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 Flavopiridol promote tumour growth and make it clear the therapeutic 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 clinical relevance, as shown by the interesting

findings published by Eriksson et al. that reported an increase in apoptosis in bioptic samples of LXH254 cell line 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 conventional 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 HM781-36B mw by reducing the vascularisation of the neoplastic

tissue. In experimental models, octreotide shows a strong antiangiogenic effect, which is probably mediated by the inhibition of the Vascular Endothelial Growth Factor (VEGF) [64–66]. The response to the treatment with octreotide would result in a significant reduction in VEGF levels compared to the baseline, since it Nintedanib (BIBF 1120) is related to patients’ survival [66]. It was observed that standard endothelial cells do not express the SSTR 2 that is present on the contrary, when they proliferate in order to form blood vessels. This could represent further opportunity to treat patients with octreotide that is able to recognise and inhibit new vessel formation both alone and with other drugs, thanks to its

high affinity with such receptor (Table 3). Immunomodulation is another indirect mechanism of action of SST analogues. Preliminary evidence suggests that they stimulate the production of immune system components with antitumour effect, such as natural-killer cells [67, 68], even if up to now it is not clear whether this can be clinically significant thus helping the antitumour efficacy of SST analogues. Few data exists on the functions mediated by the SSTR 4. However, no unanimity exists about the SST analogue ability to control (i.e. to slow) the tumour progression. In vitro studies reported that the response of different cell lines to the octreotide exposition produces a biphasic dose-response curve [69, 70]. Consequently, overdose or underdose of SST analogues may result in a suboptimal antineoplastic activity.