antitumor effect of tatoxygendependent degradationcaspase3 fusion protein specifically stabilized and activated in hypoxic tumor cells human solid tumors contain hypoxic regions that have considerably lower oxygen tension than normal tissues these impart resistance to radiotherapy and anticancer chemotherapy as well as predisposing to increased tumor metastases to develop a potentially therapeutic protein drug highly specific for solid tumors we constructed fusion proteins selectively stabilized in hypoxic tumor cells a model fusion protein oxygendependent degradation oddbetagalactosidase betagal composed of a part of the odd domain of hypoxiainducible factor1alpha fused to betagal showed increased stability in cultured cells under a hypoxiamimic condition when oddbetagal was further fused to the hivtat protein transduction domain tat4757 and ip injected to a tumorbearing mouse the biologically active fusion protein was specifically stabilized in solid tumors but was hardly detected in the normal tissue furthermore when wildtype wt caspase3 casp3wt or its catalytically inactive mutant was fused to tatodd and ip injected to a tumorbearing mouse the size of tumors was reduced by the administration of tatoddcasp3wt but not by tatoddmutant casp3 tatoddcasp3wt did not cause any obvious side effects on tumorbearing mice suggesting specific stabilization and activation of the fusion protein in the hypoxic tumor cells these results suggest that the combination of protein therapy using a cytotoxic tatodd fusion protein with radiotherapy and chemotherapy may provide a new strategy for annihilating solid tumors