CHANGES IN TUMOR BLOOD-FLOW, OXYGENATION AND INTERSTITIAL FLUID PRESSURE-INDUCED BY PENTOXIFYLLINE

Pentoxifylline (PTX) has been shown to increase radiation damage to tumours and to decrease late radiation-induced injury to normal tissues. This tumour radiation sensitisation results from increased oxygen supply via improved tumour perfusion. We propose that the improved perfusion results from decreased viscous resistance and/or geometric resistance. The decreased flow resistance may be accompanied by a reduction in microvascular pressure (MVP). Since MVP is approximately equal to the interstitial fluid pressure (IFP), PTX should lead to a decrease in IFP. To test this hypothesis, we measured Po-2, laser Doppler flow (RBC flux) and IFP in FSaII murine tumours at two doses (PTX at 25 and 100 mg per kg body weight) which sensitise this tumour to X-irradiation. We found that 25 mg kg(-1) PTX was ineffective, but 100 mg kg(-1) PTX was effective in increasing the Po-2 of this tumour. PTX at 100 mg kg(-1) (i.p.) increased median Pot from 5 to 7 mmHg (P<0.05) within 2h, and decreased the fraction of Po-2 values <5mmHg from 65% to 45% (P<0.05). In support of our hypothesis, we found that with this dose of PTX, RBC Aux in the tumour centre increased significantly (n = 6, P<0.05) prior to an similar to 40% decrease (n = 13, P<0.05) in tumour interstitial fluid pressure (TIFP), without changes in mean arterial blood pressure (MABP). In conclusion, a single i.p. administration of PTX at 100 mg kg(-1) can increase oxygen availability in the tumour due to temporarily increased RBC flux in the tumour centre, where pretreatment flow is relatively low, and thus ameliorate hypoxia in tumour microregions. Second, PTX can lower the elevated TIFP without lowering the MABP.