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Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: Randomized placebo-controlled trial

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World Journal of Gastroenterology 2007年第23期13卷 3164-3170页

作者： D Dimitroulopoulos D Xinopoulos K Tsamakidis A Zisimopoulos E Andriotis D Panagiotakos A Fotopoulou C Chrysohoou A Bazinis D Daskalopoulou E Paraskevas Liver Cancer Unit "Agios Savvas" Cancer Hospital Athens Greece Laboratory of Biostatistics Department of Nursing University of Athens Greece Hippokration Hospital University of Athens Greece Psychiatric Department "Agios Savvas" Cancer Hospital Athens Greece

AIM: To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner. RESULTS: Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49 ± 6 wk) as compared to the control group (28 ± 1 wk) and to the SSTR negative group (28 ± 2 wk), LR = 20.39, df = 2, P < 0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the f irst year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group ***: The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.

关键词： Hepatocellular cancer somatostatin Long acting octreotide somatostatin receptors Quality of life

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A novel lanreotide-modified micelle system targets paclitaxel to the tumors with overexpression of somatostatin receptors

A novel lanreotide-modified micelle system targets paclitaxe...

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加快转变医药发展方式，占领科学技术制高点——2011年中国药学大会暨第11届中国药师周

作者： Nan Zheng 1,Wenbin Dai 1,Wenwen Du 1,Haoran Zhang 1,Liandi Lei 1,Hua Zhang 1,Xueqing Wang 1,Jiancheng Wang 1,Xuan Zhang 1,Jinming Gao 2 and Qiang Zhang 1 1 State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing,People’s Republic of China 2 Harold C.Simmons Comprehensive Cancer Center,Department of Pharmacology,UT Southwestern Medical Center,USA

Many tumor cells specifically overexpress somatostatin receptors,in particular,subtype 2 (SSTR2).Lanreotide,a somatostatin analog with high affinity for SSTR2,can be exploited as a ligand for tumor targeted *** this study,lanreotide was first used to functionalize poly(ethyleneglycol)-poly (ε-caprolactone)(PEG-b-PCL),and the active targeting micelles with paclitaxel (Lanreotide-PM-PTX) or fluorescent agent were developed and characterized with various analytical *** cell lines (NCI-H446 and MCF-7) with different expression level of SSTR2 were selected as cell ***-PM-PTX was spherical in shape with a hydrodynamic diameter of 43.15±0.38nm,high drug loading density (87.1±2.8%) and slow drug release *** observed by flow cytometry,confocal microscopy and cytotoxicity studies,lanreotide modified PEG-PCL micelles demonstrated more specific uptake and cytotoxicity in SSTR2-positive tumor cells in vitro over the passive targeting micelles mostly via a receptor-mediated *** active targeting micelles were found by the near-infrared fluorescence (NIRF) imaging and confocal microscopy to achieve higher accumulation in tumor tissue and tumor cells in vivo,as well as slow elimination in ***,treatment with Lanreotide-PM-PTX resulted in superior antitumor efficacy,enhanced tumor cell apoptosis and less body weight loss in SSTR2-overexpressing tumor model in athymic nude mice,as compared with the control *** conclusion,lanreotide can serve as an effective homing peptide,and the lanreotide-modified PEG-PCL micelles hold considerable promise in the treatment of SSTR2-overexpressing solid tumors.

关键词： Lanreotide somatostatin receptors Paclitaxel Active targeting micelles Cellular uptake Distribution in tumor Antitumor efficacy

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somatostatin receptor subtypes in hormone-refractory （castration-resistant） prostatic carcinoma

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Asian Journal of Andrology 2011年第2期13卷 242-247页

作者： Roberta Mazzucchelli Doriana Morichetti Marina Scarpelli Aldo V Bono Antonio Lopez-Beltran Liang Cheng Ziya Kirkali Rodolfo Montironi Section of Pathological Anatomy Polytechnic University of the Marche Region School of Medicine United Hospitals Ancona 60126 Italy Department of Pathology Reina SofiaUniversity Hospital and Faculty of Medicine Cordoba 14001 Spain Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis IN46202 USA Department of Urology School of Medicine Dokuz Eylul University Izmir 35010 Turkey

The aim of this study was to examine the tissue expression and Iocalisation of the somatostatin receptors （SSTRs） in hormone-refractory （HR） prostate cancer （PCa）. Five SSTRs were evaluated immunohistochemically in 20 radical prostatectomies （RPs） with Gleason score （GS） 3＋3=6 PCa, in 20 RPs with GS 4＋4=8 and 4＋5=9 PCa, and 20 transurethral resection of the prostate specimens with HR PCa. The mean values in the cytoplasm （all five SSTRs were expressed）, membrane （only SSTR3 and SSTR4 were expressed） and nuclei （only SSTR4 and SSTR5 were expressed） of the glands in HR PCa were 20-70% lower than in the other two groups, the differences being statistically significant. All five SSTRs were expressed in the smooth muscle and endothelial cells of HR PCa, the mean values being lower than in the other two groups. In conclusion, this study expands our knowledge on the expression and Iocalisation of five SSTRs in the various tissue components in the HR PCa compared with hormone-sensitive PCa.

关键词： hormone-refractory prostate cancer prostate cancer progression prostatic adenocarcinoma somatostatin receptors

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Regression of liver metastases of occult carcinoid tumor with slow release Lanreotide therapy

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World Journal of Gastroenterology 2005年第13期11卷 2041-2044页

作者： Marta Bondanelli Maria Rosaria Ambrosio Maria Chiara Zatelli Luigi Cavazzini Laura Al Jandali Rifa'y Ettore C.degli Uberti Department of Biomedical Sciences and Advanced Therapies-Section of Endocrinology Department of Experimental and Diagnostic Medicine

Few clinical studies have demonstrated an anti-proliferative activity of somatostatin (SST) analogs in carcinoids. We report the case of a woman with liver metastases of neuroendocrine tumor and no evidence of the primary tumor. The liver metastases were characterized by high proliferation index, immunoreactiviy for somatostatin receptor (SSTR)-l, 2, 3 and 5 and positive octreoscan. Urinary 5-hydroxyindolacetic acid, serum serotonin and chromogranin A were elevated. Slow release lanreotide (SR-LAN) therapy for 3 mo controlled clinical and biochemical signs of carcinoid tumor and caused a clear-cut reduction in the diameter of two liver metastases and disappearance of another lesion, with further reduction after 6 and 18 mo. We demonstrated a clear-cut long-lasting anti-proliferative effect of SR-LAN on liver metastases of occult carcinoid with high proliferation index and immunoreactivity for SSTR-1, 2, 3, and 5. Immunohistochemistry for SSTRs could be a suitable method for the selection of patients with metastatic carcinoid that may benefit from SST analog therapy.

关键词： Carcinoid somatostatin analogs somatostatin receptors

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Octreotide inhibits proliferation and induces apoptosis of hepatocellular carcinoma cells

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Acta Pharmacologica Sinica 2004年第10期 140-146页

作者： Hai-lin LIU, Li HUO, Lei WANGDepartment of Gastroenterology, The Ninth People’s Hospital, Shanghai Second Medical University, Shanghai 200011, China

AIM: To study the effect of octreotide on cell proliferation and apoptosis in different hepatocellular carcinoma (HCC) cells and hepatocytes. METHODS: The proliferation of HCC cells (HepG2, SMMC-7721) and hepatocytes (L-02) was determined by MTT assay. Apoptosis was detected either by fluorescent staining, transmission electron microscopy or flow cytometry. The content of AFP in the supernatant of cultured HCC cells was determined by electrochemiluminescence immunoassay. The expression of SSTR subtypes was identified by RT-PCR. RESULTS: The proliferation of HCC cells and L-02 cells was inhibited significantly by octreotide (0.25, 0.5, 1.0, 2.0 and 4.0 mg/L). However, the apoptosis of HCC cells markedly increased in a concentration-dependent manner. Both the apoptosis index and the percentage of apoptotic cells in L-02 cells were significantly lower than those of HepG2 and SMMC-7721 cells. The content of AFP in the supernatant of cultured HepG2 cells treated with octreotide was also statistically reduced.

关键词： hepatocellular carcinoma octreotide apoptosis somatostatin receptors

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Octreotide modified PEGylated liposomes improved the anticancer efficacy of doxorubicin in somatostatin receptor II positive tumor model

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Journal of Chinese Pharmaceutical Sciences 2010年第5期19卷 363-370页

作者：章俊麟金武王学清王坚成张烜张强北京大学医学部天然药物及仿生药物国家重点实验室药学院药剂学系北京100191

Active targeting drug delivery systems （TDDS）, which could improve drug therapeutic efficacy and reduce toxicity, are still the focus of many scientific researches in cancer therapy. The drug circulation time and tumor accumulation could be significantly increased with the application of sterically stabilized liposome （SSL）. SSL could also be modified easily with certain ligands to achieve targeting drug delivery. Because many tumors overexpress somatostatin receptors （SSTRs）, octreotide （OCT） becomes a potential targeting ligand due to its high affinity to SSTRs, especially to subtype 2 （SSTR2）. In this study, OCT was conjugated to methoxypolyethyleneglycol-distearoyl-phosphatidylethanolamine （DSPE-PEG2000）, and doxorubicin （DOX）-loaded SSL with a variable percentage of octreotide-methoxypolyethyleneglycol-distearoyl-phosphatidylethanolamine （DSPE-PEG/00o-OCT） were prepared （OCT-SSL-DOX）. All liposomes were about 90 nm in diameter and negatively charged on the surface, with DOX encapsulation efficiency at above 95%. OCT modification exhibited little effect on the physicochemical properties of SSL. In this study, cellular delivery efficacy of all prepared liposomes was evaluated in SSTIL2-positive cells in vitro by flow cytometry for the optimization of the OCT density on the surface of liposomes. Lipid formulation containing 1.5% DSPE-PEG20oo-OCT exhibited the highest efficiency of intracellular drug delivery. The modification of OCT did not alter the release behaviors of liposomal DOX in vitro, but OCT-SSL-DOX increased the cytotoxicity and improved the anti-tumor effect of liposomal DOX in SST1L2- positive cells and tumor-bearing mice models. In summary, OCT-modified SSL succeeded in increasing intracellular delivery and enhancing therapeutic efficacy of encapsulated anticancer agent, suggesting that it might be a promising TDDS for the treatment of SSTR2-overexpressing cancers.

关键词： Octreotide Sterically stabilized liposomes Doxorubicin somatostatin receptors MTT Anti-tumor effect

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