To study the combinational effects of bcl-2 antisense oligodeoxynucleotide (bcl-2 ASODN) and Rituximab (anti-CD20 monoclonal antibody) on proliferation and apoptosis of B-lymphoma Raji cells in vitro and in vivo, and to explore the possible mechanisms.

METHODS:

After bcl-2 ASODN and Rituximab treating on Raji cells respectively or cooperatively, the proliferation of Raji cells, the expression of bcl-2 protein, the apoptosis and the expression of bcl-2 mRNA were detected by MTT assay, flow cytometry (FCM) and RT-PCR, respectively. The combinational antitumor activity of bcl-2 ASODN and Rituximab was evaluated in BALB/c nude mice bearing B-lymphoma inoculated with Raji cells.

RESULTS:

5-30 micromol/L bcl-2 ASODN and 1-16 mg/L Rituximab could inhibit Raji cells' growth, induce apoptosis and decrease the expression of bcl-2 protein and bcl-2 mRNA alone. But there was much more effective inhibition of growth and induction of apoptosis by their combination than alone (P<0.01). In tumor bearing mice, combination of bcl-2 ASODN and Rituximab showed a significant inhibitory effect on the growth of transplanted B-lymphoma, resulting in a statistically significant difference compared with alone (P<0.01).

CONCLUSION:

It has been found that bcl-2 ASODN combined with Rituximab could significantly inhibit the growth of Raji cells and induce their apoptosis via reinforcing specific down regulation of bcl-2 protein and bcl-2 mRNA expression.

2007-07-01·International journal of radiation oncology, biology, physics2区 · 医学

Irradiation of Human Prostate Cancer Cells Increases Uptake of Antisense Oligodeoxynucleotide

2区 · 医学

Article

作者: Steve Goodison ; Bob D. Brown ; Yoshihiko Hirao ; Satoshi Anai ; Charles J. Rosser ; Kogenta Nakamura

PURPOSE:

To investigate whether irradiation before antisense Bcl-2 oligodeoxynucleotide (ODN) administration enhances tissue uptake, and whether periodic dosing enhances cellular uptake of fluorescently labeled ODN relative to constant dosing.

METHODS AND MATERIALS:

PC-3-Bcl-2 cells (prostate cancer cell line engineered to overexpress Bcl-2) were subjected to increasing doses of irradiation (0-10 Gy) with or without increasing concentrations of fluorescently labeled antisense Bcl-2 ODN (G4243). The fluorescent signal intensity was quantified as the total grain area with commercial software. In addition, PC-3-Bcl-2 subcutaneous xenograft tumors were treated with or without irradiation in combination with various dosing schemas of G4243. The uptake of fluorescent G4243 in tumors was quantitated.

RESULTS:

The uptake of G4243 was increased in prostate cancer cells exposed to low doses of irradiation both in vitro and in vivo. Irradiation before G4243 treatment resulted in increased fluorescent signal intensity in xenograft tumors compared with those irradiated after G4243 treatment. A single weekly dose of G4243 produced higher G4243 uptake in xenograft tumors than daily dosing, even when the total dose administered per week was held constant.

CONCLUSIONS:

These findings suggest that ionizing radiation increases the uptake of therapeutic ODN in target tissues and, thus, has potential to increase the efficacy of ODN in clinical applications.

2006-07-15·International journal of cancer1区 · 医学

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

1区 · 医学

Article

作者: Yung-Chi Cheng ; Susan Grill ; Jill Lacy ; Regina Loomis ; Rocco Carbone ; Pavani Srimatkandada

Abstract:

Nasopharyngeal carcinoma (NPC) is causally linked to Epstein‐Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP‐1), is expressed in the majority of NPCs. LMP‐1 upregulates antiapoptotic genes, including bcl‐2, and Bcl‐2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl‐2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl‐2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666‐1 line, a stably infected NPC‐derived line that co‐expresses LMP‐1 and Bcl‐2. We have shown that G3139 treatment of C666‐1 in vitro caused sequence‐dependent suppression of Bcl‐2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days × 5 doses) delayed engraftment and significantly inhibited growth of established C666‐1 xenografts in SCID mice compared to control oligo‐treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days × 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real‐time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl‐2 levels were significantly decreased in G3139‐treated animals. Our studies have demonstrated that the Bcl‐2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666‐1, and in combination with CDDP, is curative in C666‐1 NPC xenograft tumors in vivo. The sequence‐dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl‐2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC. © 2006 Wiley‐Liss, Inc.

项与 Bcl-2反义硫代磷酸寡脱氧核苷酸相关的新闻（医药）

2022-11-10

·Insight数据库

阿斯利康 2022Q3 中国区收入 15.41 亿美元，再涨 8%！管线进展亮点频现（附下载）

11 月 10 日，阿斯利康发布了 2022 年度第三季度财报。在这一季度，阿斯利康总营收 110 亿美元，同比增长 19%。今年前三季度，阿斯利康总营收达到了 331 亿美元（+37%），其中产品收入占到 322 亿美元（+35%）；研发投入 71.37 亿美元（+4%）。（PPT 资料可向 Insight 公众号发送「阿斯利康 2022」即可快捷下载）基于合作里程碑的陆续达成和新冠长效中和抗体 Evusheld 的强劲贡献，阿斯利康宣布上调了 2022 年度核心每股收益（EPS）指导，从高 20% 调整至低 30%。阿斯利康 2022 前三季度业绩表现截图来自：阿斯利康官网资料后文如无特别提及，截图均来自于 AZ 官网营收情况概览分治疗领域来说，抗肿瘤板块前三季度（YTD）营收为 115 亿美元（+24%）；生物制药板块营收 151 亿美元（+21%），其中 CVRM、R&I、V&I 分别贡献 69 亿美元（+19%）、45 亿美元（+4%）和 37 亿美元（+56%）；罕见病部门营收 52 亿美元。具体营收情况将附于文末，文中不做过多赘述。在新冠领域，AZ 的腺病毒疫苗 Vaxzevria 和其他同类产品一样出现了销售额的下滑，收入 18 亿美元（-16%），不过去年末刚刚获批的 Evusheld 获得了 15 亿美元收入，已经逼近疫苗营收。Q3 各治疗领域产品营收占比（左）具体数据及主要因素（下）各治疗领域 YTD 营收基本数据（右）分地区来说，中国区域 Q3 营收 15.41 亿美元，同比增长 8%；美国区域营收 46.5 亿美元，同比增长 34%。包含（上）和不包含（下）新冠疫苗的各区域 Q3 营收销售收入 TOP20 产品相较于年中时基本无显著变化。TOP20 产品 Q3/YTD 营收及同比变化来自：阿斯利康财报，Insight 整理管线变化亮点阿斯利康在乳腺癌领域的布局值得一提。通过 ADC 药物 Enhertu（DS-8201，德曲妥珠单抗）和 Dato-DXd，口服 SERD 药物 camizestrant，AKT 抑制剂 capivasertib 和新一代 PARP 抑制剂 AZD5305，对乳腺癌各分型、各疗法线数的覆盖是全方位的。AZ 对乳腺癌适应症的覆盖尤其是前段时间，小分子药物更是接连披露积极消息，有望为 HR 阳性乳腺癌患者带来变革性的新疗法（详见 Insight 往期报道 >> 乳腺癌领域，AZ 布下「天罗地网」）。近期两款乳腺癌药物连获进展肺癌领域，AZ 在重磅炸弹奥希替尼之后，在研管线中同样亮点不少。ADC 药物 Dato-DXd 首要攻占的适应症就是 NSCLC，基于合成致死机制开发的 ATR 抑制剂 celarasertib 则旨在解决肿瘤免疫疗法耐药，联合 PD-L1 度伐利尤单抗的 LATIFY 研究预计 2023 年之后读出。EGFR/c-Met 双靶点 ADC 药物 AZD9592 本次财报中首次亮相，旨在解决奥希替尼耐药问题。这一项目来自于阿斯利康的自有 ADC 平台，而非外部合作。AZ 预计在 2022 年末至 2023 年初启动 I 期临床。阿斯利康在肺癌领域的新动态Q3 管线变化仍然值得关注。在管线移除表中，代谢领域不止一款新药发生了变化：PCSK9 寡核苷酸药物 AZD8233（高胆固醇血症）、GLP-1R/GCGR 双重激动剂 Cotadutide（2 型糖尿病、肥胖症和糖尿病肾病）从原有 II 期临床管线中被移除。Q3 管线进展（上图）；Q3 管线移除（下图）在 2022 - 2023 年，阿斯利康的潜在后期管线里程碑如下，中国部分已用红框单独圈出，可点击放大图片查看。2022 - 2023 年度潜在里程碑附 1：AZ 关键治疗领域营收情况附 2：肿瘤领域关键产品详细营收变化趋势附 3：包括中国在内的新兴市场营收附 4：详细管线附录免责声明：本文仅作消息分享，并不构成投资建议，也不代表 Insight 数据库的立场，文章观点仅供分享行业见解，请广大投资者谨慎。编辑：加一PR 稿对接：微信 insightxb投稿：微信 insightxb；邮箱 insight@dxy.cn点击卡片进入 Insight 小程序国内审评进度、全球新药开发…随时随地查！多样化功能、可溯源数据……Insight 数据库网页版等你体验点击阅读原文，立刻解锁！

抗体免疫疗法财报疫苗抗体药物偶联物

2007-05-25

·BioSpace

Genta Incorporated to Present Multiple Abstracts at the Annual Meeting of the American Society of Clinical Oncology

BERKELEY HEIGHTS, N.J., May 25 /PRNewswire-FirstCall/ -- Genta Incorporated announced that several abstracts featuring its oncology products, Genasense(R) (oblimersen sodium) Injection, and Ganite(R) (gallium nitrate injection), will be presented at the 43rd annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, June 1-5, 2007. The abstracts include the following: -- LDH is a Prognostic Factor in Stage IV Melanoma Patients but is a Predictive Factor only for Bcl-2 Antisense Treatment Efficacy: Re- analysis of GM301 and EORTC18951 Randomized Trials. Abstract #8552; Sunday, June 3, 2007. -- A Phase III Randomized Trial of Intensive Induction and Consolidation Chemotherapy +/- Oblimersen (Genasense; G3139), a Pro-Apoptotic Bcl-2 Antisense Oligonucleotide, in Untreated Acute Myeloid Leukemia Patients greater than or equal to 60 Years Old: Cancer and Leukemia Group B (CALGB) Study 10201. Abstract #7012; Saturday, June 2, 2007. -- GaRD Study: Gallium, Rituximab, and Dexamethasone for Relapsed NHL. Poster #Y1, Abstract #8079; Saturday, June 2, 2007. -- Oblimersen (Genasense(R)) Can Be Administered by Subcutaneous and Brief Intravenous Infusion: Clinical Pharmacokinetics and Pharmacodynamics in Patients with Advanced Cancer. (Publication) -- Long-term Administration of Oblimersen plus Chemotherapy: An Analysis of Safety in Patients with Solid Tumors and Hematologic Cancers. (Publication) About Genta Genta Incorporated is a biopharmaceutical company with a diversified product portfolio that is focused on delivering innovative products for the treatment of patients with cancer. The Company's research platform is anchored by two major programs that center on oligonucleotides (RNA- and DNA- based medicines) and small molecules. Genasense(R) (oblimersen sodium) Injection is the Company's lead compound from its oligonucleotide program. The lead drug in Genta's small molecule program is Ganite(R) (gallium nitrate injection), which the Company is exclusively marketing in the U.S. for treatment of symptomatic patients with cancer related hypercalcemia that is resistant to hydration. Genta is partnered with IDIS ( ) on a program whereby both Ganite(R) and Genasense(R) are available on a "named- patient" basis in countries outside the United States. For more information about Genta, please visit our website at: . Safe Harbor This press release may contain forward-looking statements with respect to business conducted by Genta Incorporated. By their nature, forward-looking statements and forecasts involve risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. Forward- looking statements include, without limitation, statements about: -- the Company's ability to obtain necessary regulatory approval for Genasense(R) from the U.S. Food and Drug Administration ("FDA") or European Medicines Agency ("EMEA"); -- the safety and efficacy of the Company's products or product candidates; -- the Company's assessment of its clinical trials; -- the commencement and completion of clinical trials; -- the Company's ability to develop, manufacture, license and sell its products or product candidates; -- the Company's ability to enter into and successfully execute license and collaborative agreements, if any; -- the adequacy of the Company's capital resources and cash flow projections, and the Company's ability to obtain sufficient financing to maintain the Company's planned operations; -- the adequacy of the Company's patents and proprietary rights; -- the impact of litigation that has been brought against the Company and its officers and directors and any proposed settlement of such litigation; -- the Company's ability to regain compliance with the NASDAQ's listing qualifications, or its ability to successfully appeal the NASDAQ delisting; and -- the other risks described under Certain Risks and Uncertainties Related to the Company's Business, as contained in the Company's Annual Report on Form 10-K and Quarterly Report on Form 10-Q. The Company does not undertake to update any forward-looking statements. There are a number of factors that could cause actual results and developments to differ materially. For a discussion of those risks and uncertainties, please see the Company's Annual Report on Form 10-K for 2006 and its most recent quarterly report on Form 10-Q. CONTACT: Tara Spiess/Andrea Romstad TS Communications Group, LLC (908) 286-3980 info@genta.com Genta Incorporated CONTACT: Tara Spiess or Andrea Romstad of TS Communications Group, LLC,+1-908-286-3980, or info@genta.com, for Genta Incorporated Web site:

寡核苷酸小分子药物ASCO会议合作

100 项与 Bcl-2反义硫代磷酸寡脱氧核苷酸相关的药物交易

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