Therapeutic implications of tumor interstitial fluid pressure in subcutaneous RG-2 tumors1
Department of Neurology, Northwestern University Medical School, Evanston Northwestern Healthcare, Evanston, IL 60201, and Northwestern University Institute for Neuroscience, Northwestern University, Evanston, IL 60208 (Y.N., E.S.S., E.N.G., C.V.A., R.M.L., D.R.G.); and Department of Neurosurgery, Northwestern University Medical School, Chicago, IL 60210 (R.M.L.); USA
2 Address correspondence to Dennis R. Groothuis, M.D., Department of Neurology, Evanston Hospital, 2650 Ridge Avenue, Evanston, IL 60201 (drgroothuis{at}northwestern.edu).
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Abstract |
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Increased interstitial fluid pressure (IFP) in brain tumors results in rapid removal of drugs from tumor extracellular space. We studied the effects of dexamethasone and hypothermia on IFP in s.c. RG-2 rat gliomas, because they could potentially be useful as means of maintaining drug concentrations in human brain tumors. We used dexamethasone, external hypothermia, combined dexamethasone and hypothermia, and infusions of room temperature saline versus chilled saline. We measured tumor IFP and efflux half-time of 14C-sucrose from tumors. In untreated s.c. tumors, IFP was 9.1 ± 2.1 mmHg, tumor temperature was 33.7°C ± 0.7°C, and efflux half-time was 7.3 ± 0.7 min. Externally induced hypothermia decreased tumor temperature to 8.9°C ± 2.9°C, tumor IFP decreased to 3.2 ± 1.1 mmHg, and efflux half-time increased to 13.5 min. Dexamethasone decreased IFP to 2.4 ± 1.0 mmHg and increased efflux half-time to 15.4 min. Combined hypothermia and dexamethasone further increased the efflux half-time to 17.6 min. We tried to lower the tumor temperature by chilling the infusion solution, but at an infusion rate of 48 µl/min, the efflux rate was the same for room temperature saline and 15°C saline. The efflux rate was increased in both infusion groups, which suggests that efflux due to tumor IFP and that of the infusate were additive. Since lowering tumor IFP decreases efflux from brain tumors, it provides a means to increase drug residence time, which in turn increases the time-concentration exposure product of therapeutic drug available to tumor.
Keywords: brain tumor, chemotherapy, drug delivery, hypothermia, interstitial fluid pressure
Received January 3, 2006; Accepted March 20, 2006
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