Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 4 of 12 Ruszniewski et al evaluated the efficacy and safety of the 28-day aqueous prolonged release formulation of lanreotide in 75 patients in a 6-month dose-titration study. Thirty percent of patients showed a biochemical response and 75% and 80% of patients reported resolu- tion of diarrhea and flushing, respectively, which is com- parable with the reported effects of other lanreotide preparations. The median decrease in levels of urinary 5-HIAA and serum chromogranin A was 24% and 38%, respectively [31]. An interim analysis of a phase II trial of SOM230 in 21 patients with metastatic carcinoid tumours whose symp- toms (diarrhea and flushing) were refractory/resistant to octreotide LAR showed symptom relief in 33% [32]. Approximately 10-15% of patients with midgut carci- noids suffer from watery diarrhoea, flushing, right-sided heart failure and bronchial constriction (carcinoid syn- drome), due to the tumour hypersecretion of a variety of endocrine substances, the most frequent of which are serotonin (5-hydroxytryptamine) and the tachykinins [33,34], and therefore somatostatin analogues are impor- tant palliative tools for these patients. In insulinoma it has been noted that octreotide treatment may make hypoglycemia worse in those patients lacking SSTRs 2 and 5, and, as glucagon secretion is also inhibited, patients have to be observed closely at the beginning of therapy to prevent severe hypoglycemia due to the reduced glucagon-dependent counter-regulation [35]. Hence, this treatment has to be started in a hospital set- ting, and should be reserved for only the minority of insulinoma patients with positive imaging on SRS. Vezzosi et al recently assessed that octreotide was effective in the control of hypoglycaemia in more than 50% of the insulinoma patients. The treatment was effective in all SSTR 2 positive patients and in a few SSTR 2 negative ones, while no relation between treat- ment effectiveness and the expression of SSTR 5 was observed [36]. These results are in concordance with other case reports and smaller series of insulinoma patients reported in the literature [37-41]. In glucagonoma patients somatostatin analogue treat- ment is indicated for alleviating the symptoms related to the characteristic skin rash (necrolytic migratory erythema) or diarrhoea [42-46]. In somatostatinomas symptoms are due to somatosta- tin hypersecretion (hyperglycaemia, cholelithiasis, diar- rhoea and steatorrhoea, hypochlorhydria) or to the mass effect [47]. Although it seems a paradox to treat patients with symptoms related to elevated SST levels with a somatostatinoma, in 1998 Angeletti et al showed that octreotide treatment was effective in reducing plasma levels of somatostatin and improving the related symp- toms in three patients with metastatic somatostatinomas [48]. Recently, have been described nine cases of VIP-oma in which octreotide was very successful as adjuvant ther- apy for symptoms control and for reducing the serum elevated VIP levels improving the diarrhoea and the electrolyte imbalance [49-51]. The anti tumour effects of SST analogues The antineoplastic activity of somatostatin analogues has been demonstrated in several experimental models in vivo and in vitro [52-57]. However, there is still little known regarding the antiproliferative role of SSA in GEP NETs, although increasing data suggest that such analogues can be tumouristatic, at least in some circum- stances [58]. The antineoplastic action of SST analogues depends on the kind of tumour and the receptor subtypes they are bound to, and occurs through direct and indirect mechanisms. While direct activities are mediated by spe- cific membrane receptors and include antimytotic and apoptotic effects, indirect effects do not depend on the receptor bonging and encompass the growth factor inhi- bition, antiangiogenic and immuno-modulating activ- ities. As a matter of fact, SST analogues are able to inhibit the growth of Swarn chondrosarcoma, used as experimental model of SSTR free tumour [59]. The mitosis inhibition is mediated by SSTRs 2 and 5 and results in the cell cycle arrest [55]. The loss of the SSTR 2 expression in some human adenocarcinomas seems to be responsible for loosing the regulation of cell proliferation [8]. The loss of SSTR 2 may consequently promote tumour growth and make it clear the therapeu- tic inefficacy of SST analogues in such kind of neoplasia. Apoptosis [programmed cell death] seems to be induced by two different processes: interaction with the SSTR 3 [53] and inhibition of the Insulin-like Growth Factor I (IGF I), potent antiapoptotic hormone [60]. The pro- apoptotic activity of SST analogues seems to have clini- cal relevance, as shown by the interesting findings published by Eriksson et al. that reported an increase in apoptosis in bioptic samples of tissues by patients with GEP NETs, after the treatment with SST analogues at high doses. It followed that apoptosis is related to the biochemical response and the disease stabilisation (70% of cases) [61,62]. However, Faiss et al. observed an overall response rate (ORR) of 6.7%, comparable to that recorded at conven- tional doses [63], in 24 patients with GEP NETs treated with high doses of lanreotide (15 mg/day). The indirect antiproliferative efficacy of SST analogues is shown by an antiangiogenic mechanism. Angiogenesis, that is the growth of new blood vessels, is essential for tumour growth and metastasis spread. Consequently, the growth can be actually controlled by reducing the vascularisation of the neoplastic tissue. In experimental