Induction of Apoptosis in Neuroendocrine Tumors of the Digestive System During Treatment with Somatostatin Analogs

Abstract

The extent of apoptosis identified by in situ DNA nick end labelling (TUNEL) on tissue samples obtained from patients with neuroendocrine tumors 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-α), n = 4, low-dose somatostatin analog (octreotide or lanreotide), n = 3, or a combination of both, n = 1. Biopsies were obtained before the start of treatment and/or after 6 months and 12 months. After 6 months of treatment, 5 patients receiving high-dose somatostatin analog showed a biochemical response (decrease in different neuroendocrine tumor markers) and 4 of these showed an increase in apoptotic index (AI: percentage of apoptotic cells) by 1.94 ± 1.71%. At 12 months, AI was also increased in patients 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-α showed any significant increase in AI during treatment. In an experimental model, nude mice were xenografted with the neuroendocrine cell line (BON-I). From the 2nd day of tumor implantation, they treatment with either placebo, high-dose octreotide, IFN-α, or a combination of both, for 28 days. In mice receiving treatment with high-dose octreotide (300 μg/kg, t.i.d) there was a threefold increase in apoptotic cells as compared to the placebo group (p = 0.0084), while the combination group had few cells with ultra-structural changes indicating apoptosis and the IFN-α treated group showed no significant changes. However, tumor growth inhibition was more pronounced in the combination group (p = 0.0011). This probably denotes that tumor growth inhibition could be achieved more efficiently by blocking the cell cycle than by inducing apoptosis. We concluded that treatment with high-dose somatostatin analogs may induce apoptosis in neuroendocrine tumors, while this is not found during treatment with low-dose somatostatin analogs or IFN-α. We also found that an increase in AI during high-dose somatostatin analog treatment was correlated with the biochemical response, but not with the tumor size as detected by CT in patients or with the tumor mass in the experimental model.