Arzneimittelforschung, Table of Contents Arzneimittelforschung 2012; 62(01): 14-17DOI: 10.1055/s-0031-1295430 Original Article © Georg Thieme Verlag KG Stuttgart · New YorkIRL-1620, an Endothelin-B Receptor Agonist, Enhanced Radiation Induced Reduction in Tumor Volume in Dalton’s Lymphoma Ascites Tumor Model A. Gulati 1 Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, USA , E. S. Sunila 2 Department of Immunology, Amala Cancer Research Center, Thrissur, Kerala, India , G. Kuttan 2 Department of Immunology, Amala Cancer Research Center, Thrissur, Kerala, India› Author AffiliationsRecommend Article Abstract Buy Article Abstract ETB receptor agonist, IRL-1620 (or SPI-1620) presently in US Phase 1 clinical trial, has been demonstrated to selectively and transiently increase tumor blood flow. The present study was conducted to determine the effect of IRL-1620 on radiation therapy in tumor bearing mice inoculated with Dalton’s Lymphoma Ascites cells. Tumors were allowed to grow for 30 days to a size of 1.10–1.29 cm3 before starting the treatment. The animals with or without IRL-1620 treatment were exposed to radiation (4 Gy/dose) on every alternate day for a total of 5 doses. Tumor volume was determined twice every week till the end of study. Radiation alone did not affect the tumor volume; however, animals treated with IRL-1620 followed by radiation produced a significant (64%) reduction in tumor volume. Survival of mice improved from 0/10 at 56 days after tumor inoculation in vehicle plus radiation group to 6/10 at 70 days in IRL-1620 (9 nmol/kg) plus radiation group. It is concluded that IRL-1620 improves the efficacy of radiation treatment in tumor bearing mice. (These findings have been earlier presented as an abstract [1]). Key words Key wordsradiotherapy - cancer - ETB receptor agonist - IRL-1620 - tumor Full Text References References 1 Reddy G, Gulati A, Kuttan G, Es S, Lenaz G. SPI-1620 significantly improves survival in mice treated with radiation. Annals of Oncology 2008; 19: 31-31 2 Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 2008; 13 (Suppl. 03) 21-26 3 Vaupel P, Kelleher DK, Thews O. Modulation of tumor oxygenation. Int J Radiat Oncol Biol Phys 1998; 42: 843-848 4 Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer 2008; 8: 967-975 5 Sanger C, Matteo R. Physiological Aspects Of The Use Of Oxygen In Radiotherapy. Acta Unio Int Contra Cancrum 1964; 20: 1778-1779 6 Bussink J, Kaanders JH, Strik AM, van der Kogel AJ. Effects of nicotinamide and carbogen on oxygenation in human tumor xenografts measured with luminescense based fiber-optic probes. Radiother Oncol 2000; 57: 21-30 7 Kaanders JH, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol 2002; 3: 728-737 8 Kaanders JH, Pop LA, Marres HA et al. ARCON: experience in 215 patients with advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002; 52: 769-778 9 Henke M, Laszig R, Rube C et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362: 1255-1260 10 Denekamp J, McNally NJ, Fowler JF et al. Misonidazole in fractionated radiotherapy: are many small fractions best?. Br J Radiol 1980; 53: 981-990 11 Hirst DG. Tumour radiosensitization by clofibrate and its analogs: possible mechanisms. Adv Exp Med Biol 1990; 277: 917-925 12 Dewhirst MW, Ong ET, Madwed D et al. Effects of the calcium channel blocker flunarizine on the hemodynamics and oxygenation of tumor microvasculature. Radiat Res 1992; 132: 61-68 13 Muruganandham M, Kasiviswanathan A, Jagannathan NR, Raghunathan P, Jain PC, Jain V. Diltiazem enhances tumor blood flow: MRI study in a murine tumor. Int J Radiat Oncol Biol Phys 1999; 43: 413-421 14 Goto K, Kasuya Y, Matsuki N et al. Endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca2+ channel in vascular smooth muscle. Proc Natl Acad Sci USA 1989; 86: 3915-3918 15 Tsukahara H, Ende H, Magazine H et al. Molecular and functional characterization of the non-isopeptide-selective ETB receptor in endothelial cells. Receptor coupling to nitric oxide synthase. J Biol Chem 1994; 269: 21778-21785 16 Gulati A, Rai A. Endothelin-1-induced Vasodilatation in Rat Breast Tumor is Mediated through Endothelin-B Receptors. J Cardiovasc Pharmacol 2004; 44: S483-S486 17 Karaki H, Sudjarwo SA, Hori M, Takai M, Urade Y, Okada T. Induction of endothelium-dependent relaxation in the rat aorta by IRL 1620, a novel and selective agonist at the endothelin ETB receptor. Br J Pharmacol. 1993 109. 486-490 18 Rai A, Gulati A. Evidence for the involvement of ET(B) receptors in ET-1-induced changes in blood flow to the rat breast tumor. Cancer Chemother Pharmacol 2003; 51: 21-28 19 Rajeshkumar NV, Rai A, Gulati A et al. receptor agonist, IRL 1620, enhances the anti-tumor efficacy of paclitaxel in breast tumor rats. Breast Cancer Res Treat 2005; 94: 237-247 20 Yanagisawa M, Kurihara H, Kimura S et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411-415 21 Ben-Baruch G, Schiff E, Galron R et al. Impaired binding properties of endothelin-1 receptors in human endometrial carcinoma tissue. Cancer 1993; 72: 1955-1958 22 Schneider MP, Boesen EI, Pollock DM. Contrasting Actions of Endothelin ET(A) and ET(B) Receptors in Cardiovascular Disease. Annu Rev Pharmacol Toxicol 2007; 47: 731-759 23 Just A, Olson AJ, Arendshorst WJ. Dual constrictor and dilator actions of ET(B) receptors in the rat renal microcirculation: interactions with ET(A) receptors. Am J Physiol Renal Physiol 2004; 286: F660-F668 24 Rai A, Rajeshkumar NV, Shord S, Gulati A. ET(B) receptor agonist, IRL 1620, does not affect paclitaxel plasma pharmacokinetics in breast tumour bearing rats. J Pharm Pharmacol. 2005 57. 869-876 25 Rajeshkumar NV, Matwyshyn G, Gulati A. IRL-1620, a tumor selective vasodilator, augments the uptake and efficacy of chemotherapeutic agents in prostate tumor rats. Prostate 2007; 67: 701-713 26 Ajith TA, Harikumar KB, Thasna H et al. Proapoptotic and antitumor activities of the HMG-CoA reductase inhibitor, lovastatin, against Dalton’s lymphoma ascites tumor in mice. Clin Chim Acta 2006; 366: 322-328 27 Ghosh M, Sadhu U, Bhattacharya S et al. Evaluation of toxicity of beta-tethymustine, a new anticancer compound, in mice. Cancer Lett 1999; 138: 107-114 28 Ansiaux R, Baudelet C, Jordan BF et al. Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clin Cancer Res 2005; 11: 743-750 29 Ansiaux R, Baudelet C, Cron GO et al. Botulinum toxin potentiates cancer radiotherapy and chemotherapy. Clin Cancer Res 2006; 12: 1276-1283 30 Sonveaux P, Dessy C, Martinive P et al. Endothelin-1 is a critical mediator of myogenic tone in tumor arterioles: implications for cancer treatment. Cancer Res 2004; 64: 3209-3214 31 Muramatsu M, Oka M, Morio Y et al. Chronic hypoxia augments endothelin-B receptor-mediated vasodilation in isolated perfused rat lungs. Am J Physiol 1999; 276: L358-L364 32 Takai M, Umemura I, Yamasaki K et al. A potent and specific agonist, Suc-[Glu9,Ala11,15]-endothelin-1(8-21), IRL 1620, for the ETB receptor. Biochem Biophys Res Commun. 1992 184. 953-959
