Annual Report

27. Therapy of Radiation Damage to Normal Tissues with Selective Inhibitors of Cyclooxygenese-2: YM177 Tends to Reduce Mouse Mortality from Haemopoietic Syndrome

Itsuro Tamanoi, Masatoshi Itoh1, Hisamasa Joshima, Tatsuo Hayao and Adam S.Michalowski2 (1 Cyclotron Radioisotope Center, Tohoku Univ.; 28 Ollgar Close, London,U.K.)

Keywords: cyclooxygenase, NSAID, COX-1, COX-2, haemopoietic syndrome

Various non-steroidal anti-inflammatory drugs (NSAID) have been successfully used in animals and humans to alleviate ionizing radiation-induced reactions in normal tissue. They act by interfering primarily with cyclooxygenase (COX)-1, a constitutive enzyme normally present in most types of cells. NSAID are less effective as inhibitors of COX-2. For this reasons the drugs, when administered repeatedly in high therapeutic doses, cause serious side-effects affecting especially the stomach. New generation NSAID selectively inhibit COX-2 while sparing COX-1 and thus exert their anti-inflammatory action without causing damage to the gastro-intestinal tract. We have begun studying therapeutic effectiveness of these highly selective COX-2 inhibitors, that is, YM-177(4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H-pyrazole-1-yl] benzensulfonamide from Yamanouchi Pharmaceutical Co.) in reducing undesirable radiation reactions. YM-177 was administered in drinking water to C57BL/6J male mice irradiated with 5.5 to 6.5 Gy to achieve a constant level of the inhibitor while measuring its intake. The treatment was aimed at a specific humoral component of the radiation reactions only. Accordingly, it was began 24 h after whole body irradiation to avoid interference with an instantaneous reduction in the number of clonogenic cells and rapid intracellular repair process. YM-177 was given until the end of the month long observation period following radiation exposure. Mouse survival rate (LD50/30) and duration of survival of those animals which succumbed due to haemopoietic failure within the first post-irradiation month served as criteria of therapeutic effectiveness of YM-177 administered in doses ranging from 0.17 to 3.4 mg/kg· day. Only the two lowest doses of YM-177 significantly reduced mouse mortality suggesting that in whole body-irradiated mice endogenous prostanoids synthesized with the involvement of COX-2 can contribute to death from haemopoietic syndrome.

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