Isolation of drug delivery from drug effect: Problems of optimizing drug delivery parameters1

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 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.