INDUCTION OF APOPTOSIS IN NEUROENDOCRINE TUMORS OF THE DIGESTIVE-SYSTEM DURING TREATMENT WITH SOMATOSTATIN ANALOGS

The extent of apoptosis identified by in situ DNA nick end labelling ( TUNEL) on tissue samples obtained from patients with neuroendocrine tu mors was correlated with the clinical outcome in patients treated with high-dose somatostatin analog (lanreotide 12 mg/day), n = 8, or other biotherapy including interferon-alpha (IFN-alpha), n = 4, low-dose so matostatin analog (octreotide or lanreotide), n = 3, or a combination of both, n = 1. Biopsies were obtained before the start of treatment a nd/or after 6 months and 12 months. After 6 months of treatment, 5 pat ients receiving high-dose somatostatin analog showed a biochemical res ponse (decrease in different neuroendocrine tumor markers) and 4 of th ese showed an increase in apoptotic index (AI: percentage of apoptotic cells) by 1.94 +/- 1.71%. At 12 months, AI was also increased in pati ents with a biochemical response (4.22 +/- 3.93%). However none showed a decrease in tumor size on computerized tomography (CT) and none of the patients treated with low-dose somatostatin analog or IFN-alpha sh owed any significant increase in AI during treatment. In an experiment al model, nude mice were xenografted with the neuroendocrine cell line (BON-1). From the 2nd day of tumor implantation, they received treatm ent with either placebo, high-dose octreotide, IFN-alpha, or a combina tion of both, for 28 days. In mice receiving treatment with high-dose octreotide (300 mu g/kg, t.i.d) there was a threefold increase in apop totic cells as compared to the placebo group (p = 0.0084), while the c ombination group had few cells with ultra-structural changes indicatin g apoptosis and the IFN-alpha treated group showed no significant chan ges. However, tumor growth inhibition was more pronounced in the combi nation group (p=0.0011). This probably denotes that tumor growth inhib ition could be achieved more efficiently by blocking the cell cycle th an by inducing apoptosis. We concluded that treatment with high-dose s omatostatin analogs may induce apoptosis in neuroendocrine tumors, whi le this is not found during treatment with low-dose somatostatin analo gs or IFN-alpha. We also found that an increase in AI during high-dose somatostatin analog treatment was correlated with the biochemical res ponse, but not with the tumor size as detected by CT in patients or wi th the tumor mass in the experimental model.