We demonstrated that ET-1 administered to breast tumor bearing rats increased blood flow selectively to tumor tissue by stimulating ETB receptors. The present study was conducted to determine effect of ETB receptor agonist, N-Suc-[Glu9, Ala11, 15]ET-1(8-21) on concentration of paclitaxel and its efficacy on breast tumor bearing rats. Breast tumor bearing rats (N-methyl nitrosourea, 50 mg/kg, i.p) were selected for the study. [3H]-paclitaxel (40 μCi/rat) was administered to rats at 15, 120 and 240 min after N-Suc-[Glu9, Ala11, 15]ET-1(8-21) (3 nmol/kg, i.v) or saline (0.3 ml/kg, i.v.) treatment. The animals were sacrificed 180 min after [3H]-paclitaxel administration. Tumor and major organs were excised, weighed and solubilized in tissue solubilizer and radioactivity was measured. In another study, rats were treated with 5 mg/kg of paclitaxel administered 15 min after administration of N-Suc-[Glu9, Ala11, 15]ET-1(8-21) or saline. Paclitaxel treatment was carried out every third day for a total of 5 doses. Tumor size, progression, stasis, partial regression or complete regression of tumor growth was monitored every third day for a total of 30 days after the last dose of paclitaxel. The concentration of paclitaxel in the tumor was significantly increased in N-Suc-[Glu9, Ala11, 15]ET-1(8-21) treated rats compared to saline treated rats. An increase of 277.1, 151.9 and 34.7 % in tumor paclitaxel concentration was observed when paclitaxel was administered 15, 120 and 240 min respectively after N-Suc-[Glu9, Ala11, 15]ET-1(8-21) administration. N-Suc-[Glu9, Ala11, 15]ET-1(8-21) administration did not alter the accumulation of paclitaxel in the liver, lungs, kidneys, spleen and heart compared to control animals. Efficacy study using breast tumor bearing rats revealed that administration of N-Suc-[Glu9, Ala11, 15]ET-1(8-21) followed by paclitaxel significantly reduced the tumor volume (130.48 %) compared to paclitaxel alone (Fig.1) and complete remission of the tumor was observed in 15% of rats. ETB receptor agonist N-Suc-[Glu9, Ala11, 15]ET-1(8-21) can be used as an adjuvant to increase the efficacy of blood-borne antineoplastic agents.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]