INTERFERON-ALPHA INDUCES BCL-2 PROTOONCOGENE IN PATIENTS WITH NEUROENDOCRINE GUT TUMOR RESPONDING TO ITS ANTITUMOR ACTION

We have studied the expression of apoptosis regulating genes bcl-2 and bax in neuroendocrine gut tumors. The expression pattern of these gen es was compared with the clinical response (changes in the tumor marke rs and changes of the tumor size determined by radiology) after treatm ent with interferon-alpha (IFN-alpha, n=13), somatostatin analog (octr eotide, n=3; lanreotide, n=2) or a combination of both (n=5). Immunohi stochemistry and in situ RT-PCR were performed and expressions were sc ored from 0 (no staining) to 6 (strong and wide-spread staining). With regard to clinical outcome, the scores (mean +/- SEM) of immunohistoc hemical staining of bcl-2 and bax were 1.77+/-0.25 and 4+/-0.22 for pa tients with stable disease and, 0.54+/-0.28 and 4.68+/-0.21 for patien ts with progressive disease. The scores of bcl-2 and bax staining for IFN-alpha-treated patients were 1.96+/-0.35 and 4.12+/-0.31 and for un treated patients were 0.5+/-0.25 and 4.5+/-0.21, respectively. Express ion of bcl-2 was observed in all IFN-a-treated patients who responded to the drug but not in nonresponsive patients (p=0.0027). In contrast, bax, a promotor of apoptosis was expressed in all patients with highe r degree of expression seen in patients with progressive disease (p=0. 0364). We have also detected bcl-2 expression by western blot analysis in neuroendocrine tumor tissues grown in nude mice, which were treate d with IFN-alpha for 28 days. Our results indicate that, IFN-alpha can induce bcl-2. Thus, we, propose that bcl-2 may be used as a prognosti c market for IFN-alpha sensitivity of neuroendocrine tumors.