Showing papers by "Shinae Kizaka-Kondoh published in 2003"

Tumor hypoxia : A target for selective cancer therapy

Abstract: Tumor hypoxia has been considered to be a potential therapeutic problem because it renders solid tumors more resistant to sparsely ionizing radiation (IR) and chemotherapeutic drugs Moreover, recent laboratory and clinical data have shown that tumor hypoxia is also associated with a more malignant phenotype and poor survival in patients suffering from various solid tumors Therefore, selective targeting of hypoxic tumor cells has been explored, and since severe hypoxia (pO(2) < 033%, 25 mmHg) does not occur in normal tissue, tumor hypoxia could be exploited for therapeutic advantage However, the following three characteristics of hypoxic tumor regions present obstacles in targeting hypoxic cells First, it is difficult to deliver a sufficient amount of drug to a region that is remote from blood vessels Second, one must specifically target hypoxic tumor cells while sparing normal well-oxygenated tissue from damage Finally, the severely hypoxic tumor cells to be attacked have often stopped dividing Therefore, high delivery efficiency, high specificity and selective cytotoxicity are all necessary to target and combat hypoxic tumor cells The current review describes progress on the biological aspects of tumor hypoxia and provides a compilation of the recent molecular approaches used to target hypoxic tumors These approaches include our work with a unique hypoxia-targeting protein drug, TOP3, with which we have sought to address the above three difficulties

Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2

Abstract: Cyclooxygenase (COX)-2, a rate-limiting enzyme of prostaglandin (PG) production, is overexpressed in colorectal adenomas and adenocarcinomas, and its inhibition by nonsteroidal antiinflammatory drugs protects against colorectal cancer. Mechanisms of cancer promotion by COX-2 are not fully understood, but signaling through prostaglandin (PG)E2 receptors is a contributing factor. The major PGE2 receptors on epithelial cells, EP2 and EP4, increase cAMP production, which promotes growth and inhibits apoptosis in some cell types. Here, we show that cAMP agonists, including PGE2, cholera toxin, and a membrane-permeant cAMP analog, protect normal and transformed intestinal epithelial cells from apoptosis induced by diverse stimuli. This protection is associated with cAMP-mediated, rapid induction of cellular inhibitor of apoptosis protein (c-IAP)-2 and delayed induction of LIVIN, but not of six other members of the IAP family. Concurrently and characteristic of IAP functions, the activity, but not generation, of the cleaved form of the central executioner caspase 3 is inhibited. Induction of c-IAP2 expression by cAMP agonists is accompanied by phosphorylation of cAMP response element binding protein and cAMP response element-dependent activation of transcriptional reporters. Furthermore, inhibition of COX-2 in cells overexpressing the enzyme decreases c-IAP2 expression and promotes apoptosis, both of which are reversible by PGE2 addition, suggesting that COX-2-promoted antiapoptosis is mediated by release of PGE2 and subsequent cAMP-dependent c-IAP2 induction. These results help to explain the cancer chemoprotective effects of nonsteroidal antiinflammatory drugs by defining a mechanism through which cAMP signaling can promote the development of colorectal and possibly other epithelial cancers by means of disruption of normal apoptotic processes.