[Frontiers in Bioscience 2, d271-282, June 1, 1997]
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THE ROLE OF LANGERHANS ISLETS IN PANCREATIC DUCTAL ADENOCARCINOMA
Parviz M. Pour

The UNMC/Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE

Received 5/6/97 Accepted 6/2/97

6. EVIDENCE FOR THE IMPORTANCE OF INTACT ISLETS FOR PANCREATIC ADENOCARCINOMA INDUCTION

Several studies have demonstrated that intact islet cells are a prerequisite for the induction of exocrine pancreatic cancer from within islets. Alloxan, a nitroso compound that almost selectively destroys b-cells and causes diabetes, when it was given shortly before the pancreatic carcinogen, N­nitrosobis(2­oxopropyl)amine (BOP), significantly inhibited the induction of pancreatic cancer from both ductal/ductular cells and within islets in the hamster model (54). A more dramatic effect was obtained by the pretreatment of hamsters with a more potent b-cell cytotoxic agent, streptozotocin (55). A complete destruction of b-cells by large doses of streptozotocin before BOP treatment totally prevented induction of any exocrine pancreatic lesions, although all control hamsters not pretreated with streptozotocin often had multiple cancers (56). Apparently, not only the b-cells but also the pluripotent pancreatic cells (the target of the carcinogen) are damaged by this drug. The tumor protective effect of streptozotocin was lost when it was given after BOP treatment or when the cytotoxic action of streptozotocin on the b-cells was prevented by nicotinamide (56,57). This suggests that this diabetogenic compound directly (by destroying the BOP target cells) or indirectly (by causing metabolic alterations) interferes with the initiation stage of pancreatic carcinogenesis. The indirect effect of streptozotocin on the induction of pancreatic cancer was suggested by the experiment of Bell et al. in a two­pancreas hamster model (58). In this technically difficult but superbly executed experiment, the pancreas of the streptozotocin-treated hamsters (SZ-pancreas) were transplanted, as a second pancreas, into the untreated host hamsters that received BOP after transplantation. The incidence of developing pancreatic tumors in SZ-pancreas did not differ from the incidence of tumorigenesis in the native pancreas of the host. In addition, there was an inverse relationship between the plasma glucose level of the host and the tumor incidence in both transplanted and native pancreata. From this study it was concluded that the inhibitory effect of streptozotocin appears to be systemic, i.e., related to diabetes, rather than to its toxic effect on the pancreas.