Approximately 18-45 patients with Hepatocellular Carcinoma (HCC) will be treated with DENSPM at approximately 5 centers in the United States. First, we will be trying to determine the highest dose that can be given safely and is well tolerated (this is called the maximally tolerated dose, or the MTD, for short). Once that is established, we will enroll additional patients to learn more about potential side effects and to see whether DENSPM can slow the growth of HCC tumors. We also want to learn about the safety of DENSPM. Many medications used to treat cancer cause side effects (discomforts or illness). In this study, we want to understand what side effects occur in patients with HCC who are treated with DENSPM.Study was terminated after initial assessment of insufficient data to support clinical benefit in this population.

开始日期2004-03-01

申办/合作机构

Genzyme Corp.

100 项与二乙基去甲精胺相关的临床结果

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100 项与二乙基去甲精胺相关的转化医学

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100 项与二乙基去甲精胺相关的专利（医药）

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104

项与二乙基去甲精胺相关的文献（医药）

2024-01-16·Endocrinology

Discordant Effects of Polyamine Depletion by DENSpm and DFMO on β-cell Cytokine Stress and Diabetes Outcomes in Mice

Article

作者: Mirmira, Raghavendra G ; May, Sarah C ; Nelson, Jennifer B ; Hammoud, Batoul ; Tersey, Sarah A

AbstractType 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β-cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA-sequencing analysis, however, suggests that the cellular responses to DENSpm and DFMO differ, with both showing effects on cellular proliferation but the latter showing additional effects on mRNA translation and protein-folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm, unlike DFMO, did not prevent or delay diabetes outcomes but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In nonobese diabetic (NOD) mice, short-term DENSpm administration resulted in a slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.

2022-05-01·Biomaterials Advances

Hyaluronate-coated perfluoroalkyl polyamine prodrugs as bioactive siRNA delivery systems for the treatment of peritoneal cancers

Article

作者: Sil, Diptesh ; Oupický, David ; Stewart, Tracy Murray ; Panja, Sudipta ; Foley, Jackson ; Ding, Ling ; Jia, Huizhen ; Tang, Weimin ; Yu, Ao ; Tang, Siyuan ; Casero, Robert A ; Smith, Lynette M ; Hang, Yu ; Holbert, Cassandra E

RNA interference (RNAi) is an emerging therapeutic modality for cancer, which remains in critical need of effective delivery vectors due to the unfavorable biopharmaceutical properties of small RNAs. Polyamines are essential for functioning of mammalian cells. Dysregulated polyamine metabolism is found in many cancers and has been an attractive therapeutic target in combination therapies. Combination therapies based on drugs that affect polyamine metabolism and nucleic acids promise to enhance anticancer activity due to a cooperative effect on multiple oncogenic pathways. Here, we report bioactive polycationic prodrug (F-PaP) based on an anticancer polyamine analog bisethylnorspermine (BENSpm) modified with perfluoroalkyl moieties. Following encapsulation of siRNA, F-PaP/siRNA nanoparticles were coated with hyaluronic acid (HA) to form ternary nanoparticles HA@F-PaP/siRNA. The presence of perfluoroalkyl moieties and HA reduced cell membrane toxicity and improved stability of the particles with cooperatively enhanced siRNA delivery in pancreatic and colon cancer cell lines. We then tested a therapeutic hypothesis that combining BENSpm with siRNA silencing of polo-like kinase 1 (PLK1) would result in cooperative cancer cell killing. HA@F-PaP/siPLK1 induced polyamine catabolism and cell cycle arrest, leading to enhanced apoptosis in the tested cell lines. The HA-coated nanoparticles facilitated tumor accumulation and contributed to strong tumor inhibition and favorable modulation of the immune tumor microenvironment in orthotopic pancreatic cancer model. Combination anticancer therapy with polyamine prodrug-mediated delivery of siRNA. Hyaluronate coating of the siRNA nanoparticles facilitates selective accumulation in orthotopic pancreatic tumors. Perfluoroalkyl conjugation reduces toxicity and improves gene silencing effect. Nanoparticle treatment induces polyamine catabolism and cell cycle arrest leading to strong tumor inhibition and favorable modulation of immune tumor microenvironment.

2020-09-01·Metabolism1区 · 医学

Targeting pheochromocytoma/paraganglioma with polyamine inhibitors

1区 · 医学

Article

作者: Taieb, David ; Tevosian, Sergei G ; Ghayee, Hans K ; Tischler, Arthur S ; Garrett, Timothy J ; Timmers, Henri ; Beuschlein, Felix ; Plant, Daniel ; Kong, Kimi ; Bergeron, Raymond ; Calsina, Bruna ; Bril, Fernando ; Robledo, Mercedes ; Trevino, Jose ; Beecher, Chris ; Shelton, Laura ; Lee, Douglas ; Kalavalapalli, Srilaxmi ; Rai, Sudhir Kumar ; Jha, Abhishek ; Richter, Susan ; Kriti, Kriti ; Gupta, Priyanka ; Kroiss, Matthias ; Kirby, Austin ; Luthra, Soumya ; Click, Arielle ; Hromas, Robert A ; Powers, James F ; Jatav, Shashank ; Eisenhofer, Graeme ; Guingab-Cagmat, Joy ; Langton, Katharina ; Bibb, James ; Cusi, Kenneth ; Bose, Prodip ; Hatch, Heather M ; Pacak, Karel ; Xu, Yiling

BACKGROUNDPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.METHODSMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N¹,N¹¹-diethylnorspermine (DENSPM) and N¹,N¹²- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.RESULTSComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.CONCLUSIONSThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

100 项与二乙基去甲精胺相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06445

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	临床2期	-	Nippon Kayaku Co., Ltd.	-
阿尔茨海默症	临床2期	-	Pfizer Inc.	-
阿尔茨海默症	临床2期	-	Sanofi	-
肝癌	临床2期	-	Pfizer Inc.	-
肝癌	临床2期	-	Nippon Kayaku Co., Ltd.	-
肝癌	临床2期	-	Sanofi	-
黑色素瘤	临床2期	-	Sanofi	-
肾细胞癌	临床2期	-	Sanofi	-
肾细胞癌	临床2期	-	Nippon Kayaku Co., Ltd.	-
肾细胞癌	临床2期	-	Pfizer Inc.	-