The endothelin B (ETB) receptor agonist IRL 1620 is highly vasoconstrictive in two syngeneic rat tumour lines: potential for selective tumour blood flow modification

Abstract

The vascular effects of the endothelin B (ET B ) receptor agonist IRL 1620 were investigated in the rat P22 carcinosarcoma and a range of normal tissues in BDIX rats. Tissue blood flow rate was calculated from measurements of tissue uptake of radiolabelled iodoantipyrine. A comparison of vascular effects in the P22 tumour and the HSN sarcoma growing in CBH/CBi rats was made using laser Doppler flowmetry, showing similar effects of IRL 1620, with red cell flux rapidly decreasing by 50 -60% and then returning to control levels within approximately 30 min. This corresponded to similar levels but different spatial organisation of ET B binding sites in the two tumours, as measured by autoradiography. The decrease in tumour blood flow and an increase in vascular resistance suggest that the vascular component of ET B receptors in the P22 tumour is localised on contractile elements rather than on endothelial cells. ET A receptors were also identified. Vasoconstriction occurred uniformly throughout the P22 tumour mass, consistent with a measured homogeneous distribution of ET B receptors. IRL 1620 caused vasoconstriction in normal skeletal muscle, kidney and small intestine of the BDIX rat as well as in tumour, but did not affect blood flow in other tissues. These effects could be useful for limiting toxicity of certain chemotherapeutic agents. Fully functional ET B receptors are clearly expressed on tumour vasculature and IRL 1620 shows promise for short-term modification of tumour blood flow. Expression levels of ET B receptors on the tumour vasculature could be useful for predicting which tumours are likely to respond to IRL 1620.

IRL‐1620, a tumor selective vasodilator, augments the uptake and efficacy of chemotherapeutic agents in prostate tumor rats

“…A similar observation of the reduction of response at higher dose has been reported for another ET B receptor agonist, sarafotoxin S6c in rats [62]. However, effect of IRL-1620 on tumor blood vessels in the HSN fibrosarcoma has been reported to be vasoconstrictive [63,64]. While, sarafotoxin S6c administration increased tumor blood flow (176%) compared to control animals in the same model [65].…”

“…The Prostate DOI 10.1002/pros [67]. Rapid blood flow reduction observed with IRL-1620 in the P22 tumor and the HSN sarcoma [64] might be due to the existence of larger population of VSMCs in the sarcoma (muscle) tumor model employed for the study and/or may be attributed to doses of ET B receptor agonists used.…”

Tumor immune surveillance and ovarian cancer

“…We never observed an autoimmunity of inflammation associated with ETBR blockade in mice, which contrasts with more robust immune therapies that can cause adverse events like autoimmunity [151]. ETBR blockade is likely to have also direct antiangiogenic effects through suppression of endothelial nitric oxide or tumor-derived VEGF, and although the antitumor effect of ETBR blockade, singly, may be modest, the combined use of ETBR antagonists with immunotherapy may act synergistically to inhibit angiogenesis [144,152].…”

Endothelin B Receptor, a New Target in Cancer Immune Therapy

“…Unlike in patients with sepsis (97), NO inhibition is safe and has been well tolerated in cancer patients (98). Although the anticancer effect of ET B R (or NO) blockade as monotherapy may be modest, the concomitant administration of immunotherapy may act synergistically against angiogenesis (86, 99). …”