Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 8 of 12 30- to 40-times higher for SSTR 1 and SSTR 5 than octreotide. In a multicentre study on metastatic carci- noid tumours patients whose symptoms (diarrhoea and flushing) were refractory to octreotide-LAR, pasireotide at dosages between 450 μg and 1200 μg twice a day effectively controlled symptoms in 33% of these patients [97]. These results support the hypothesis that pasireo- tide may have potential in the treatment of these tumours. Subtypes of somatostatin and dopamine recep- tors may form homo- and hetero-dimers at the mem- brane level, and this receptor “association” may be induced by addition of either dopamine or somatostatin. Recently, subtype selective analogues and antagonists, as well as bi-specific and hybrid somatostatin/dopamine compounds, binding to SSTR 2, SSTR 5 and dopamine 2 receptors have been developed [98]. Their effects have been studied in several animal and human cell lines, and also in primary cultures from human tumours. Regard- ing their activity the literature is scanty. Further studies are needed to understand their complex and heteroge- neous effects. Chimeric somatostatin-dopamine com- pounds (dopastatins) with high affinity for SSTRs 2 and D2 receptor (D2R) (BIM-23A387) or to SSTRs 2, 5 and D2R (BIM-23A760) have been showed to inhibit cell proliferation of the non-small-cell lung cancer cell line Calu-6, which expresses SSTRs 2, 5 and D2R with higher potency and efficacy than SSTR 2 and D2R ana- logues [99]. BIM23A760 can also inhibit ECL cell prolif- eration with similar potency but with higher efficacy than lanreotide and D2R analogue [9]. The enhanced potency/efficacy of BIM-23A387 and BIM-23A760 may in part be due to the high affinity of these compounds for SSTR 2. However, SSTR 2 can heterodimerize with SSTR 5, and SSTRs 2 and 5 can form heterodimers with D2R which can alter receptor ligand binding affinity and/or signaling and/or receptor trafficking [100-102]. The presence of SSTRs in a higher density in NETs and their ability to form a receptor-ligand complex, can per- mit the internalisation and the accumulation of radio- pharmaceutical inside the tumour [103]. A novel targeted cytotoxic somatostatin octapeptide conjugates such as RC-121 and RC-160 coupled to dox- orubicin or its superactive derivative, 2-pyrrolino-DOX (AN-201) was synthesised from Schally and coworkers [56]. AN-238, which contains AN-201 linked to carrier RC-121, has been demonstrated to suppress the growth of Hs746T and NCI-N87 human gastric cancers, which display a high concentration of SSTRs 2 and 5 and seems to target vascular SSTRs in a xenograft tumour model derived from SSTRs negative tumour cells [56]. Another cytotoxic somatostatin analog termed JF-10- 81 has been synthesized by Coy and coworkers. This somatostatin analogue, conjugated to camptothecin, inhibits prostate cancer PC-3 cell invasion through a signaling pathway involving PI3K, integrin aVb3/aVb5 and matrix metalloproteinases 2 and 9 and exhibited anti-invasive and anti-angiogenic properties in vivo [103]. SSTRs are able to form a receptor-ligand complex, that permit the internalisation and the accumulation of the radiopharmaceutical inside the tumour. Peptide-receptor radionuclide therapy (PRRT) repre- sents an important treatment strategy for tumours that express adequate densities of SSTRs and has proven to be safe and effective. It was initially performed using indium-111 [19,104]. Recently, the development of somatostatin peptides with higher receptor affinity conjugated with radio-metal labelling chelators, such as DOTA (1,4,7,10-tetrazacyclo- dodecane-N, N’, N”, N"’-tetraacetic acid), which may be allow stable labelling with gallium, yttrium or lutetium, changing the affinity profile for particular subtypes of SSTRs can permit new therapeutic options [105]. Wald- herr et al evaluated the tumour response to targeted irradiation with the radiolabelled somatostatin analogue 90Y-DOTATOC in 41 patients with GEP NET and bronchial tumours. They reported an overall response rate of 24%. For endocrine pancreatic tumours it was 36%. A complete remission was found in 2%, a partial remission (PR) in 22%, a minor response in 12%, stable disease in 49% and progressive disease in 15% of patients. The treatment was well tolerated and there was a significant reduction of symptoms and the 2-year survival time was 76 ± 16% [106]. 177Lu DOTATATE [177Lu]DOTA-Tyr(3)-octreotate, a selective analogue of SSTRs 2. In spite of its favour- able affinity profile, at its maximum tolerated dose, it is limited by toxic effects on the kidney and bone marrow. Nevertheless, the results seem encouraging compared with historical therapeutic data [107]. Kwekkeboom et al obtained promising results using 177Lu DOTATATE [177Lu]DOTA-Tyr(3)-octreotate in 131 patients with NETs. A complete remission was observed in 2% of patients, a partial remission in 26%, a minor response in 19%, stable disease in 35%, and pro- gressive disease in 18% of patients. Higher remission rates were positively correlated with high uptake on pre- therapy SSTRs imaging, whereas progressive disease was significantly more frequent in patients with extensive disease. Median time to progression was more than 36 months [19]. The combination of 90Y- and 177Lu-labeled analogues [108] seems to have had superior antitumour effects when compared with either 90Y- or 177Lu-analogue in animals presenting with tumours of various sizes. It has been reported that 177 Lutetium may be more effective for smaller tumours whereas 90yttrium may be more effective for larger tumours [109,110].