Isolation of drug delivery from drug effect: Problems of optimizing delivery parameters

Mir J. Ali, Yot Navalitloha, Michael W. Vavra, Eric W Y Kang, Andrea C. Itskovich, P. Molnár, Robert M. Levy, Dennis R. Groothuis

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A recurring question in the treatment of malignant brain tumors has been whether treatment failure is due to inadequate delivery or ineffective drugs. To isolate these issues, we tested a paradigm in which the "therapeutic" agent was a toxin about which there could be no question of efficacy, provided it was delivered in adequate amounts; we used 10% formalin. We infused 10% formalin into 5- to 8-mm subcutaneous RG-2 and D54-MG gliomas at increasing rates until we achieved 100% tumor cell kill. In RG-2 gliomas, infusions of 10 μl/h × 7 days, and 2, 4, 6, and 8 μl/min × 2 h failed to kill tumors, although growth was delayed, while infusion rates of 12 μl/min × 60 min and 48 μl/min × 15 min produced 100% tumor kill. In D54-MG tumors, infusions of 4, 8, and 24 μl/min produced 100% tumor kill. 14C-Formalin autoradiographs showed a heterogeneous distribution after infusions of 2 μl/min × 2 h, whereas infusions of 48 μl/min × 15 min showed a homogeneous distribution within the tumor, but more than 95% of tissue radioactivity was found in tissue surrounding tumor. Drug delivery remains a major issue in brain tumor treatment: Distribution inhomogeneity, rapid efflux, and consequent treatment failures are likely due to high interstitial fluid pressure. Because the infusion rates being used in the treatment of human brain tumors are low and the tumors are larger, treatment failures can be expected on the basis of inadequate drug delivery alone, regardless of the effectiveness of the drug.

Original languageEnglish
Pages (from-to)109-118
Number of pages10
JournalNeuro-Oncology
Volume8
Issue number2
DOIs
Publication statusPublished - Apr 2006

Fingerprint

Pharmaceutical Preparations
Neoplasms
Treatment Failure
Brain Neoplasms
Formaldehyde
Glioma
Extracellular Fluid
Radioactivity
Pressure
Growth
Therapeutics

Keywords

  • Brain tumors
  • Convection-enhanced delivery
  • Drug delivery
  • Glioma
  • Interstitial fluid pressure

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Ali, M. J., Navalitloha, Y., Vavra, M. W., Kang, E. W. Y., Itskovich, A. C., Molnár, P., ... Groothuis, D. R. (2006). Isolation of drug delivery from drug effect: Problems of optimizing delivery parameters. Neuro-Oncology, 8(2), 109-118. https://doi.org/10.1215/15228517-2005-007

Isolation of drug delivery from drug effect : Problems of optimizing delivery parameters. / Ali, Mir J.; Navalitloha, Yot; Vavra, Michael W.; Kang, Eric W Y; Itskovich, Andrea C.; Molnár, P.; Levy, Robert M.; Groothuis, Dennis R.

In: Neuro-Oncology, Vol. 8, No. 2, 04.2006, p. 109-118.

Research output: Contribution to journalArticle

Ali, MJ, Navalitloha, Y, Vavra, MW, Kang, EWY, Itskovich, AC, Molnár, P, Levy, RM & Groothuis, DR 2006, 'Isolation of drug delivery from drug effect: Problems of optimizing delivery parameters', Neuro-Oncology, vol. 8, no. 2, pp. 109-118. https://doi.org/10.1215/15228517-2005-007
Ali, Mir J. ; Navalitloha, Yot ; Vavra, Michael W. ; Kang, Eric W Y ; Itskovich, Andrea C. ; Molnár, P. ; Levy, Robert M. ; Groothuis, Dennis R. / Isolation of drug delivery from drug effect : Problems of optimizing delivery parameters. In: Neuro-Oncology. 2006 ; Vol. 8, No. 2. pp. 109-118.
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