Somatostatin Research 1979 - 1997
Department of Neurosurgery, Rush University, College of Medicine, Chicago, Illinois, USA.
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Therapeutic potential of octreotide in the treatment of liver metastases

Davies-N; Cooke-TG; Jenkins-SA

Department of Surgery, Musgrove Park Hospital, Somerset, England, UK.

Anticancer-Drugs. 1996 Jan; 7 Suppl 1: 23-31

Octreotide is a synthetic analogue of somatostatin that has clear inhibitory effects on the growth of many animal and human cell lines, including colorectal cell lines both in vitro and in vivo. Colorectal cancer metastatic to the liver is clinically important, both in terms of the number of patients affected and the lack of any effective treatment for the majority of patients. Octreotide inhibits the growth of colorectal liver tumour in a number of experimental models and, in at least three tumour types, inhibits the growth of established micro-metastases. The precise mechanism of action is not known. However, the drug is likely to be most beneficial in the treatment of liver metastases when the tumour burden is relatively small. The available evidence, although experimental, suggests that octreotide may also have a beneficial effect on the development of liver metastases when used as an adjuvant to surgery in colorectal cancer and this area warrants urgent clinical investigation. The cytotoxics which are currently used as an adjuvant to surgery for colorectal cancer have unpleasant side effects which can be life-threatening. There will also be a proportion of patients who have undergone a truly curative resection of their tumour and will thus be treated unnecessarily. The potential benefits of octreotide in the adjuvant setting, although promising, remain speculative, but octreotide has an acceptably low incidence of side effects and can be administered safely for a prolonged period of time.

 

 

Somatostatin receptor imaging in small cell lung cancer

Berenger-N; Moretti-JL; Boaziz-C; Vigneron-N; Morere-JF; Breau-JL

Department of Nuclear Medicine, CHU Paris XIII, Bobigny, France.

Eur-J-Cancer. 1996 Jul; 32A(8): 1429-3

To determine its usefulness, we evaluated 111In-DTPA-Octreotide (octreotide scintigraphy) in the initial staging of 19 patients with histologically proven small cell lung cancer (SCLC) and compared the results to those of conventional imaging. Images performed during initial staging demonstrated 21 known pulmonary lesions and two known supraclavicular nodes. We detected a previously unknown mediastinal lesion. The number of metastases was underestimated, with no liver (5), brain (1) or skin metastases detected. Bone lesions were identified in 4 out of 5 patients. There were fewer lesions detected with octreotide scintigraphy than with bone scintigraphy (except for one case). We therefore conclude that octreotide scintigraphy is a highly effective method for detecting SCLC primary tumour and supraclavicular nodes; the procedure is of limited value for distant metastasis. Further studies are needed to establish its ability for detecting residual intrathoracic disease, and confirm the value of octreotide scintigraphy in differentiating residual disease from other benign lesions.

 

 

The diagnostic utility of somatostatin receptor scintigraphy in oncology

Valkema-R; Steens-J; Cleton-FJ; Pauwels-EK

Department of Diagnostic Radiology and Nuclear Medicine, University Hospital, Leiden, The Netherlands.

J-Cancer-Res-Clin-Oncol. 1996; 122(9): 513-32

Somatostatin receptor scintigraphy (SRS) with the diethylenetriaminopentaacetic-acid-conjugated somatostatin analogue [111In-DTPA-D-Phe1] octreotide, also known as 111In-pentetreotide, is a new non-invasive modality for the evaluation of tumours that express receptors for somatostatin. These receptors are present on neuroendocrine and other tumours, including lymphomas and some breast cancers. In oncology SRS is a promising diagnostic tool for localizing primary tumours, staging, control and follow-up after therapy, and for identification of patients who may benefit from therapy with unlabelled octreotide or, in the future, with radiolabelled octreotide. In the past few years many small and large studies investigating various aspects of SRS have been reported. In this review the value of SRS in the management of individual tumour types is explored. For many tumours the best sensitivity in lesion detection is only achieved by very careful imaging after the administration of at least 200 MBq 111In-pentetreotide. On the basis of the current experience the main value of SRS in oncology is in the staging and evaluation of gastroenteropancreatic tumours, paragangliomas, small-cell lung cancer and lymphomas. Promising areas for SRS are the evaluation of breast cancer, non-medullary thyroid cancer and melanoma, and initial results with targeted radionuclide therapy using radiolabelled octreotide have been reported.

 

 

Treatment of advanced medullary thyroid carcinoma with a combination of recombinant interferon alpha-2b and octreotide

Lupoli-G; Cascone-E; Arlotta-F; Vitale-G; Celentano-L; Salvatore-M; Lombardi-G

Department of Molecular and Clinical Endocrinology and Oncology, School of Medicine, University,

Federico II, Naples, Italy.

Cancer. 1996 Sep 1; 78(5): 1114-8

BACKGROUND. The medical treatment of advanced medullary thyroid carcinoma (MTC) is still questionable. Results of chemotherapy are disappointing with almost no curative responses, few partial responses, and many side-effects. A recent report has suggested the activity of combination recombinant interferon alpha-2b (rIFN-alpha-2b) and octreotide, a somatostatin analogue, in the treatment of a metastatic carcinoid tumor. This new therapeutic schedule may be used in other neuroendocrine tumors. In this study we evaluated the therapeutic effectiveness of octreotide and rIFN-alpha-2b in patients with advanced MTC.
METHODS. Eight patients affected by advanced MTC received octreotide at a daily dose of 150 micrograms for 6 months and subsequently at a daily dose of 300 micrograms for another 6 months, subcutaneously, and rIFN-alpha-2b at a daily dose of 5.000.000 IU intramuscularly 3 times a week for 12 months. Plasma calcitonin, carcinoembryonic antigenic levels, and morphologic staging were evaluated at 0, 1, 3, 6, and 12 months.
RESULTS. The therapy was stopped in two patients because of diarrhea and toxicity of drugs used. Pre-existing diarrhea in four patients and flushing in one significantly improved during treatment. A maximum decrease of calcitonin was reached after 1 month in 2 patients and after 3 months in 4. In all of the patients carcinoembryonic antigen levels decreased during treatment. No significant changes of size of metastases were observed.
CONCLUSIONS. The combination of octreotide and interferon is well tolerated and can be recommended for the treatment of advanced MTC.

 

 

Expression of the somatostatin receptor subtype-2 gene predicts response of human pancreatic cancer to octreotide

Fisher-WE; Muscarella-P; O'Dorisio-TM; O'Dorisio-MS; Kim-JA; Doran-TA; Sabourin-CL; Schirmer-WJ

Department of Surgery, Ohio State University, Columbus 43210, USA.

Surgery. 1996 Aug; 120(2): 234-40; discussion 240-1

BACKGROUND: Somatostatin inhibits proliferation of many solid tumors. The current study examines whether inhibition of the growth of pancreatic cancer by the somatostatin analog, octreotide, requires tumor expression of somatostatin receptors.
METHODS: We studied five human pancreatic cancer cell lines, Capan-1, Capan-2, CAV, MIA PaCa-2, and Panc-1. Solid tumors were established in nude mice (n = 20/cell line) by flank injection of tumor cells. Subcutaneous octreotide (500 micrograms/kg/day) was administered by osmotic pumps to 10 of the animals in each group, and the other 10 received control infusions of saline solution. On day 36, the tumors were excised and weighed. Plasma levels of the putative trophic peptides cholecystokinin, epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and insulin were assessed by radioimmunoassay. Each of the five cell lines was assayed for the presence of cell surface somatostatin receptors by using whole cell competitive binding assays with 125I-somatostatin. Expression of the somatostatin receptor subtype-2 (SSR2) gene was determined with reverse transcriptase-polymerase chain reactions. Southern blot hybridization was used to assess the presence of the SSR2 gene.
RESULTS: Octreotide inhibited tumor growth in the MIA PaCa-2 group (512 +/- 75 mg control versus 285 +/- 71 mg treated; p < 0.05) but had no significant effect on tumor weight in the other four cell lines. Plasma levels of cholecystokinin, epidermal growth factor, insulin-like growth factor-1, and insulin were not altered by chronic octreotide infusion. Cell surface somatostatin receptors and SSR2 gene expression were detected only in the MIA PaCa-2 tumors. The gene for the SSR2 receptor was found in all five tumor lines.
CONCLUSIONS: Octreotide-mediated inhibition of pancreatic cancer growth is dependent on expression of somatostatin receptors. The expression of somatostatin receptors should be considered in the design and interpretation of clinical trials with somatostatin analogs for treatment of pancreatic cancer.

 

 

The use of somatostatin receptor scintigraphy in the differential diagnosis of pancreatic duct cancers and islet cell tumors

van-Eijck-CH; Lamberts-SW; Lemaire-LC; Jeekel-H; Bosman-FT; Reubi-JC; Bruining-HA; Krenning-EP

Department of Surgery, University Hospital, Rotterdam, The Netherlands.

Ann-Surg. 1996 Aug; 224(2): 119-24

OBJECTIVE: In the present study, the diagnostic value of somatostatin receptor scintigraphy (SRS) was evaluated in the preoperative workup in patients with pancreatic duct cancers and islet cell tumors, as well as in the follow-up of these patients.
METHODS: Twenty-six patients with suspected primary pancreatic duct cancers and 48 patients with islet cell tumors were studied. The SRS was performed using the radionuclide-labeled somatostatin analogue 111In-octreotide. Another group of 12 patients who were still alive more than 3 years after pancreaticoduodenectomy for pancreatic duct adenocarcinomas also underwent SRS.
RESULTS: In 31 (65%) of 48 patients, the primary pancreatic islet cell tumor as well as its often previously not yet recognized metastases could be visualized. In contrast, none of the 26 pancreatic adenocarcinomas or their metastases could be seen. In 5 of 12 patients who were alive more than 3 years after pancreaticoduodenectomy for pancreatic duct adenocarcinomas, metastatic lesions were visualized at SRS. In retrospect, these patients were not operated on for adenocarcinomas but for "nonfunctioning" islet cell tumors.
CONCLUSIONS: The present study supports the concept that SRS has a place in the preoperative differential diagnosis of islet cell tumors and pancreatic duct cancers as well as in the follow-up, especially in those cases in which no tumor histologic analysis was obtained, or the pathologic examination of the tumor tissue had not included special staining procedures for neuroendocrine characteristics. Our results also indicate that the evaluation of the results of investigations on the role of surgery or radiation therapy and chemotherapy or both in pancreatic duct cancer have to be interpreted with caution, if no histologic analysis and staining for neuroendocrine characteristics was performed.

 

 

Intrathecal octreotide for relief of intractable nonmalignant pain: 5-year experience with two cases

Paice-JA; Penn-RD; Kroin-JS

Department of Neurosurgery, Rush University, College of Medicine, Chicago, Illinois, USA.

Neurosurgery. 1996 Jan; 38(1): 203-7

Somatostatin is distributed in the substantia gelatinosa in the dorsal horn of the spinal cord, and its application has been found to produce an inhibitory effect on nociceptive neurons. Although intraspinal administration of somatostatin-14 produces pain relief in patients with cancer and in postoperative patients, its short half-life limits its clinical usefulness. Octreotide, a synthetic analog of somatostatin, is more stable and not been associated with neurodegenerative changes when administered intrathecally in dogs. Intrathecal octreotide provides analgesia without adverse drug effects when administered chronically for cancer pain; however, treatment periods have been limited. This article describes the 5-year clinical course of two patients receiving intrathecal octreotide for severe, intractable nonmalignant pain. Included in this description are the results of blinded, randomized "N of 1" trials conducted in each of these patients.

 

 

Somatostatin analogue treatment for malignant hypercalcemia associated with advanced breast cancer

Shiba-E; Inoue-T; Akazawa-K; Takai-S

Department of Surgical Oncology, Osaka University Medical School, Japan.

Gan-To-Kagaku-Ryoho. 1996 Feb; 23(3): 343-7

We describe the successful treatment with octreotide, a somatostatin analogue, of a patient with malignant hypercalcemia associated with advanced breast cancer. A 70-year-old female with advanced breast cancer was admitted to our department for treatment of hypercalcemia. The administration of pamidronate disodium was effective to decrease serum calcium from 6.2 mEq/l to 4.0 mEq/l for the first time, but her hypercalcemia later responded less to pamidronate, and her serum calcium remained raised in spite of the administration of pamidronate and elcatonin. Then, her condition deteriorated with hypercalcemic symptoms, such as nausea vomiting and drowsiness. After octreotide treatment (100 microg/body/day, s.c.) with a combination of prednisolone, her serum calcium level improved from 6.7 mEq/l to 5.0-5.5 mEq/l, Leading to a dramatic improvement in her symptoms. During these treatments, anti-cancer therapy, hydration and the administration of diuretics have been continued. We think octreotide is very useful for the treatment of malignant hypercalcemia associated with advanced breast cancer.

 

 

Iodine-131 labelled octreotide: not an option for somatostatin receptor therapy

Bakker-WH; Breeman-WAP; van-der-Pluijm-ME; de-Jong-M; Visser-TJ; Krenning-EP

Department of Nuclear Medicine, University Hospital Dijkzigt and Erasmus University Medical School,

Rotterdam, The Netherlands.

Eur-J-Nucl-Med. 1996 Jul; 23(7): 775-81

Gamma-emitting radiopeptides are useful for scintigraphy of tumours on the basis of receptor binding.
Likewise, beta-emitting radiopeptides may be used in radionuclide therapy of such tumours. As iodine-131suggested to be suitable for this purpose, experiments were performed using three somatostatin analogues, in which the effects of coupling of a therapeutic dose of 131I to such peptides were investigated. This study deals with the radioiodination of very small amounts of peptide on a therapeutic scale, the required purification procedures after radioiodination, and the influence of high beta fluxes from 131I on a peptide during radioiodination and purification. Based on the regularly used therapeutic doses of 131I in cancer treatment and our previous experience with [111In-DTPA-D-Phe1]-octreotide, it was assumed that a minimal effective therapeutic dose of 3.7 GBq 131I has to be coupled to a maximum of approximately 100 microg peptide, representing only a slight excess of peptide over 131I. This contrasts with non-peptide radiopharmaceuticals in which high compound to radionuclide ratios are usually used. Labelling at low peptide to radionuclide ratios (low labelling yields) results in the formation of di-iodinated compounds, whereas at high peptide to radionuclide ratios (high labelling yields) mono-iodinated products of low specific activity are formed. Thus, after radioiodination the desired mono-iodinated peptide has to be separated from unreacted iodide, and from di-iodinated and unreacted peptide, as both compounds compete for the receptors. Possible radiolysis of the peptide during labelling and separation steps were investigated by irradiating 30 microgram unlabelled peptide with 370 MBq 131I in a small volume. The peptide composition of the incubation mixtures was investigated by high-performance liquid chromatography after irradiation for 30 min to 24 h. The results showed that the peptide was degraded with a half-life of less than 1 h. During the preparation of a real therapeutic dose (at much higher beta-flux) the peptide will be degraded even faster during the various steps required. In conclusion, intact mono-iodinated 131I-labelled somatostatin analogues for peptide receptor therapy will be difficult to obtain.

 

 

Dynamic indium-111-pentetreotide scintigraphy in breast cancer

Bajc-M; Ingvar-C; Palmer-J

Department of Clinical Physiology, Lund University, Sweden.

J-Nucl-Med. 1996 Apr; 37(4): 622-6

The efficacy of imaging breast cancer with 111In-pentetreotide (somatostatin receptor scintigraphy) was evaluate before surgery. METHODS: Seventy-one whole-body scintigrams in 24 patients with known breast cancer and 24 whole-body scintigrams in 8 controls were obtained at 0.5, 5 and 24 hr after intravenous injection of 110 MBq 111In-pentetreotide. Anterior and posterior projection images were acquired simultaneously. SPECT of the thorax was performed at 5 or 24 hr after injection in all breast cancer patients. The specimens were imaged immediately after surgery and the distribution of pentetreotide was assessed qualitatively and quantitatively.
RESULTS: Somatostatin receptor-positive tumors were found in 18/24 patients with breast cancer. Pentetreotide uptake was significantly greater in breast cancer patients compared to control patients. In all patients with positive images, the early scintigram (0.5 hr) showed abnormal uptake. It was possible to delineate three different dynamic patterns. Increased uptake was visually most distinct at each time (9 patients). Moreover, bilaterally increased pentetreotide uptake was observed in 10/18 true-positive patients (in 8 at each time and in 2 patients only at 5 hr), but only one patient had a known bilateral tumor.
CONCLUSION: We found higher incidence of somatostatin receptors in patients with breast cancer than in the control group. Moreover, bilaterally increased pentetreotide uptake in clinically unilateral disease was an unexpected finding.

 

 

Somatostatin analog octreotide inhibits the growth of differentiated thyroid cancer cells in vitro, but not in vivo

Hoelting-T; Duh-QY; Clark-OH; Herfarth-C

Department of Surgery, University of Heidelberg, Germany.

J-Clin-Endocrinol-Metab. 1996 Jul; 81(7): 2638-41

Somatostatin and its analogs are antiproliferative in a wide range of normal and neoplastic tissues. In this study we investigated the effect of octreotide (SMS 201-995) on the invasion and growth of three follicular thyroid cancer (FTC) cell lines from one patient in vitro and in vivo. FTC133 was established from the primary tumor, FTC236 from a cervical lymph node metastasis, and FTC238 from a lung metastasis. Invasion was the ability of tumor cells to penetrate 8-microns pore polycarbonate membranes coated with Matrigel. Invasion and proliferation were analyzed using the MTT assay. For in vivo experiments, athymic nude mice were sc inoculated with 500,000 calls of FTC133. The animals were treated twice daily with octreotide sc (100-300 micrograms/kg). RIA studies yielded dose-dependent high plasma levels of octreotide (3.43-6.5 ng/mL). Octreotide had a biphasic effect, enhancing growth at low concentrations (1-10 nmol/mL) and inhibiting it at high concentrations (100 nmol to 1 mumol/mL). Octreotide had also a dose-dependent biphasic effect on the invasion of FTC, inhibiting the invasion of all follicular thyroid cancer lines at high concentrations. However, it affected invasion less than growth. Octreotide (10 nmol/mL) stimulated the invasion of FTC133 by 13%, whereas stimulation was lower in both FTC metastases (FTC236, 6%; FTC238, 7%; P < 0.01). At higher concentrations (100 nmol to 1 mumol/mL), octreotide inhibited invasion of FTC133 by 17% (FTC236, 15%; FTC238, 17%; P < 0.01). During a 3-week treatment period, octreotide had no antiproliferative effect on the growth of FTC133 cells in nude mice. In conclusion, octreotide at low concentrations stimulates and at high concentrations inhibits the growth and invasion of follicular thyroid cancer cells in culture. However, it has no effect on the growth of FTC cells in animal experiments. Thus, the value of octreotide as an antitumoral agent in follicular thyroid cancer must be critically questioned.

 

 

A dose-finding study of lanreotide (a somatostatin analog) in patients with colorectal carcinoma

Di-Leo-A; Bajetta-E; Ferrari-L; Biganzoli-L; Mariani-L; Carnaghi-C; Camerini-E; Buzzoni-R; Ruiz-JM

Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Cancer. 1996 Jul 1; 78(1): 35-42

BACKGROUND: Laboratory data suggest that insulin-like growth factor-1 (IGF-1) may stimulate the growth of different human tumors. At least in acromegalic patients, somatostatin (SMS) analogs, such as lanreotide, suppress the serum levels of growth hormone (GH) and IGF-1.
METHODS: To evaluate the tolerability and biologic activity of different doses of lanreotide in patients with advanced colorectal carcinoma, consecutive groups of 3 patients each were subcutaneous treated with lanreotide at doses of 1, 2, 3, 4, 5, or 6 mg three times a day for 2 months. In the event of Grade 3 side effects, 3 additional patients were treated with the same dose before the next dose escalation. Serum samples were obtained on Days 0, 15, 30, and 60 for serum GH, IGF-1, and lanreotide assessment.
RESULTS: Twenty-four patients were enrolled and all were evaluable. Except for the 3 and 6 mg doses, for which the observation of a Grade 3 side effect required that an additional three patients be treated, it was sufficient to treat 3 patients at each dose. The overall incidence of side effects was as follows: changes in bowel habits, 83%; abdominal cramps, 79%; diarrhea, 17%; vomiting, 17%; nausea, 21%; steatorrhea, 78%; hyperglycemia, 35%; laboratory hypothyroidism, 39%; gallstones, 13%; and weight loss, 17%. No evidence of an increase in the incidence, intensity, or duration of side effects was observed with dose escalation. Serum IGF-1 levels were as follows: Day 15: 63%, 60%, and 67% of the baseline values for the low (1-2 mg), intermediate (3-4 mg), and high (5-6 mg) dose groups, respectively; Day 30: 63%, 59%, and 51%, respectively; and Day 60: 73%, 69%, and 47%, respectively. Serum lanreotide levels declined during treatment in all of the dose groups (90 ng/mL on Day 15, and 35 ng/mL on Day 60 for the 5-6 mg group; 10 ng/mL on Day 15, and 1.5 ng/mL on Day 60 for the 1-2 mg group). No antitumor activity or tumor marker reduction was observed.
CONCLUSIONS: No increase in toxicity was observed when subcutaneous lanreotide doses were escalated to 6 mg three times a day for 2 months. The highest doses seemed to maintain reduced serum IGF-1 levels; with the lowest doses, a "rebound" in serum IGF-1 levels was observed during treatment. Nevertheless, intermittent subcutaneous injections do not ensure constant serum drug concentrations over time.

 

 

New insights in the molecular mechanism of progestin-induced proliferation of mammary epithelium: induction of the local biosynthesis of growth hormone (GH) in the mammary glands of dogs, cats and humans

Mol-JA; van-Garderen-E; Rutteman-GR; Rijnberk-A

Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.

J-Steroid-Biochem-Mol-Biol. 1996 Jan; 57(1-2): 67-71

In contrast to the protective, anti-proliferative, action of progestins on the development of endometrium cancer, progestins may have local stimulatory and inhibitory effects on the proliferation of mammary epithelium. Until now there was no final molecular explanation of this discrepancy. Prolonged treatment of dogs with depot medroxyprogesterone acetate (DPMA) or with proligestone (PROL) results in enhanced plasma concentrations of growth hormone (GH), insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins, together with the development of benign mammary tumours. The stimulated plasma GH levels do not have the typical pulsatile secretion pattern, and are not sensitive to stimulation with GHRH or to inhibition with somatostatin. The autonomous secretion can be inhibited by the anti-progestin RUU-486. The source of progestin-induced plasma GH levels has been demonstrated to be the canine mammary gland where progestins induce the expression of the gene encoding GH. The expression of the GH gene is restricted to focal areas of hyperplastic epithelium as shown by immunohistochemistry, and is predominantly located in single positive epithelial cells with an intermediate position between luminal- and myo-epithelium. Progestin-induced fibroadenomatous changes in the mammary gland of cats are also associated with locally enhanced GH expression. In both normal, benign and malignant mammary tumours of humans GH mRNA expression has been demonstrated by RT-PCR. The presence of GH mRNA is associated with the presence of immunoreactive GH as shown by immunohistochemistry. Sequence analysis revealed 100% homology to the pituitary expressed GH gene. In malignant mammary tumours of humans and dogs GH expression is also found in specimens negative for progesterone receptors as measured by ligand binding. It is concluded that the gene encoding GH is expressed in the mammary gland of a variety of species, including man. This appears to represent a contribution to the molecular explanation of the action of progestins on proliferation of mammary epithelium. It needs, however, to be proven whether this local biosynthesis of GH in the mammary gland is the cause of the local stimulatory effect of progestins on the proliferation of mammary epithelium.

 

 

Somatostatin analog RC-160 inhibits the growth of human osteosarcomas in nude mice

Pinski-J; Schally-AV; Halmos-G; Szepeshazi-K; Groot-K

Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146, USA.

Int-J-Cancer. 1996 Mar 15; 65(6): 870-4

We investigated the effects of the potent somatostatin analog RC-160 on the growth of human osteosarcoma cell lines SK-ES-1 and MNNG/HOS, transplanted into nude mice or cultured in vitro. Growth of SK-ES-1 and MNNG/HOS tumors in nude mice was significantly inhibited after 4 weeks of treatment with daily s.c. injections of 100 micrograms RC-160, as measured by a reduction in tumor volume and weight. Histologically, the number of mitotic cells was decreased in the groups treated with RC-160. In mice bearing either tumor model, administration of RC-160 significantly decreased serum growth hormone and insulin-like growth factor I (IGF-I) levels. Specific high-affinity receptors for somatostatin and epidermal growth factor were found on membranes of MNNG/HOS tumors but not on SK-ES-1 tumors. Receptor analyses also demonstrated high-affinity binding sites for IGF-I on membranes of both tumors. In cell cultures, the proliferation rate of MNNG/HOS cells, but not of SK-ES-1, was significantly suppressed by RC-160. Our findings demonstrate that RC-160 can significantly inhibit the growth of SK-ES-1 and MNNG/HOS osteosarcomas in mice.

 

 

Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors.A study by the Italian Trials in Medical Oncology Group

di-Bartolomeo-M; Bajetta-E; Buzzoni-R; Mariani-L; Carnaghi-C; Somma-L; Zilembo-N; di-Leo-A

Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Cancer. 1996 Jan 15; 77(2): 402-8

BACKGROUND. The unsatisfactory control of neuroendocrine tumor growth with chemotherapy and/or interferon (IFN-2a) stimulated us to investigate the role of the somatostatin analogue octreotide (SMS 201.995), which is reported to be highly effective in controlling carcinoid syndrome symptoms. Octreotide has been used in a wide range of doses, and it was postulated that higher doses might lead to an objective response.
METHODS. The aim of the present multicenter Phase II study was to determine the safety and efficacy of SMS 201.995 in controlling carcinoids and other neuroendocrine tumors. Fifty-eight patients were treated subcutaneously with 2 sequential doses of the drug (Sandostatina, Sandoz, Inc., S.b.A. Pharmaceuticals, Basel, Switzerland). The first 23 patients received 500 micrograms 3 times a day and the remaining 35 patients received 1000 micrograms 3 times a day. The treatment was continued until the tumor progressed.
RESULTS. All of the patients were adequately treated and evaluated. The predominant histotype was carcinoid, although there were instances of medullary thyroid carcinoma, pancreatic islet cell tumors, and Merkel cell carcinoma. Carcinoid syndrome was documented in 16 patients and abnormal urinary 5-hydroxyindoloacetic acid excretion in 15. The median treatment duration was 5 months (range, 2-31 months). The responses were evaluated in three categories: tumor regression for tumor growth control, symptom response, and biochemical response. There was an effect on tumor growth in two patients with carcinoids. Symptomatic control was achieved in 73% of patients and a biochemical response in 77% of patients. In twenty-seven patients, the disease stabilized for at least 6 months (range, 6-32+). The median survival time for all patients was 22 months (range, 1-32+).
CONCLUSIONS. In terms of tumor regression, octreotide is disappointing (partial response: 3%); symptomatic response and biochemical control are satisfactory. These data confirm that somatostatin analogues are comparable to interferons in the treatment of carcinoid syndrome, although other efforts are necessary to control tumor regression.

 

 

Loss of sst2 somatostatin receptor gene expression in human pancreatic and colorectal cancer

Buscail-L; Saint-Laurent-N; Chastre-E; Vaillant-JC; Gespach-C; Capella-G; Kalthoff-H; Lluis-F; Vaysse-N; Susini-C

INSERM U151, Institut Louis Bugnard, Toulouse, France.

Cancer-Res. 1996 Apr 15; 56(8): 1823-7

Five somatostatin receptor subtypes (sst1 to sst5) have been cloned. We demonstrated previously that sst2 and sst5 mediate the antiproliferative effect of the somatostatin analogues octreotide and vapreotide. Using reverse transcription-PCR, we investigated gene expression of the five receptors in 47 human normal and cancerous tissues or cell lines from pancreatic and colorectal origin. mRNAs of somatostatin receptor subtypes were detected in 98% of samples, with more than two mRNA subtypes being expressed in 55% of cases. sst1, sst4, and sst5 were heterogeneously expressed in both normal and cancerous tissues; sst3 was rarely or not expressed. sst2 was present in normal pancreatic tissues but was absent in exocrine pancreatic carcinomas and their metastases. sst2 mRNAs were detected in normal colon, sporadic polyadenomas, and 50% of Dukes' stage B and 20% of Dukes' stage C carcinomas but were undetectable in Dukes' stage D carcinomas, hepatic metastases, and adenomas from familial adenomatous polyposis. The loss of sst2 expression could represent a growth advantage in these tumors and provide an explanation for the lack of therapeutic effect of somatostatin analogues in such adenocarcinomas. A subtyping of somatostatin receptors should be carried out before considering a somatostatin analogue treatment in patients with colorectal or pancreatic cancer.

 

 

Somatostatin analogue in the localization and treatment of bronchial carcinoid tumours

Temeck-BK; Koong-SS; Reynolds-JC; Pass-HI

Thoracic Oncology Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1502, USA.

Surg-Oncol. 1996 Oct-Dec; 5(5-6): 195-200

Octreotide scanning is increasingly being used to detect tumours with somatostatin receptors. Moreover, there is growing interest in the use of somatostatin analogues for the treatment of tumours with somatostatin receptors. This review documents the use at our institution of the octreotide scan in three patients with intrathoracic pathology, and comments on overall experience in the literature with this technology.
 

Angiopeptin inhibits thymidine incorporation by explants of porcine coronary arteries

Vargas-R; Wroblewska-B; Rego-A; Cathapermal-S; Ramwell-PW

Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC 20007, USA.

J-Cardiovasc-Pharmacol. 1997 Feb; 29(2): 278-83

Angiopeptin, a stable octapeptide analog of somatostatin, inhibits proliferation in a variety of cancer cell lines. We studied the effect of angiopeptin on 3H-thymidine uptake into ring segments from the porcine coronary tree. The incorporation of 3H-thymidine into segments of porcine left anterior descending (LAD) coronary artery was time dependent and reached a plateau after 48 h. The addition of angiopeptin (48.1 and 96.2 nM) to the culture medium significantly inhibited 3H-thymidine incorporation into the segments by 36.7 +/- 10.1% and 48.3 +/- 2.3% of the control, respectively. Forskolin (100 microM), inhibited 3H-thymidine incorporation (52.7 +/- 10.1%) to the same degree as did angiopeptin (96.2 nM). Incubation of the segments with 125I-labeled angiopeptin, for 2 h at 37 degrees C, showed angiopeptin uptake to be time dependent and exhibited a first-order kinetics, reaching equilibrium after 30 min. Autoradiographic studies showed a uniform distribution of angiopeptin within the endothelium, media, and adventitia. Most of the labeling was associated with the nuclei of the cells. Angiopeptin, after 30-min incubation, did not significantly modify the basal levels of cyclic adenosine monophosphate (cAMP). In contrast, forskolin (100 microM) elicited a 50-fold increase of the basal levels of cAMP. These results indicate that in addition to its endocrine effects, angiopeptin reduces the rate of proliferation by acting directly on the vessel wall.

 

 

Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines

Ain-KB; Taylor-KD; Tofiq-S; Venkataraman-G

Thyroid Cancer Research Laboratory, Medical Service, Veterans Affairs Medical Center, Lexington, Kentucky 40511, USA.

J-Clin-Endocrinol-Metab. 1997 Jun; 82(6): 1857-62

Somatostatin (SRIH) analogs can suppress the proliferation of human differentiated thyroid carcinoma cell lines that express SRIH receptors (SSTRs) demonstrated by radioligand binding analysis. Five distinct human SSTR subtypes (hSSTR1-5) that bind native SRIH exhibit diverse affinities to a wide range of SRIH analogs. Reverse transcriptase-PCR amplification of ribonucleic acids (RNAs) obtained from normal thyroid tissues and nine human thyroid carcinoma cell lines, grown as monolayer cultures and xenograft tumors in nude mice, were used to discriminate expression of SSTR subtype messenger RNAs (mRNAs). The cell lines were derived from a follicular adenoma (KAK-1), two follicular carcinomas (MRO-87 and WRO-82), two papillary carcinomas (NPA87 and KAT-10), and four anaplastic thyroid carcinomas (DRO-90, ARO-81, KAT-4, and KAT-18). Most thyroid cancer cell line monolayers and xenografts expressed SSTR3 and SSTR5 mRNAs. SSTR1 expression was more varied between monolayers and xenografts, whereas SSTR2 mRNA was only faintly detectable at the most extreme resolution. SSTR4 mRNA was faintly positive in only one anaplastic carcinoma xenograft. Normal thyroid also expressed SSTR3 and SSTR5 mRNAs, with only faint expression of SSTR1 and SSTR2 mRNAs (in one of five and three of five samples, respectively). SSTR mRNA expression was dependent upon in vitro culture conditions, as xenograft SSTR mRNA expression tended to decrease compared to that in each respective monolayer culture. Characterization of SSTR subtype expression in human thyroid carcinomas may permit targeting of specific SRIH analogs to inhibit proliferation of differentiated and anaplastic thyroid carcinomas in patients.
 

Clinical aspects of local and regional tumor therapy with 188Re-RC-160

Bender-H; Zamora-PO; Rhodes-BA; Guhlke-S; Biersack-HJ

Department of Nuclear Medicine, University of Bonn, Germany.

Anticancer-Res. 1997 May-Jun; 17(3B): 1705-12

Somatostatin-receptors have been found to be overexpressed in a variety of neuro-endocrine and epithelial cancers. While the introduction of a long-acting somatostatin-analogue, octreotide, exerted mainly anti-cancer activity in neuro-endocrine tumors, no convincing results have been demonstrated in other cancers. RC-160, another somatostatin-analogue has been selected because of its high receptor affinity and its anti-cancer activity. 188Re is a generator produced radionuclide with favourable gamma and beta-emission, allowing diagnostic and therapeutic application. The results of in vivo biodistribution and therapeutic outcome following systemic, intralesional and intracavitary application in animal studies employing 188Re-RC-160 are summarized. Safety considerations, dosimetry estimates and applicable indications are outlined. The clinical impacts of this radiopharmaceutical in cancer management are discussed.

 

 

The role of somatostatin analogues in complete antiandrogen treatment in patients with prostatic carcinoma

Vainas-G; Pasaitou-V; Galaktidou-G; Maris-K; Christodoulou-K; Constantinidis-C; Kortsaris-AH

Department of Endocrinology and Research Center, Theagenion Cancer Institute, Thessaloniki, Greece.

J-Exp-Clin-Cancer-Res. 1997 Mar; 16(1): 119-26

Somatostatin analogues (SMS-A) have been found to inhibit the growth of experimental tumors, as of prostate cancer, via several mechanisms as antihormonal and direct antimitogenic actions. It was demonstrated also that several SMS-A induce greater prostatic tumor regression with more pronounced histological changes if combined with LHRH analogues or in association with complete androgen blockade (CAB). In a phase II clinical trial we administered, in addition to CAB, SMS-A octreotide in 14 patients with stage D2 (group B) prostate cancer-8 previously hormonally treated (PHT) and 6 without any previous hormone treatment (NPHT); 4 other patients, 3 NPHT and one PHT, were treated with CAB only (group A). Antiandrogen and antitumoral activity followed assaying a) plasma testosterone b) prostatic specific antigen (PSA) c) prostatic acid phosphatase (PAP) levels and d) objective (o) and subjective (s) clinical improvement according to WHO criteria. Somatostatin activity was evaluated assaying Insulin like Growth Factor-1 (IGF-1) and Epidermal Growth Factor (EGF). In group B we observed 3 responses, with the best quality of response (oPR/sCR) among the 6 NPHT-patients (50%) and 3 responses among the PHT-patients (37,5%), two of them with an incomplete PHT. In group A, 2 out of 3 NPHT-patients had a response (oPR/sPR). Among group B patients we observed long symptom-free survival, when they responded (17 months), in comparison to group A patients (12 months), but almost the same total duration of survival in the two groups, 18.5 and 18 months, respectively. EGF and IGF-1 serum levels showed a distinct drop parallel to the decrease of PSA serum levels, among the patients with response vs. nonrespondent patients of group B during the treatment. Although our results showed that octreotide in small doses, in addition to CAB, having mild toxicity, enhance number, quality and perhaps the duration of symptom-free responses in patients with stage 2 prostate cancer, the therapeutic efficacy of this combined treatment remains to be ascertained in wider and better randomized clinical trials.

 
Novel endocrine therapies in breast cancer

Klijn-JG; Setyono-Han-B; Bontenbal-M; Seynaeve-C; Foekens-J

Department of Medical Oncology, Rotterdam Cancer Institute, Dr Daniel den Hoed Kliniek, The Netherlands.

Acta-Oncol. 1996; 35 Suppl 5: 30-7

Endocrine therapy of breast cancer consists of a variety of both medical and surgical ablative treatment modalities, but ablative therapy is increasingly replaced by medical treatment. Most endocrine therapies have more than one endocrine effect, frequently together with direct growth inhibitory actions via receptors. Endocrine therapy can be effective in all phases of the disease, but curative only in early disease while in advanced cancer it can only prolong survival. In the past decade the number of available endocrine agents has been drastically increased. Novel approaches in the endocrine therapy of breast cancer are application of new antiestrogens, antiprogestins, new potent aromatase inhibitors, analogues of luteinizing hormone-releasing hormone (LHRH-A) and somatostatin, inhibitors of prolactin secretion, vitamin A and D analogues, bisphosphonates, growth factor antagonists, tyrosine protein kinase inhibitors, protease inhibitors, inhibitors of angiogenesis, radiolabeled hormones and monoclonal antibodies. New cell biological factors such as oncogenes and suppressorgenes, secretory proteins and membrane receptors can be used not only as prognostic factors but also for prediction of type of response to endocrine and chemotherapy. Thus, these cell biological parameters can be used to select high and low risk patients, type of systemic treatment, and can also be used as targets for new treatment modalities. Future studies on treatment of all stages of disease will increasingly focus on promising combined treatment modalities.

 

 

Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes ("chimney sign") in occult metastatic medullary thyroid cancer: a typical site of tumour manifestation?

Behr-TM; Gratz-S; Markus-PM; Dunn-RM; Hufner-M; Becker-H; Becker-W

Department of Nuclear Medicine, Georg-August-University of Gottingen, Germany.

Eur-J-Nucl-Med. 1997 Feb; 24(2): 184-91

In medullary thyroid cancer (MTC), post-surgically elevated plasma calcitonin and/or carcinoembryonic antigen levels frequently indicate persisting metastatic disease, although conventional diagnostic procedures fail to localize the responsible lesions (occult disease). Somatostatin analogues have been used successfully in disease localization, but recently concerns have been raised that increased thoracic uptake of indium-111 pentetreotide in patients with previous external beam irradiation may represent a false-positive finding, caused by post-irradiation pulmonary fibrosis. We recently examined seven patients with metastatic MTC by somatostatin receptor scintigraphy (six with occult and one with established disease). In four patients, all of whom had stable or slowly rising tumour marker levels over several years, a chimney-like bilateral mediastinal uptake of indium-111 pentetreotide was found. In two patients with persisting hypercalcitonaemia immediately after primary surgery, supraclavicular lymph node metastases were identified as the responsible lesions. None of these seven patients had prior external beam radiation therapy. In two cases, histological confirmation was obtained. In one patient, disease progression could be shown during follow-up. These data suggest that bilateral mediastinal lymph node involvement is a typical site of disease in slowly progressing occult metastatic MTC; the "chimney sign" may represent a typical finding with somatostatin analogues in such cases. Therefore, we believe that even in the case of prior external beam irradiation, mediastinal uptake of octreotide might represent metastatic MTC rather than radiation fibrosis.

 sst2 somatostatin receptor expression reverses tumorigenicity of human pancreatic cancer cells

Delesque-N; Buscail-L; Esteve-JP; Saint-Laurent-N; Muller-C; Weckbecker-G; Bruns-C; Vaysse-N; Susini-C

Institut National de la Sante et de la Recherche Medicale U151, CentreHospitalier Universitaire Rangueil, Toulouse, France.

Cancer-Res. 1997 Mar 1; 57(5): 956-62

Among the five cloned somatostatin receptor subtypes (sst1 to sst5), sst2 mediates the antiproliferative effect of somatostatin analogues in vitro. Somatostatin analogues have been shown to inhibit cell growth in vitro and in vivo in pancreatic cancer models that expressed sst2. We recently demonstrated the loss of sst2 gene expression in human pancreatic adenocarcinomas and most of the derived pancreatic cancer cell lines. In the present study, we corrected the sst2 defect in human pancreatic cancer BxPC-3 and Capan-1 cells by stable transfection with human sst2 cDNA. In the absence of exogenous ligand, both BxPC-3 and Capan-1 cells expressing sst2 showed a significant reduction in cell growth. This inhibitory effect was blocked by treatment with antiserum to somatostatin. sst2-expressing cells produced somatostatin-like immunoreactivity that mainly corresponded to somatostatin 14, indicating the induction of a negative autocrine loop. In other respects, sst2 expression in Capan-1 cells induced a significant reduction of clonogenicity in soft agar. Moreover, a significantly reduced (Capan-1 cells) or suppressed (BxPC-3 cells) tumor growth in athymic nude mice was observed. The reversal of tumorigenicity induced by the restoration of sst2 expression suggests that the loss of sst2 contributes to the malignancy of human pancreatic cancers.
 

Analysis of somatostatin receptor subtype mRNA expression in human breast cancer

Evans-AA; Crook-T; Laws-SA; Gough-AC; Royle-GT; Primrose-JN

Academic Department of Surgery, Southampton General Hospital, UK.

Br-J-Cancer. 1997; 75(6): 798-803

Somatostatin is a widely distributed inhibitory peptide with growth-inhibitory effects in several human tumours, including breast cancer, raising the possibility that it may have therapeutic potential. The effects of somatostatin are mediated via a family of cell-surface receptors that differ in their tissue distribution, pharmacological properties and intracellular response mediators, suggesting that they mediate different functions of the peptide. We have analysed the expression of somatostatin receptor subtype (SSTR1-5) mRNA in normal and malignant breast tissue. Receptor expression was analysed by reverse transcription-polymerase chain reaction (RT-PCR) using receptor subtype-specific primers and by in situ hybridization (ISH) with riboprobes synthesized by in vitro transcription of cloned PCR products. A total of 51 breast carcinomas, 36 samples of matched normal tissue, two axillary node metastases and eight normal/benign breast tissue samples were analysed. SSTR2 expression was ubiquitous in both normal and malignant breast tissue. Expression of SSTR5 was detected in approximately one-third of tumour and normal tissue, but fewer than 13% of all tissues expressed SSTR1, 3 and 4. These data suggest that SSTR2 gene expression is ubiquitous in breast cancer. Although this is unlikely to have diagnostic or prognostic significance, SSTR2-specific somatostatin analogues may have therapeutic potential in breast cancer.

Somatostatin-14 mainly binds the somatostatin receptor subtype 2 in human neuroblastoma tumors

Prevost-G; Veber-N; Viollet-C; Roubert-V; Roubert-P; Benard-J; Eden-P

Institut d'Oncologie Cellulaire et Moleculaire Humaine, Bobigny, France.

Neuroendocrinology. 1996 Feb; 63(2): 188-97

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.

 

111In-octreotide scintigraphy in small cell lung cancer

Semprebene-A; Ferraironi-A; Franciotti-G; Venturo-I; Giunta-S; Lopez-M; Maini-CL

Nuclear Medicine Department, Regina Elena National Cancer Institute, Rome, Italy.

Q-J-Nucl-Med. 1995 Dec; 39(4 Suppl 1): 108-10

Somatostatin receptors have been identified on the cellular surface of a subset of patients with small cell lung cancer (SCLC) and may be associated with a less aggressive evolution of the tumor. Moreover, medicaltherapy with somatostatin analogues holds promise for neoplastic growth control. We performed planar imaging in 22 patients with histologically proven SCLC at 2-4 and 24 hours after the injection of 111-185 MBq of 111In-DTPA-octreotide (Octreoscan, Byk-Gulden). Tumor uptake was observed in 19 patients in both early and late scans, while 2 patients previously treated with chemotherapy showed negative early and late scans. One patient had a positive early scan and a negative late scan. All the scintigraphic studies showed more extensive disease than expected by CT. No significant modification in tumor uptake of radiooctreotide was observed in three patients studied before and after chemotherapy. In conclusion, 111In-octreotide is a suitable radiopharmaceutical for the in vivo evaluation of the somatostatin receptors of small lung cancer. The prognostic and therapeutical implications of this nuclear technique must be further investigated, however.

 

 

Clinical relevance of 111In-octreotide scans in CNS tumors

Sciuto-R; Ferraironi-A; Semprebene-A; Occhipinti-E; Mastrostefano-R; Crecco-M; Mottolese-M; Maini-CL

Department of Nuclear Medicine, Regina Elena, National Cancer Institute, Rome, Italy.

Q-J-Nucl-Med. 1995 Dec; 39(4 Suppl 1): 101-3

Sixty-six patients with a clinical and neuroradiological diagnosis of CNS tumors were evaluated by 111In-octreotide scintigraphy. Planar images were acquired at 2-4 and 24 hours after the injection of 111-185 MBq of 111In-octreotide (Octreoscan, Byk-Gulden). In the positive scans the tumor/non-tumor ratio was evaluated using a standard ROI method, and an uptake index (U.I.) of the lesion was determined. In vitro binding assays were performed on frozen sections from surgical specimens from 17 patients. All 32 meningiomas demonstrated a positive 111In-octreotide scan with a high U.I. Only 13 of 21 gliomas showed a positive scan, but the U.I. was significantly lower (p < 0.001 by "t"-test); one lymphoma showed a faint tracer uptake. All the other histotypes evaluated yielded negative scans. In all cases the receptorial pattern shown by the immunohistochemical staining technique was concordant with the scintigraphic results. 111In-octreotide scintigraphy allowed a differential diagnosis of meningioma versus other CNS tumors in 6 patients (4 neurinomas, 1 brain metastasis of melanoma, 1 lymphoma). In conclusion, 111In-octreotide scintigraphy is a promising tool to evaluate the SS receptorial pattern of CNS tumors and to increase the diagnostic specificity of conventional imaging providing useful information in selected cases for the therapeutic strategy.

 

 

Somatostatin receptor subtype mRNA expression in human colorectal cancer and normal colonic mucosae

Laws-SA; Gough-AC; Evans-AA; Bains-MA; Primrose-JN

University Department of Surgery, Southampton General Hospital, Hampshire, UK.

Br-J-Cancer. 1997; 75(3): 360-6

Somatostatin analogues may be useful novel agents in the systemic treatment of advanced colorectal cancer, as somatostatin inhibits proliferation in a wide variety of cell types. Here, we report the expression profiles of somatostatin receptor mRNAs in 32 pairs of malignant and normal colonic epithelia. Receptor subtype 2 (hSSTR2) mRNA was detected throughout nearly 90% of both malignant and normal tissue by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. Subtype 5 (hSSTR5) mRNA was detected in 46% and 45% of tumour and mucosal samples respectively, but in 75% (9/12) of early-stage tumours (tubulovillous adenomas, Dukes' A and B) compared with 31% (5/16) of late-stage tumours (Dukes' C and 'D' tumours), 0.05>P>0.025 (chi2 with Yates' correction). There was also reduced expression of hSSTR5 in samples of metastatic tumour (11%, 1/9) compared with all tumour samples (56%, 18/32) 0.025>P>0.01 (chi2 with Yates' correction). Other hSSTRs (1, 3 and 4) were expressed infrequently. Thus, hSSTR2 expression is retained after malignant transformation in colonic epithelium and, although it may potentially be a target for antiproliferative therapy, its ubiquitous expression militates against this. hSSTR5 warrants investigation as a tumour suppressor.

 

 

Octreotide as first-line treatment for women with metastatic breast cancer

Ingle-JN; Kardinal-CG; Suman-VJ; Krook-JE; Hatfield-AK

Mayo Clinic, Rochester, MN 55905, USA.

Invest-New-Drugs. 1996; 14(2): 235-7

Octreotide is a synthetic somatostatin analogue which has shown inhibitory activity against human breast cancer cells in culture. Ten patients with metastatic breast cancer and no prior hormonal therapy exposure received octreotide at 150 micrograms subcutaneously thrice daily. No objective responses were observed and the median time to treatment failure was short at 57 days.

 

 

The role of somatostatin analogues in the treatment of gastro-enteropancreatic endocrine tumours

Bajetta-E; Carnaghi-C; Ferrari-L; Spagnoli-I; Mazzaferro-V; Buzzoni-R

Medical Oncology Division B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Digestion. 1996; 57 Suppl 1: 72-6

Neuroendocrine (NE) cells are involved in gastro-enteropancreatic (GEP) neoplasms. Biological markers, such as peptides hypersecreted by biologically active NE tumours, aid in the evaluation of response to treatment. For surgically untreatable NE neoplasms, the therapeutic approach remains undefined. Somatostatin analogues, particularly octreotide, can control the clinical effects of hormone overproduction in NE neoplasms and they have revolutionised individualised treatment, particularly for biologically active tumours. So far, like interferon, octreotide used at standard dosages has failed to control neoplastic growth per se. We gave the somatostatin analogue lanreotide to women with advanced breast cancer and to colorectal carcinoma patients. Results confirmed that inhibition of the production of insulin-like growth factor-1, which plays an important role in neoplastic proliferation, could be obtained using the highest doses. Considering these data, we started a clinical trial of 58 patients affected by NE tumours, treated with two sequential doses (500 and 1,000 micrograms subcutaneously t.i.d.) of octreotide. Long-term disease stabilisation (> 6 months) was achieved in 43% of patients but an objective response in only 3%. Good control of clinical symptoms and markers was obtained in 73 and 77% of cases, respectively. Toxicity was negligible. Somatostatin analogues should be carefully evaluated at high doses for possible anti-proliferative effects. Studies are currently investigating their promising association with interferon.

 

 

Enhancement of the anti-neoplastic effects of tamoxifen by somatostatin analogues

Pollak-M

Department of Medicine, McGill University, Montreal, Canada.

Digestion. 1996; 57 Suppl 1: 29-33

Tamoxifen is useful in the treatment of breast cancer, but its effects in metastatic disease are rarely long term, and development of resistance to the drug is common. In vitro and in vivo data demonstrate anti-neoplastic (anti-proliferative) effects of somatostatin analogues, which may occur via binding to somatostatin receptors on the neoplastic cells, and/or via reductions in insulin-like growth factor-1 bioactivity. Moreover, several lines of evidence from in vitro and in vivo studies indicate that the long-acting somatostatin analogue octreotide enhances the anti-neoplastic effects of anti-oestrogenic agents such as tamoxifen. The anti-oestrogen-somatostatin approach appears to have a favourable long-term toxicity profile. Large-scale clinical trials are currently being planned to investigate the efficacy of combined tamoxifen plus octreotide therapy compared to tamoxifen alone in patients with breast cancer.

 

 

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

Weckbecker-G; Raulf-F; Tolcsvai-L; Bruns-C

Preclinical Research Department, Sandoz Pharma Ltd., Basel, Switzerland.

Digestion. 1996; 57 Suppl 1: 22-8

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.

 

 

A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity

Keri-G; Erchegyi-J; Horvath-A; Mezo-I; Idei-M; Vantus-T; Balogh-A; Vadasz-Z; Bokonyi-G; Seprodi-J; Teplan-I; Csuka-O; Tejeda-M; Gaal-D; Szegedi-Z; Szende-B; Roze-C; Kalthoff-H; Ullrich-A

Joint Research Organization, Hungarian Academy of Sciences, Budapest, Hungary.

Proc-Natl-Acad-Sci-U-S-A. 1996 Oct 29; 93(22): 12513-8

We report a series of new in vitro and in vivo data proving the selective antitumor activity of our somatostatin structural derivative, TT-232. In vitro, it inhibited the proliferation of 20 different human tumor cell lines in the range of 50-95% and induced a very strong apoptosis. In vivo TT-232 was effective on transplanted animal tumors (Colon 26, B16 melanoma, and S180 sarcoma) and on human tumor xenografts. Treatment of MDA-MB-231 human breast cancer xenografted in mice with low submaximal doses of TT-232 [0.25 and 0.5 mg/kg of body weight (b.w.)] caused an average 80% decrease in the tumor volume resulting in 30% tumor-free animals surviving for longer than 200 days. Treatment of prostate tumor (PC-3) xenografted animals with 20 mg/kg of b.w. of TT-232 for 3 weeks resulted in 60% decrease in tumor volume and 100% survival even after 60 days, while 80% of nontreated animals perished. We have demonstrated that TT-232 did not bind to the membrane preparation of rat pituitary and cortex and had no antisecretory activity. TT-232 was not toxic at a dose of 120 mg/kg of b.w. in mice. Long-term incubation (24 h) of tumor cells with TT-232 caused significant inhibition of tyrosine kinases in good correlation with the apoptosis-inducing effect. The level of p53 or KU86 did not change following TT-232 treatment, suggesting a p53-independent apoptotic effect. Preincubation of human breast cancer cells (MDA-MB-453) with TT-232 for 2 h decreased the growth factor receptor autophosphorylation. All of these data suggest that TT-232 is a promising and selective antitumor agent.

 

 

Somatostatin analogue treatment of neuroendocrine tumours

de-Herder-WW; van-der-Lely-AJ; Lamberts-SW

Department of Internal Medicine III, University Hospital, Rotterdam, Netherlands.

Postgrad-Med-J. 1996 Jul; 72(849): 403-8

The long-acting analogues of somatostatin have an established place in the medical treatment of patients with neuroendocrine tumours. They act through binding with specific, high-affinity membrane receptors. Somatostatin analogue therapy is an effective and safe treatment for most growth hormone and thyrothropin-secreting pituitary adenomas. The potential therapeutic consequences of the presence of somatostatin receptors on clinically 'nonfunctioning' pituitary tumours are still uncertain. Somatostatin analogues are not useful in the treatment of patients with prolactinomas, or adrenocorticotropin (ACTH)-secreting adenomas. However, the somatostatin analogue octreotide suppressed pathological ACTH release in some patients with Nelson's syndrome and ACTH and cortisol secretion in several patients with Cushing's syndrome caused by ectopic ACTH secretion. Somatostatin analogues are effective in the sympatomatic treatment of most (metastatic) pancreatic islet cell tumours and most (metastatic) carcinoids. In some of these patients, they also induce tumour stabilisation or reduction. In some patients with (metastatic) medullary thyroid carcinomas, continuous treatment with very high doses of octreotide can be of temporary relief. The clinical effectiveness of somatostatin analogues in patients with small cell lung cancer is currently under investigation. Long-term therapy with somatostatin analogues of catecholamine-secreting (malignant) paragangliomas and phaeochromocytomas has not shown clinical benefits.

 

 

Somatostatin and cancer

Robbins-RJ

Department of Endocrinology and Metabolism, Cornell University Medical College, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Metabolism. 1996 Aug; 45(8 Suppl 1): 98-100

The potential role of somatostatin (SRIF) in the diagnosis and treatment of nonendocrine human cancers is reviewed. There have been many reports of the growth-inhibitory activity of SRIF on normal and transformed cells in vitro. Many processes involved in malignant tumor growth depend on autocrine growth mechanisms, and somatostatin receptors (ssts) are present on many human cancers. It is possible that mutations in ssts result in a loss of check on proliferation in cancer cells. SRIF analogs may have a number of roles in clinical oncology. Use of radiolabeled tracers enables imaging of tumors bearing ssts; newer agents may enable positron emission tomography (PET) analyses or may be used to deliver lethal radiation doses to cells bearing a unique subset of sst. Although the ability of SRIF and its analogs to inhibit cellular proliferation has been shown in vitro, it has yet to be demonstrated in humans with cancer. Clinical improvements seen with SRIF or its analogs in cancer patients may be related to indirect effects, such as pain relief, reduction of gastrointestinal side effects of chemotherapeutic agents, effects on local production of growth factors, and inhibition of tumoral angiogenesis. Thus, with regard to their potential therapeutic role, SRIF analogs are likely to be used only in conjunction with other approaches, such as radiation, immunotherapy, chemotherapy, and growth factor modulation. Further research into the fundamental functions of each of the ssts and the intracellular actions of SRIF analogs will be needed to assess the potential usefulness of the latter in slowing the progression of human cancers.

 

 

Systemic treatment with epidermal growth factor in pigs induces ductal proliferations in the pancreas

Vinter-Jensen-L; Juhl-CO; Teglbjaerg-PS; Poulsen-SS; Dajani-EZ; Nexo-E

Department of Clinical Biochemistry, KH, Aarhus University Hospital, Denmark.

Gastroenterology. 1997 Oct; 113(4): 1367-74

BACKGROUND & AIMS: Epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and the EGF receptor are often overexpressed in chronic pancreatitis and in malignant pancreatic growth. Transgenic mice overexpressing TGF-alpha develop tissue changes in the pancrease resembling changes found in chronic pancreatitis. The effects of systemic treatment with EGF on the porcine pancrease were investigated in this study.
METHODS: Mature Goettingen minipigs were treated with solvent (n = 5), EGF (30 micrograms.kg-1.day-1; n = 6) for 4 weeks, or EGF (30 micrograms.kg-1.day-1; n = 5) for 5 weeks followed by 3 weeks of recovery. Pancreata were studied by routine histological examination and electron microscopy and were immunostained for proliferating cell nuclear antigen (PCNA).
RESULTS: In the EGF-treated animals, mainly larger interlobular ducts of the pancreas appeared to be considerably hyperplastic, with an increased number of nuclei that stained for PCNA. The epithelia of these ducts were increased in height, with accumulations of glycoconjugates in the columnar cells and in an increased number of goblet cells.
CONCLUSIONS: A new approach to experimentally induced hyperplastic changes of the excretory ducts of the pancreas is presented. Because ductal changes with glycoconjugate accumulations are common features of chronic pancreatitis and pancreatic cancer, the findings may be relevant to the pathogeneses of these conditions.

 

 

Characterization and localization of mitochondrial oligopeptidase (MOP) (EC 3.4.24.16) activity in the human cervical adenocarcinoma cell line HeLa

Krause-DR; Piva-TJ; Brown-SB; Ellem-KA

QCF Cancer Research Unit, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Australia.

J-Cell-Biochem. 1997 Sep 1; 66(3): 297-308

In this study we describe the partial purification and characterization of the HeLa cell oligopeptidase M or endopeptidase 3.4.24.16. The HeLa enzyme was isolated initially by its ability to hydrolyse a nonapeptide substrate (P9) which was cognate to the N-terminal cleavage site of preproTGF alpha. The enzyme was shown to be a metalloprotease as it was inhibited by Zn(2+)-chelating agents and DTT, and had an approximate molecular weight of 55-63 kD determined by gel filtration. Neurotensin, dynorphin A1-17 and GnRH1-9 were rapidly degraded by the enzyme while GnRH1-10 and somatostatin were not. Neurotensin was cleaved at the Pro10-Tyr11 bond, leading to the formation of neurotensin (1-10) and neurotensin (11-13). The K(m) for neurotensin cleavage was 7 microM and the Ki for the specific 24.16 dipeptide inhibitor (Pro-ile) was 140 microM which were similar to those observed from the human brain enzyme [Vincent et al. (1996): Brain Res 709:51-58]. Through the use of specific antibodies, the purified HeLa enzyme was shown to be oligopeptidase M. This enzyme and its closely related family member thimet oligopeptidase were shown to co-elute during the isolation procedure but were finally separated using a MonoQ column. Oligopeptidase M is located mainly in mitochondria though it was detected on the plasma membrane in an inactive form. The results obtained demonstrate the first recorded instance of this enzyme in human tissue cultured cells, and raise the issue of its function therein.

 

 

Different expression patterns of somatostatin receptor subtypes in cultured epithelial cells from human normal prostate and prostate cancer

Sinisi-AA; Bellastella-A; Prezioso-D; Nicchio-MR; Lotti-T; Salvatore-M; Pasquali-D

Istituto di Endocrinologia, Facolta di Medicina, Seconda Universita di Napoli, Italy.

J-Clin-Endocrinol-Metab. 1997 Aug; 82(8): 2566-9

The transcripts of five SRIH receptor subtypes (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5) were investigated by RT-PCR in epithelial cells (EC) and stromal cells (SC) from primary cultures of five normal human prostates and six prostate cancers. Primary cultures of prostate EC were established in serum-free keratynocyte medium with 5% FCS, epidermal growth factor, and bovine pituitary extract; SC were cultured in MEM with 10% FCS. Total RNA was extracted from EC and SC using a modified guanidine thiocyanate method. RT-PCR was performed after deoxyribonuclease treatment, using SSTR1-, SSTR2-, SSTR3-, SSTR4-, and SSTR5-specific-primers and adding glyceraldehyde-3-phosphate dehydrogenase-specific primers as internal control. A PCR product of the expected size of 334 bp, corresponding to SSTR1, was expressed only in EC from prostate cancer, whereas the expected 461-bp product of SSTR2 was found only in EC from normal prostate. SSTR3 messenger RNA was undetectable in normal and cancer EC, whereas SSTR4 and SSTR5 were present in both cell types. SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 messenger RNAs were not expressed in SC from both normal and cancer prostates. The RT-PCR method clearly demonstrated SSTRs' expression in the human prostate EC in vitro with differences between normal and tumoral samples. Our results may explain the ineffectiveness of some SSTR2 selective SRIH analogues in the treatment of prostate cancer and suggest that the absence of SSTR2 could represent a growth advantage in prostate cancer.

Non-cytotoxic control of colorectal cancer

Dwerryhouse-SJ; Morris-DL

University of New South Wales, Department of Surgery, St George Hospital, Kogarah, Australia.

J-R-Coll-Surg-Edinb. 1997 Jun; 42(3): 147-53
 

A phase III evaluation of a somatostatin analogue (octreotide) in the treatment of patients with asymptomatic advanced colon carcinoma [letter; comment]

Morris-DL

  
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