Somatostatin (SS) can inhibit growth hormone (GH) secretion from the pituitary and tumor cell proliferation via membrane-bound receptors (SST). Five SST subtypes have been cloned and can be discriminated by specific peptides. In order to evaluate the human tissue distribution of the SSTs, we first used the cross-linking assay with the 125I-SS-14. A cross-linked complex of 57 kDa was detected in a majority (76%) of the surgical biopsies of normal and tumoral tissues examined (N = 222) and in all tested cell lines (N = 20). However, in regard to the organs, the incidence varied from 33% (epiploon metastases) to 100% (colorectal adenocarcinoma, prostate). Additional, minor SS-14 cross-linked complexes were detected in a few samples, suggesting the simultaneous existence of other SST subtypes. In tumor cell lines, the 57-kDa complex was reduced by the SST2-selective SS analogs BIM23014, BIM23060, and BIM23068, and by SS-14 but not by the non-SST2-selective BIM23052 and BIM23056. Its pharmacological profile therefore corresponded to SST2. Northern blot analysis showed one 2.5-kb human SST2 mRNA in these cell lines. We demonstrate that SST2 is detectable in normal and tumoral human tissues and thus represents an SST subtype target for the development of more specific SS analogs.

Neuroblastoma is a pediatric cancer for which a cure is elusive for most children with disseminated disease. Neuroblastomas possess receptors for somatostatin (SS). Some SS analogues can inhibit their proliferation. In addition, when SS analogues were used as agents for scintigraphy, neuroblastoma tumor sites can be localized with high efficiency. In this study, to better characterize the SS receptor subtype(s) (sst1-5) present in primary tumors and metastases of neuroblastoma, we show that: (1) The ligand 125I-Tyr11-SS-14 binding on membrane proteins from primary tumors and metastases of neuroblastoma cell line IGR-N-91 developed in nude mice shows similar values of Kd (in order of 0.1 nM) and Bmax (in order of fmol/mg) by filter-retention assay. These data are close to those measured on two other neuroblastoma cell lines: SK-N-SH and IGR-N-835 or to that measured on the rat cerebral cortex. (2) The IGR-N-91 sublines derived from primary tumor and metastases show one major complex of 57 kD by the chemical cross-linking assay using the ligands: 125I-SS-14 and 125I-BIM23014. One similar major complex of 57 kD was also detected in SK-N-SH and IGR-N-835 or in the cerebral cortex. (3) Addition of excess nonlabeled peptides selective for sst2 (BIM23014, BIM23060, BIM23068) suppressed the formation of the complex 57 kD whereas addition of BIM23052 or BIM23056 (sst5 and sst3 selective respectively) does not. This pharmacological profile corresponds to sst2. (4) Only RNA message of sst2 gene is detected in IGR-N-91 cells and its metastases derived sublines by reverse-transcription-polymerase chain reaction and Northern hybridization in keeping with the presence of sst2. (5) In human biopsies, the complex of 57 kD corresponding to sst2 is consistently detected in three samples of the histological subset of the disease: benign ganglioneuroma, ganglioneuroblastoma and immature neuroblastoma. Therefore, the sst2 should be considered as the primary target to develop more potent SS analogues for neuroblastoma therapy or/and scintigraphy.

A prescriptive method for conceptual data analysis is presented. The method uses a data model which is well defined and has natural expressiveness.