Partial inhibition of the growth of transplanted dunning rat prostate tumors with the long-acting somatostatin analogue sandostatin (SMS 201-995).

The growth-inhibiting effects of the long-acting somatostatin analogue Sandostatin on the transplanted Dunning R3327-H androgen-sensitive rat prostate tumor were investigated. Recipient animals were male Copenhagen x Fischer F1 rats (N = 36). When mean tumor volume reached 700 mm3 (20 weeks following transplantation), the rats were divided into four groups: control; Sandostatin (100 micrograms/kg s.c. twice a day); castrate; castrate/Sandostatin. Tumor size was assessed by magnetic resonance imaging 21, 42, 63, 105, and 138 days subsequently. Administration of Sandostatin was interrupted between days 43 and 62. As assessed by transplant volume, Sandostatin caused a moderate (up to 50%) but highly significant (P less than 0.001) suppression of tumor growth in the intact rats; the effect was reversed when drug administration was stopped. In the castrates, in which tumor growth was markedly less than in intact rats, no significant effect of Sandostatin was seen. Analysis of the tumor growth rate demonstrated that Sandostatin led to a 19% reduction (P less than 0.05) in growth rate in intact rats and a 9% decrease (not significant) in castrates. These findings extend previous reports of partial suppression of various types of tumors in vivo with Sandostatin and other somatostatin analogues. Their relevance with regard to the possible use of Sandostatin in the treatment of prostatic carcinoma in humans is discussed.

Antiproliferative effects of the somatostatin analogue octreotide (SMS 201-995) on ZR-75-1 human breast cancer cells in vivo and in vitro.

The somatostatin analogue octreotide (SMS 201-995) inhibits secretion and growth of certain tumor cells, and current efforts are directed toward the elucidation of its mode of antiproliferative action. In this study, the effect of octreotide on the growth of ZR-75-1 human breast cancer cells has been characterized in immunodeficient nude mice and in cell culture. These results have been related to the expression of somatostatin receptors in vivo and in vitro. Continuous infusion of 10 micrograms/kg/h of octreotide yielded plasma levels of 5.7 ng/ml and elicited highly significant growth inhibitory effects on solid ZR-75-1 breast tumors in nude mice. After 2 and 4 weeks of treatment, tumor volumes in the octreotide group were 39.1 and 36.7% of those of control animals treated with vehicle, respectively. Autoradiographic studies demonstrated that 8 of 12 ZR-75-1 tumors studied were somatostatin receptor positive. When ZR-75-1 tumor cells were exposed in vitro to nanomolar concentrations of octreotide, a dose-dependent inhibition of cell growth was observed in the presence of 5% fetal calf serum or under serum-free conditions using epidermal growth factor, insulin-like growth factor type I, or insulin as growth stimulus. In parallel receptor-binding experiments, ZR-75-1 cells were shown to express specific high-affinity somatostatin receptors (Kd value = 0.9 nM, Bmax = 6000 sites/cell). From these experiments, we conclude that octreotide is a powerful inhibitor of ZR-75-1 tumor cell growth in nude mice and in culture. This inhibitory action of octreotide and the presence of somatostatin receptors on ZR-75-1 tumor cells in vitro and in vivo suggest a direct, somatostatin receptor-mediated effect of octreotide.

Somatostatin analogue octreotide enhances the antineoplastic effects of tamoxifen and ovariectomy on 7,12-dimethylbenz(alpha)anthracene-induced rat mammary carcinomas.

The efficacy of tamoxifen and ovariectomy in the management of breast cancer is limited by the resistance of many neoplasms to these endocrine therapies and by the fact that initially responding tumors often escape from control during long-term treatment. We evaluated the effect of coadministration of the somatostatin analogue octreotide, which has single agent activity in several in vivo and in vitro breast cancer models, on the antineoplastic actions of tamoxifen and ovariectomy on 7,12-dimethylbenz(alpha)anthracene-induced mammary tumors. Rats received tamoxifen (0.5 mg/kg twice weekly s.c.), octreotide (10 micrograms/kg/h for 6 weeks by osmotic minipump), or the combination 7 weeks following 7,12-dimethylbenz(alpha)anthracene administration. The number of tumors per animal and the sum of the volumes of palpable tumors per animal were significantly less in the combination treatment than in the others. In ovariectomized rats the marked regression of established tumors in the initial 4 weeks after ovariectomy was frequently followed by tumor regrowth. However, continuous infusion of octreotide (50 micrograms/kg/h for 6 weeks postovariectomy) significantly (P < 0.01) suppressed this regrowth. Our data suggest that octreotide enhances the antitumor effects of tamoxifen or ovariectomy in the 7,12-dimethylbenz(alpha)anthracene mammary cancer model.

Tifluadom-induced diuresis in rats. Evidence for an opioid receptor-mediated central action.

Tifluadom dose-dependently induced diuresis in rats after subcutaneous injection and oral application. (+)Tifluadom was at least 100-fold more potent than the (-)enantiomer in inducing diuresis. The diuretic action of tifluadom was dose-relatedly reduced by the opioid receptor antagonists naloxone and MR 2266. Naloxone methobromide did not antagonize the diuretic effect of tifluadom nor did the benzodiazepine receptor blocker Ro 15-1788. These data demonstrate that the diuretic effect of tifluadom is mediated centrally via an agonistic interaction between the drug and opioid receptors.

Effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on 5-HTP-induced head shaking and behavioral symptoms induced by 5-methoxy-N,N,dimethyltryptamine in rats: comparison with some other 5-HT receptor antagonists.

The effect of the selective 5-HT3 receptor antagonists ICS 205-930 and MDL 72222 on head shaking behavior induced by L-5-HTP and behavioral symptoms induced with 5-methoxy-N,N,-dimethyltryptamine (5-MeODMT) in rats was evaluated. Both drugs dose-dependently reduced L-5-HTP-induced head shaking but were at least 600 times less potent than pirenperone and ketanserin and at least 50 times less potent than methysergide. ICS 205-930 and MDL 72222 were more than 1000 times less potent than pirenperone or methysergide and 100 times less potent than ketanserin in blocking 5-MeODMT-induced forepaw treading and tremor. Since it appears that head shakes induced by L-5-HTP are mediated by 5-HT2 receptors, these data suggest that ICS 205-930 and MDL 72222 do not significantly interact with 5-HT2 receptors in the brain. Furthermore, the data suggest that ICS 205-930 and MDL 72222 lack appreciable antagonistic activity at the 5-HT receptor(s) mediating those behavioral effects induced by 5-MeODMT.

Preclinical studies on the anticancer activity of the somatostatin analogue octreotide (SMS 201-995).

The antiproliferative effect of somatostatin-14 and its analogue, octreotide, on in vitro pancreatic and breast tumor cells has led to the suggestion that octreotide may have further oncological indications in addition to its use in the treatment of gastroentero-pancreatic (GEP) tumors. To extend these in vitro observations, we evaluated the effect of octreotide in rodent models of pancreatic and breast tumors. Octreotide at a dose of 5 micrograms or 50 micrograms twice a day in nude mice bearing solid MiaPaCa pancreatic tumors (subline 21) or ZR-75-1 breast tumors induced a significant inhibition of tumor growth from week 2 until the end of treatment at week 5. After 5 weeks, the mean volume of ZR-75-1 tumors in animals treated with the 50-micrograms regimen was 48% of that in controls. Autoradiographic studies showed that a high percentage (71%) of ZR-75-1 tumors were somatostatin receptor-positive. In addition, the growth of ZR-75-1 cells in vitro was significantly inhibited by octreotide. The drug was also tested in a second breast cancer model, 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors in rats, and continuous administration of 10 micrograms/kg/h over 6 weeks led to an approximate 50% reduction in the number of tumors arising in the rat mammary gland. These data suggest that pancreatic and breast cancer may be among the malignant diseases clinically susceptible to octreotide.

Preclinical studies on the anticancer activity of the somatostatin analog octreotide (SMS 201-995).

The antiproliferative effect of somatostatin-14 and its analog octreotide on in vitro pancreatic and breast tumor cells has led to the suggestion that octreotide may have further oncological indications in addition to gastroenteropancreatic tumors. To extend these in vitro observations, we evaluated the effect of octreotide in rodent models of pancreatic and breast tumors. Octreotide of 5 or 50 micrograms b.i.d. in nude mice bearing solid MiaPaCa pancreatic tumors (subline 21) or ZR-75-1 breast tumors induced significant inhibition of tumor growth from week 2 until the end of treatment at week 5. After 5 weeks the mean volume of ZR-75-1 tumors in animals treated with the 50-micrograms regimen was 48% that of control. Autoradiographic studies showed a high percentage (71%) of ZR-75-1 tumors to be somatostatin receptor-positive. In addition, the growth of ZR-75-1 cells in vitro was significantly inhibited by octreotide. The drug was also tested in a second breast cancer model, DMBA-induced mammary tumors in rats, and continuous administration of 10 micrograms/kg/h over 6 weeks led to an approximately 50% reduction in the number of tumors arising in the rat mammary gland. These data suggest that pancreatic and breast cancer may be among the malignant diseases clinically susceptible to octreotide.

Visualization and quantification of transplanted Dunning prostate tumors in rats using magnetic resonance imaging.

Quantitative magnetic resonance imaging (MRI) has been used for the in vivo size determination of subcutaneously implanted Dunning R3327-H tumors in male Copenhagen-Fisher rats (N = 18). Images have been recorded using a multislice spin-echo sequence SE(1000/36) with a resolution of 0.2 x 0.2 mm2 in the imaging plane and a slice thickness of 2 mm. The reliability in the MRI size determination was of the order of 10%. The MRI results were compared with caliper measurements. Five months after tumor implantation nine rats were castrated. Orchiectomy led to a marked and statistically significant reduction in tumor growth rate as determined by both methods of quantification. Qualitative MRI information regarding the tumor morphology was compared with that for histological specimens.

Potentiation of the anti-proliferative effects of anti-cancer drugs by octreotide in vitro and in vivo.

The somatostatin analogue octreotide (SMS 201-995) exerts potent anti-proliferative effects in a number of experimental cancer models. Here we report on the inhibitory effect of octreotide in combination with the chemotherapeutic agents mitomycin C, doxorubicin, 5-fluorouracil, or taxol on the growth of AR42J pancreatic cancer cells in vitro. The dose-dependent anti-proliferative effects of mitomycin C, doxorubicin and taxol were synergistically enhanced by octreotide. Combinations of octreotide and 5-fluorouracil resulted either in additive or, at high concentrations of the chemotherapeutic agent, in synergistic interactions. Combined treatment with doxorubicin and octreotide was also studied for time dependency and potential efficacy in tumour-bearing animals. Pretreatment (24 h) with doxorubicin resulted in clear synergy. However, pretreatment with octreotide 24 h prior to addition of doxorubicin resulted only in an additive interaction. It was shown in AR42J-tumour-bearing nude mice that the combination of doxorubicin and octreotide was well tolerated. Tumour growth was inhibited to 9% of controls, compared with 44% in the doxorubicin alone arm (day 14 of treatment). Our in vitro and in vivo interaction studies suggest that octreotide potentiates the effect of various chemotherapeutic agents in a synergistic or additive manner.

Pharmacodynamic profile of CQP 201-403, a novel 8 alpha-amino-ergoline.

The profile of action in animals of CQP 201-403, a novel 8 alpha-amino-ergoline, is in most aspects that of a very potent dopaminomimetic, both as a prolactin secretion inhibitor, and at the levels of the CNS and the cardiovascular system. Qualitatively CQP 201-403 differs slightly from bromocriptine and apomorphine in its effects on the CNS (no influence on serotonin metabolism in the rat cortex; induction of masculine mounting behavior in rats) and the cardiovascular system of the dog (reflex tachycardia in response to a blood-pressure fall). In man the new compound proved to be highly active in lowering prolactin serum levels and be more potent than bromocriptine (Parlodel).

Somatostatin analogues for somatostatin-receptor-mediated radiotherapy of cancer.

The aim of the present study was to selectively target a beta-emitter-labelled octreotide analogue to somatostatin (SRIF)-receptor-expressing tumours and to evaluate the feasibility of SRIF-receptor-mediated radiotherapy by delivering a lethal dose of radiation to the tumour. The most promising compound in a series of DTPA-coupled octreotide analogues was DTPA-benzyl-acetamido-D-Phe1, Tyr3-octreotide (SDZ413). In vitro, SDZ413 binds with nanomolar affinity to SRIF-receptors (IC50 = 4.0 nM) and inhibits growth hormone release from primary cultures of rat pituitary cells with an IC50 of 7.2 nM. Biodistribution studies with [90Y]SDZ413 demonstrated a fast and significant SRIF-receptor-specific accumulation of the labelled conjugate (tumour/muscle ratio after 24 h: 52/1). [90Y]SDZ413 was effective in the radiotherapy of SRIF-receptor-positive tumours in a nude mouse model. A single treatment with [90Y]SDZ413 led to a significant decrease (25%) of tumour mass. This effect was mediated by the intact radioligand, since treatment with [90Y]SDZ978, a derivative of SDZ413 which does not bind with high affinity to SRIF-receptors or with the unlabelled SDZ413 alone, failed to affect tumour growth. These results suggest that receptor-targeted radiotherapy with a 90Y-labelled octreotide analogue represents a new strategy for the treatment of SRIF-receptor-positive tumours that have been previously diagnosed with OctreoScan111 (pentetreotide).