Objective: This study compared the potency of a somatostatin receptor (sstr)2 -sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide. Materials and methods: The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations. Results: In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels^S.E.M. 0.4^0.1, 5.3^1.9 and 2.0^0.4 copy/copy b-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30^3%) and BIM-23244 (28^3%) was greater than that produced by octreotide (23^3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM-23A761 produced greater maximal suppression of GH secretion than octreotide (33^5, 38^2 and 41^2 vs 24^2%). Their EC 50 values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41^2 vs 32^4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62^8 to 74^5 vs 46^11%). Conclusions: Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC 50 1-10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated.

Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for a-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9G2.6 copy/copy b-glucuronidase; meanGS.E.M.), when compared with sstr3 and sstr2 (0.6G1.0 and 0.3G0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [ 3 H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC 50 Z1.2 pM and E max ZK33.6G3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.

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Summary Acceleration of secondary tumour growth and metastases following excision of a primary tumour has been attributed to the consequent removal of primary tumour-generated inhibitory factors. However, our studies have shown that surgical wounding of normal tissues significantly stimulated the growth of malignant tissues without the concomitant presence or excision of a tumour mass. A humoral stimulating component was indicated by the proliferative response of tumours and metastases distant from the surgical wound. All 16 human and murine tumours, of nine different histologies, showed a measurable acceleration of growth when implanted in surgically treated animals, suggesting that the ability of malignant tissue to respond to surgical wounding of normal tissue was not histologically or species specific. The proliferative surge of malignant tissues was detectable soon after wounding and had a duration of 2-3 days. The surgical wound as the source of the tumour-stimulating factor(s) was affirmed by the significant inhibition of tumour proliferative responses when a somatostatin analogue was applied topically to the surgical wound within 1 h of wounding, and/or during the critical tumour-stimulatory period of 1-2 days after wounding. A potential therapeutic window for reducing a risk factor that may be inadvertently imposed upon every surgical/oncology patient is indicated.Keywords: surgical wounding; wound-generated tumour growth factor; tumour proliferative response; lanreotide; normal tissue trauma Inhibition of tumour growth by tumour mass is a phenomenon recognized and repeatedly studied since the early 1900s (Ehrlich, 1908;Marie and Clunet, 1910;Tyzzer, 1913). Numerous reports, summarized more recently by Keller (1983) and O'Reilly et al (1994), have indicated that the presence of a primary tumour inhibits the growth rate of metastases or of a second tumour implant, and that removal or eradication of the primary tumour accelerates growth at secondary sites. Early explanations for apparent exacerbations of disease reflected Ehrlich's hypothesis of 'Athrepsia'; that any actively growing tumour removed certain specific nutritive material necessary for growth from the host animal (Ehrlich and Apolant, 1905). Subsequent explanations stressed surgical relief from growth-limiting factors, such as anatomical boundaries, anoxia and nutritional deficiencies, or that the immunological relation between host and tumour was somehow altered by surgery, thereby facilitating tumour escape. However, the underlying cause of the occasional explosive metastatic manifestation after resection of 'primary' malignancy remained in question. An alternative explanation, proposed by Keller (1983) inhibitor (angiostatin). They postulated that a primary tumour, while capable of stimulating angiogenesis in its own vascular bed by generating angiogenic stimulators in excess of angiogenesis inhibitors, the angiogenesis inhibitor, by virtue of its longer halflife in the circulation, reaches the vascular bed of a secondary tumour in excess o...

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As cotreatment of somatostatin (SRIF) and dopamine (DA) agonists reduces GH in acromegaly more effectively than either agonist alone, SRIF and DA receptors (SSTR and DAR) may interact with enhanced functional activity. The selective SSTR2 agonist, BIM-23023 (50% effective dose, 0.42), and the DAR2 agonist, BIM-53097 (50% effective dose, 22.1), dose- dependently inhibited GH secretion in cultured primary rat and human fetal as well as in human pituitary tumor cells derived from GH-secreting adenomas. The combination of individual SSTR2 and DAR2 agonists was additive for suppressing GH secretion in both rat and human pituitary cells. BIM-23A387 is a chimeric compound that contains structural elements of both SRIF and DA in a single molecule and retains potent, selective binding to DAR2 and SSTR2. BIM-23A387 (50% effective dose, 0.16 for SSTR2 and 24.5 for DAR2), displayed similar efficacy in suppressing GH secretion from rat pituitary cells as the combination of the two individual agonists. In contrast, the chimeric molecule was more potent than individual selective analogs in suppressing GH secretion by human fetal pituitary and GH-secreting adenoma cells (P < 0.05). Although the DAR2 antagonist, sulpiride, reversed BIM-23A387-induced GH suppression, blockade of SSTR2 by the selective SSTR antagonist, BIM-23454, did not block BIM-23A387-suppressed GH secretion. These results indicate that mechanisms by which the chimeric molecule suppresses pituitary GH secretion may not be mediated by individual SSTR2 or DAR2 signaling, respectively. Functional interaction of the two receptors may explain the clinical observation that more effective GH suppression is achieved when DAR2 and SSTR2 agonists are administered in combination. The SRIF/DA chimeric molecule, BIM-23A387, represents a novel tool for effective drug treatment of acromegaly and for prolactinomas otherwise resistant to dopaminergic therapy.

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