Activation of the Ki-ras proto-oncogene is common in colon carcinogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit carcinogen-induced colon carcinogenesis, decrease the frequency of Ki-ras mutations in the azoxymethane-treated rat model, and induce apoptosis in a variety of cell types. Sulindac, as well as other non-steroidal anti-inflammatory agents, are provided in combination with DFMO the prevention and/or treatment of cancers characterized by the expression of an activated Ki-ras. Provided with the present invention are pharmaceutically acceptable compositions that include a non-steroidal anti-inflammatory agent, sulindac, together with an effective amount of difluoromethylornithine.
This application claims the benefit of U.S. Provisional Application, Ser. No. 60/079,850, filed Mar. 28, 1998. The government owns rights in the present invention pursuant to grant number CA-72008 from the National Institutes of Health.
Treatment of normal, non-cancerous, animal cells with an agent that depletes polyamines within the cells results in an inhibition of apoptosis when the cells are exposed to an inducer of apoptosis. This inhibition of apoptosis is not observed, or is observed to a lesser extent, in similarly treated cancerous cells. The method of the invention is useful in obtaining preferential killing of cancer cells, as opposed to normal cells, due to anti-cancer therapy.
Treatment of normal, non-cancerous, animal cells with an agent that depletes polyamines within the cells results in an inhibition of apoptosis when the cells are exposed to an inducer of apoptosis. This inhibition of apoptosis is not observed, or is observed to a lesser extent, in similarly treated cancerous cells. The method of the invention is useful in obtaining preferential killing of cancer cells, as opposed to normal cells, due to anti-cancer therapy.
Genes encoding an apoptosis-induced eukaryotic initiation Factor-5A (eIF-5A) and an apoptosis-induced deoxyhypusine synthase (DHS), whose expressions are induced by the onset of apoptosis, are identified. The DHS gene and the eIF-5A gene, alone or in combination, as well as inhibitors of the DHS reaction, are used to modulate apoptosis in animals and humans. For example, modulation of apoptosis in cells of animals and humans is achieved by introduction of a gene or gene fragment encoding apoptosis-induced eIF-5A, apoptosis-induced DHS, or both into the animal or human cell in antisense orientation.
Celecoxib, a COX-2 specific non-steroidal anti-inflammatory agent, is provided in combination with DFMO for the prevention and/or treatment of cancers. Provided with the present invention are pharmaceutically acceptable compositions that include a non-steroidal anti-inflammatory agent, celecoxib, together with an effective amount of difluoromethylornithine.
