Therapeutic implications of tumor interstitial fluid pressure in subcutaneous RG-2 tumors

Abstract

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 degrees C +/- 0.7 degrees C, and efflux half-time was 7.3 +/- 0.7 min. Externally induced hypothermia decreased tumor temperature to 8.9 degrees C +/- 2.9 degrees 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 mul/min, the efflux rate was the same for room temperature saline and 15 degrees 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.

Fig. 1

The effect of hypothermia and dexamethasone on tumor IFP. In contrast to the IFP in untreated control RG-2 tumors (Control), tumor IFP was significantly lowered (P < 0.005) by decreasing tumor temperature (Hypothermia) and by administration of dexamethasone (Dex). Values are shown as mean ± SD.

Fig. 2

Tissue radioactivity values versus time in three treatment groups. Shown are the data (±SD) and linear least-squares fits for the hypothermia group (r² = 0.9337) (▪), dexamethasone group (r² = 0.8741) (•), and combined hypothermia-dexamethasone group (r² = 1.0) (▴). Efflux half-times were calculated from an exponential fit to the data.

Fig. 3

Temperature versus time in RG-2 tumors receiving CED infusions. The temperatures (°C ± SD) are shown for the group receiving a 48-μl/min infusion of saline containing ¹⁴C-sucrose at room temperature (□) or chilled to 15°C (○). The differences were not statistically significant.

Fig. 4

Tumor interstitial pressure versus time in RG-2 tumors receiving CED infusions. Tumor IFP (±SD) was recorded every minute during a 15-min infusion at 48 μl/min of saline containing ¹⁴C-sucrose at room temperature (□) and chilled to 15°C (○). The differences were not statistically significant.

Fig. 5

Tissue radioactivity values versus time in treatment groups of infusion of room temperature saline versus saline chilled to 15°C. There is almost no radioactivity remaining in the tumors of the room temperature saline group (▪) or the chilled saline group (•). The triangles (▴) show the expected amount of radioactivity that would be in the tumors if none of the ¹⁴C-sucrose had left.