1972) Quantitative structure-activity relationships of antineoplastic drugs: nitrosoureas and triazenoimidazoles. Cancer Chemother Rep 56:443–456

    PubMed  CAS  Google Scholar 

  17. Mori T, Mineura K, Katakura R (1979) Chemotherapy of malignant brain tumor by a water-soluble anti-tumor nitrosourea, ACNU. Neurol Med Chir (Tokyo) 19:1157–1171

    Article  CAS  Google Scholar 

  18. Takakura K, Abe H, Tanaka R, Kitamura K, Miwa T, Takeuchi K, Yamamoto S, Kageyama N, Handa H, Mogami H et al (1986) Effects of ACNU and radiotherapy on malignant glioma. J Neurosurg 64:53–57

    PubMed  CAS  Google Scholar 

  19. Weller M, Muller B, Koch R, Bamberg M, Krauseneck P, Neuro-Oncology Working Group of the German Cancer Society (2003) Neuro-oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma. J Clin Oncol 21:3276–3284

    Article  PubMed  CAS  Google Scholar 

  20. Saito R, Bringas JR, McKnight TR, Wendland MF, Mamot C, Drummond DC, Kirpotin DB, Park JW, Berger MS, Bankiewicz KS (2004) Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res 64:2572–2579

    Article  PubMed  CAS  Google Scholar 

  21. Krauze MT, Saito R, Noble C, Tamas M, Bringas J, Park JW, Berger MS, Bankiewicz K (2005) Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 103:923–929

    Article  PubMed  Google Scholar 

  22. Kunwar S (2003) Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. Acta Neurochir Suppl 88:105–111

    PubMed  CAS  Google Scholar 

  23. Noble CO, Krauze MT, Drummond DC, Yamashita Y, Saito R, Berger MS, Kirpotin DB, Bankiewicz KS, Park JW (2006) Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy. Cancer Res 66:2801–2806

    Article  PubMed  CAS  Google Scholar 

  24. Saito R, Krauze MT, Noble CO, Drummond DC, Kirpotin DB, Berger MS, Park JW, Bankiewicz KS (2006) Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model. Neuro-oncol 24:S1522–S8517

    Google Scholar 

  25. Yamashita Y, Saito R, Krauze MT, Kawaguchi T, Noble CO, Drummond DC, Kirpotin DB, Berger MS, Park JW, Berger MS, Bankiewicz KS (2006) Convection-enhanced delivery of liposomal doxorubicin in intracranial brain tumor xenografts. Targeted Oncol 1:79–85

    Article  Google Scholar 

  26. Vavra M, Ali MJ, Kang EW, Navalitloha Y, Ebert A, Allen CV, Groothuis DR (2004) Comparative pharmacokinetics of 14C-sucrose in RG-2 rat gliomas after intravenous and convection-enhanced delivery. Neuro-oncol 6:104–112

    Article  PubMed  CAS  Google Scholar 

  27. Wakabayashi T, Yoshida J, Mizuno M, Kajita Y (2001) Intratumoral microinfusion of nimustine (ACNU) for recurrent glioma. Brain Tumor Pathol 18:23–28

    Article  PubMed  CAS  Google Scholar 

  28. Levin VA, Byrd D, Campbell J, Giannini DD, Borcich JK, Davis RL (1985) Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricular 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitro soureas and other nitrosoureas in beagles. Cancer Res 45:3803–3809

    PubMed  CAS  Google Scholar 

  29. Ushio Y, Kochi M, Kitamura I, Kuratsu J (1998) Ventriculolumber perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl-1-nitrosourea hydrochloride for subarachnoid dissemination of gliomas. J Neurooncol 38:207–212

    Article  PubMed  CAS  Google Scholar 

  30. Kochi M, Kuratsu J, Mihara Y, Takaki S, Seto H, Uemura S, Ushio Y (1993) Ventriculolumbar perfusion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride. Neurosurgery 33:817–823

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yoji Yamashita.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugiyama, Si., Yamashita, Y., Kikuchi, T. et al. Safety and efficacy of convection-enhanced delivery of ACNU, a hydrophilic nitrosourea, in intracranial brain tumor models. J Neurooncol 82, 41–47 (2007). https://doi.org/10.1007/s11060-006-9247-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-006-9247-5

Keywords

Navigation