| Currently, chemotherapy provides the only hope of curing brain tumors or improving treatment outcome. Patient survival time is increased, although only marginally, when chemotherapy is added to surgery and radiation therapy in the treatment protocol. The lack of efficiency of chemotherapy has chiefly been attributed to tumor cell resistance and inadequate drug delivery to tumors.; The aim of this study was to improve drug delivery to brain tumors. I first separated the issues of drug delivery and therapeutic efficacy in a subcutaneous RG-2 model by showing that tumors could be cured, if an agent, in this case, 10% formalin, known to be 100% effective, was delivered to the tumors in sufficient quantity. In a subsequent pharmacokinetic study of 14C-sucrose in RG-2 tumors, I demonstrated that tumor treatment failure is in part due to insufficient drug delivery to and inhomogeneous drug distribution inside of tumors, both caused by high interstitial fluid pressure (IFP). While lowering IFP through hypothermia and dexamethasone increased drug residence time inside subcutaneous RG-2 tumors, an experimental treatment with a combination of reduced IFP plus a chemotherapeutic drug, BiCNU, delivered by convection-enhanced delivery (CED) failed to produce a cure. Inadequate tissue distribution of the drug inside tumors during the infusion was believed to be one of the causes of this failure. Lacking a tool for visualizing and monitoring the volume of distribution (VD) of the drug during CED, I developed a non-invasive and real-time method for this purpose using T1-weighted MRI. With this technique, the VD of a chemotherapeutic agent delivered by CED to tumors could be followed during infusion, so that the catheter position or the infusion rate could be adjusted to ensure that the chemotherapeutic agent is distributed throughout the tumor.; Future studies of chemotherapeutic drugs and their efficacy with regard to brain tumors should incorporate information regarding physiological properties of a tumor and the properties of the chemotherapeutic drug and use this information to design the best treatment protocol for each individual tumor. A method of confirming that the intended dosage actually reaches all tumor cells must be an integral part of any treatment protocol. |
