Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappa B

Programmed cell death (apoptosis) seems to be the principal mechanism where by anti-oncogenic therapies such as chemotherapy and radiation effect their responses. Resistance to apoptosis, therefore, is probably a principal mec hanism whereby tumors are able to overcome these cancer therapies. The tran scription factor NF-kappa B is activated by chemotherapy and by irradiation in some cancer cell lines. Furthermore, inhibition of NF-kappa B in vitro leads to enhanced apoptosis in response to a variety of different stimuli. We show here that inhibition of NF-kappa B through the adenoviral delivery of a modified form of I kappa B alpha, the inhibitor of NF-kappa B, sensiti zes chemoresistant tumors to the apoptotic potential of TNF alpha and of th e chemotherapeutic compound CPT-11, resulting in tumor regression. These re sults demonstrate that the activation of NF-kappa B in response to chemothe rapy is a principal mechanism of inducible tumor chemoresistance, and estab lish the inhibition of NF-kappa B as a new approach to adjuvant therapy in cancer treatment.