SELECTIVE BLOOD-TUMOR BARRIER DISRUPTION BY LEUKOTRIENES

The authors have previously reported that intracarotid infusion of 5-mu-g leukotriene C4 (LTC4) selectively increases blood-tumor barrier permeability in rat RG-2 tumors. In this study, rats harboring RG-2 tumors were given 15-minute intracarotid infusions of LTC4 at concentrations ranging from 0.5-mu-g to 50.0-mu-g (seven rats in each dose group). Blood-tumor and blood-brain barrier permeability were determined by quantitative autoradiography using C-14 aminoisobutyric acid. The transfer constant for permeability (K(i)) within the tumors was increased twofold by LTC4 doses of 2.5, 5.0, and 50.0-mu-g compared to vehicle alone (90.00 +/- 21.14, 92.68 +/- 15.04, and 80.17 +/- 16.15 vs. 39.37 +/- 6.45-mu-l/gm/min, respectively; mean +/- standard deviation; p < 0.01). No significant change in K(i) within the tumors was observed at the 0.5-mu-g LTC4 dose. Blood-brain barrier permeability was selectively increased within the tumors. At no dose in this study did leukotrienes increase permeability within normal brain. To determine the duration of increased opening of the blood-tumor barrier by LTC4 administration, K(i) was measured at 15, 30, and 60 minutes after termination of a 15-minute LTC4 infusion (seven rats at each time point). The mean K(i) value was still high at 15 minutes (92.68 +/- 15.04-mu-l/gm/min), but declined at 30 minutes (56.58 +/- 12.50-mu-l/gm/min) and 60 minutes (55.40 +/-8.10-mu-l/gm/min) after the end of LTC4 infusion. Sulfidopeptide leukotfienes LTC4, LTD4, LTE4 and LTF4 were infused to compare their potency in opening the blood-tumor barrier. The mean leukotriene E4 Was the most potent, increasing the permeability value 31/2-fold compared with vehicle alone (139.86 +/- 23.95 vs. 39.37 +/-6.45-mu-l/gm/min).