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

Neuro-oncology
Mir J AliDennis R Groothuis

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 microl/h x 7 days, and 2, 4, 6, and 8 microl/min x 2 h failed to kill tumors, although growth was delayed, while infusion rates of 12 microl/min x 60 min and 48 microl/min x 15 min produced 100% tumor kill. In D54-MG tumors, infusions of 4, 8, and 24 microl/min produced 100% tumor kill. 14C-Formalin autoradiographs showed a heterogeneous distribution after infusions of 2 microl/min x 2 h, whereas infusions of 48 microl/min x 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 lik...Continue Reading

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Citations

Oct 5, 2011·Neuromodulation : Journal of the International Neuromodulation Society·Robert M Levy
Jun 16, 2006·Neuro-oncology·Yot NavalitlohaDennis R Groothuis
Aug 19, 2009·Neurosurgery·Francisco VallesKrystof S Bankiewicz
Jun 1, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Leslie L MuldoonEdward A Neuwelt
Apr 1, 2017·Journal of Neurosurgery·Jonathan G ThomasFrederick F Lang
Jul 8, 2017·Journal of Neurosurgery. Pediatrics·Iryna IvasykMark M Souweidane
Nov 10, 2011·Toxins·Massimo S FiandacaKrystof S Bankiewicz

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