PARENT SESSION
1:30 PM to 3:30 PM
Sunday, April 21, 2002
Poster Session 8 Radiosensitizers and Bioreductive Drugs
Room: Nevada Exhibition Center
(P13-123) Radiosensitization of Ehrlich ascites tumor cells by DNA ligand H-33342 in vitro and in vivo.
Dwarakanath, Bilikere*,1, Gupta, Seema1, Tripathi, Neelima1, Adhikari, Jawahar1, Chandna, Sudhir1, Mathew, T. Lazar, Jain, Viney2,3, 1 Institute of Nuclear Medicine and Allied Sciences, Delhi, India2 Wallace-Kettering Neuroscience Institute, Kettering, OH3 Department of Emergency Medicine, Kettering, OH
ABSTRACT-
The minor groove DNA ligand bisbenzimidazole, Hoechst-33342 (H-342),scavenges radiation induced hydoxyl radicals and quenches DNA radicals, which could explain the reduction in strand breaks observed in irradiated DNA solutions. H-342 binds preferably to AT rich regions, alters the chromatin structure, interferes in the functioning of topoisomerases and protects normal tissues against radiation injuries in whole-body irradiated mice. The purpose of the present studies was to compare the radiomodifying effects of H-342 in transformed cells grown in cell cultures versus solid tumors in mice.Treatment of Ehrlich ascites (EA) cells in culture with H-342(5-20 mM),1h before gamma irradiation reduced the induced DNA damage in a concentration dependent manner, inhibited the initial rate of DNA repair and marginally decreased (~15 %) the micronuclei formation. If added immediately following irradiation,H-342 enhanced radiation-induced micronuclei formation and cell death (apoptosis). This radiosensitizing effect of H-342, however,was significantly reduced, if H-342 was added 1-2h post-irradiation. In the absence of irradiation, H-342 induced small but significant level of micronuclei formation and apoptosis. Focal irradiation (Co-60 gamma rays)of the EA solid tumor grown in mice resulted in a dose dependent(5-20 Gy) delay in tumor growth but did not lead to complete regression.Intravenous administration of H-342,1h before irradiation enhanced radiation-induced growth delay in a dose dependent manner(5 to 20 mg/kg b.wt),while it was ineffective, when administered after irradiation. A complete regression of the tumor was observed only at a dose of 10 mg/kg b.wt. resulting in a cure rate (tumor free survival for more than 200 days)of 55 %.The radiosensitizing effects of H-342 were more prominent in smaller tumors (<300 mm3) whereas no significant effects on the unirradiated tumor were observed.The mechanisms underlying the differential radiomodifying effects induced by H-342 in various cell systems and microenvironments are under investigation. Radiosensitization of the tumor and radioprotection of normal tissues by H-342 (Singh et al.,1998:Indian J.Exp.Biol.36, 375-84) suggest, however,that under appropriate conditions,H-342 could be useful in improving tumor radiotherapy.
KEYWORDS: differential radiomodification, DNA ligand H-33342, Ehrlich ascites tumor cells, tumor regression and cure rate