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1. 发明授权

US08361981B2 Chemo- and radiation-sensitization of cancer by antisense TRPM-2 oligodeoxynucleotides 有权
公开(公告)号：US08361981B2
公开(公告)日：2013-01-29
申请号：US12431997
申请日：2009-04-29
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson , Tobias Zellweger
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson , Tobias Zellweger
IPC分类号： A61K31/70 , C07H21/04
CPC分类号： A61K31/7125 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K45/06 , A61K48/00 , C07K14/775 , A61K2300/00
摘要： Administration of antisense oligodeoxynucleotides (ODN) targeted against the testosterone-repressed prostate message-2 (TRPM-2) gene can reduce the amount of TRPM-2 in renal cell cancer (RCC) cells and other cancer cells, and as a result enhance chemosensitivity of these cells to chemotherapy agents and radiation. Thus, for example, the sensitivity of renal cell cancer cells to a chemotherapeutic agent can be increased by exposing renal cell cancer cells to a chemotherapeutic agent and an agent which reduces the amount of TRPM-2 in the renal cell cancer cells. This provides an improved method for treatment of renal cell cancer, which is generally resistant to treatment with known chemotherapy agents.

2. 发明申请

US20090258089A1 Chemo- and Radiation-sensitization of Cancer by Antisense TRPM-2 Oligodeoxynucleotides 有权
标题翻译：反义TRPM-2寡脱氧核苷酸对癌症的化学和辐射敏化
公开(公告)号：US20090258089A1
公开(公告)日：2009-10-15
申请号：US12431997
申请日：2009-04-29
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson , Tobias Zellweger
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson , Tobias Zellweger
IPC分类号： A61K31/7088 , A61P35/00 , A61K33/24
CPC分类号： A61K31/7125 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K45/06 , A61K48/00 , C07K14/775 , A61K2300/00
摘要： Administration of antisense oligodeoxynucleotides (ODN) targeted against the testosterone-repressed prostate message-2 (TRPM-2) gene can reduce the amount of TRPM-2 in renal cell cancer (RCC) cells and other cancer cells, and as a result enhance chemosensitivity of these cells to chemotherapy agents and radiation. Thus, for example, the sensitivity of renal cell cancer cells to a chemotherapeutic agent can be increased by exposing renal cell cancer cells to a chemotherapeutic agent and an agent which reduces the amount of TRPM-2 in the renal cell cancer cells. This provides an improved method for treatment of renal cell cancer, which is generally resistant to treatment with known chemotherapy agents.
摘要翻译：针对睾丸激素抑制前列腺消息-2（TRPM-2）基因的反义寡脱氧核苷酸（ODN）的施用可以减少肾细胞癌（RCC）细胞和其他癌细胞中TRPM-2的量，从而增强化学敏感性的这些细胞对化疗药物和辐射。因此，例如，可以通过将肾细胞癌细胞暴露于化疗剂和减少肾细胞癌细胞中TRPM-2的量的试剂来增加肾细胞癌细胞对化疗剂的敏感性。这提供了治疗肾细胞癌的改进方法，其通常对已知化疗剂的治疗具有抗性。

3. 发明授权

US07592323B1 TRPM-2 antisense therapy 失效
公开(公告)号：US07592323B1
公开(公告)日：2009-09-22
申请号：US11276581
申请日：2006-03-06
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
IPC分类号： A61K31/70 , C07H21/04
CPC分类号： C12N15/1135 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/0038 , A61K45/06 , A61K48/00 , C07H21/00 , C07K14/775 , C12N15/113 , C12N2310/315 , C12N2310/321 , C12N2310/3341 , C12N2310/341 , C12N2310/346 , A61K2300/00 , C12N2310/3525
摘要： It has now been determined that antisense therapy which reduces the expression of TRPM-2 provides therapeutic benefits in the treatment of cancer. In particular, such antisense therapy can be applied in treatment of prostate cancer and renal cell cancer. Addition of antisense TRPM-2 ODN to prostatic tumor cells in vivo is effective for delaying the onset of androgen independence. Thus, prostate cancer can be treated in an individual suffering from prostate cancer by initiating androgen-withdrawal to induce apoptotic cell death of prostatic tumor cells in the individual, and administering to the individual a composition effective to inhibit expression of TRPM-2 by the tumor cells, thereby delaying the progression of prostatic tumor cells to an androgen-independent state in an individual Combined use of antisense TRPM-2 and taxanes synergistically enhances cytotoxic chemosensitivity of androgen-independent prostate cancer. In addition, it has also been found that antisense TRPM-2 has beneficial effect for other cancer types. Specifically, antisense TRPM-2 ODN enhances chemosensitivity in human Renal cell cancer, a normally chemoresistant disease with no active chemotherapeutic agent having an objective response rate higher than 10%. Radiation sensitivity is also enhanced when cells expressing TRPM-2 are treated with antisense TRPM-2 ODN. Thus, the antisense TRPM-2 ODNs can be used to enhance hormone sensitivity, chemosensitivity and radiation sensitivity of a variety of cancer types in which expression of TRPM-2 has been observed.

4. 发明授权

US07368436B2 TRPM-2 antisense therapy 有权
标题翻译： TRPM-2反义治疗
公开(公告)号：US07368436B2
公开(公告)日：2008-05-06
申请号：US09944326
申请日：2001-08-30
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
IPC分类号： A61K31/70 , C07H21/04 , C07H21/00
CPC分类号： C12N15/1135 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/0038 , A61K45/06 , A61K48/00 , C07H21/00 , C07K14/775 , C12N15/113 , C12N2310/315 , C12N2310/321 , C12N2310/3341 , C12N2310/341 , C12N2310/346 , A61K2300/00 , C12N2310/3525
摘要： It has been determined that antisense therapy which reduces the expression of TRPM-2 provides therapeutic benefits in the treatment of cancer, particularly prostate and renal cell cancers. Addition of antisense TRPM-2 ODN to prostatic tumor cells in vivo is effective for delaying the onset of androgen independence, thus prostate cancer can be treated by initiating androgen-withdrawal to induce apoptotic cell death of prostatic tumor cells in an individual, and administering a composition effective to inhibit expression of TRPM-2 by the tumor cells. Combined use of antisense TRPM-2 and taxanes synergistically enhances cytotoxic chemosensitivity of androgen-independent prostate cancer and in human Renal cell cancer. Radiation sensitivity is also enhanced when cells expressing TRPM-2 are treated with antisense TRPM-2 ODN. Thus, the antisense TRPM-2 ODNs can be used to enhance hormone sensitivity, chemosensitivity and radiation sensitivity of a variety of cancer types in which expression of TRPM-2 has been observed.
摘要翻译：已经确定减少TRPM-2表达的反义治疗在治疗癌症，特别是前列腺和肾细胞癌方面提供了治疗益处。反义TRPM-2 ODN在体内对前列腺肿瘤细胞的添加对于延缓雄激素独立性的发作是有效的，因此前列腺癌可以通过引发雄激素停药来诱导个体中前列腺肿瘤细胞的凋亡性细胞死亡，并施用有效抑制肿瘤细胞表达TRPM-2的组合物。结合使用反义TRPM-2和紫杉烷类物质协同增强雄激素非依赖性前列腺癌和人类肾细胞癌的细胞毒性化学敏感性。当用反义TRPM-2 ODN处理表达TRPM-2的细胞时，辐射敏感性也增强。因此，反义TRPM-2 ODN可用于增强已观察到TRPM-2表达的各种癌症类型的激素敏感性，化学敏感性和辐射敏感性。

5. 发明申请

US20140100261A1 TRPM-2 ANTISENSE THERAPY 有权
标题翻译： TRPM-2抗体治疗
公开(公告)号：US20140100261A1
公开(公告)日：2014-04-10
申请号：US14027693
申请日：2013-09-16
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
IPC分类号： C12N15/113 , A61K31/337
CPC分类号： C12N15/1135 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/0038 , A61K45/06 , A61K48/00 , C07H21/00 , C07K14/775 , C12N15/113 , C12N2310/315 , C12N2310/321 , C12N2310/3341 , C12N2310/341 , C12N2310/346 , A61K2300/00 , C12N2310/3525
摘要： A method for treating an individual suffering from a cancer comprising administering to the individual a chemotherapeutic agent, and ii) one antisense oligonucleotide having nucleotides in the sequence set forth in Seq. ID No. 4 and which antisense oligonucleotide has a phosphorothioate modification that increases the stability thereof in vivo, wherein the cancer expresses testosterone-repressed prostate message-2 (TRPM-2), thereby treating said individual.
摘要翻译：一种用于治疗患有癌症的个体的方法，包括向所述个体施用化学治疗剂，和ii）一种具有Seq。所述序列中具有核苷酸的反义寡核苷酸。 ID No.4，反义寡核苷酸具有增加其在体内的稳定性的硫代磷酸酯修饰，其中癌症表达睾丸激素抑制前列腺消息-2（TRPM-2），从而治疗所述个体。

6. 发明申请

US20120322850A1 TRPM-2 ANTISENSE THERAPY 失效
标题翻译： TRPM-2抗体治疗
公开(公告)号：US20120322850A1
公开(公告)日：2012-12-20
申请号：US13464670
申请日：2012-05-04
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Helson
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Helson
IPC分类号： A61K31/713 , A61P35/00
CPC分类号： C12N15/1135 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/0038 , A61K45/06 , A61K48/00 , C07H21/00 , C07K14/775 , C12N15/113 , C12N2310/315 , C12N2310/321 , C12N2310/3341 , C12N2310/341 , C12N2310/346 , A61K2300/00 , C12N2310/3525
摘要： It has now been determined that antisense therapy which reduces the expression of TRPM-2 provides therapeutic benefits in the treatment of cancer. Addition of antisense TRPM-2 ODN to prostatic tumor cells in vivo is effective for delaying the onset of androgen independence. Combined use of antisense TRPM-2 and taxanes synergistically enhances cytotoxic chemosensitivity of androgen-independent prostate cancer. In addition, it has also been found that antisense TRPM-2 has beneficial effect for other cancer types. Specifically, antisense TRPM-2 ODN enhances chemosensitivity in human Renal cell cancer, a normally chemoresistant disease with no active chemotherapeutic agent having an objective response rate higher than 10%. Radiation sensitivity is also enhanced when cells expressing TRPM-2 are treated with antisense TRPM-2 ODN. Thus, the antisense TRPM-2 ODNs can be used to enhance hormone sensitivity, chemosensitivity and radiation sensitivity of a variety of cancer types in which expression of TRPM-2 has been observed.
摘要翻译：现在已经确定减少TRPM-2表达的反义治疗在治疗癌症方面提供了治疗益处。反义TRPM-2 ODN在体内向前列腺肿瘤细胞的添加对于延缓雄激素独立性的发生是有效的。结合使用反义TRPM-2和紫杉烷类物质协同增强雄激素依赖性前列腺癌的细胞毒性化学敏感性。此外，还已经发现反义TRPM-2对其他癌症类型具有有益的作用。具体地，反义TRPM-2 ODN增强了人肾细胞癌的化学敏感性，这是一种没有活性化学治疗剂的客观反应率高于10％的正常化疗耐药性疾病。当用反义TRPM-2 ODN处理表达TRPM-2的细胞时，放射敏感性也增强。因此，反义TRPM-2 ODN可用于增强已经观察到TRPM-2表达的各种癌症类型的激素敏感性，化学敏感性和辐射敏感性。

7. 发明授权

US07569551B2 Chemo- and radiation-sensitization of cancer by antisense TRPM-2 oligodeoxynucleotides 失效
标题翻译：通过反义TRPM-2寡脱氧核苷酸对癌症的化学和放射敏化
公开(公告)号：US07569551B2
公开(公告)日：2009-08-04
申请号：US09967726
申请日：2001-09-28
申请人： Martin Gleave , Paul S. Rennie , Hikeaki Miyake , Colleen Nelson , Tobias Zellweger
发明人： Martin Gleave , Paul S. Rennie , Hikeaki Miyake , Colleen Nelson , Tobias Zellweger
IPC分类号： A61K31/70 , A61K31/00 , C07H21/04
CPC分类号： A61K31/7125 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K45/06 , A61K48/00 , C07K14/775 , A61K2300/00
摘要： Administration of antisense oligodeoxynucleotides (ODN) targeted against the testosterone-repressed prostate message-2 (TRPM-2) gene can reduce the amount of TRPM-2 in renal cell cancer (RCC) cells and other cancer cells, and as a result enhance chemosensitivity of these cells to chemotherapy agents and radiation. Thus, for example, the sensitivity of renal cell cancer cells to a chemotherapeutic agent can be increased by exposing renal cell cancer cells to a chemotherapeutic agent and an agent which reduces the amount of TRPM-2 in the renal cell cancer cells. This provides an improved method for treatment of renal cell cancer, which is generally resistant to treatment with known chemotherapy agents.
摘要翻译：针对睾丸激素抑制前列腺消息-2（TRPM-2）基因的反义寡脱氧核苷酸（ODN）的施用可以减少肾细胞癌（RCC）细胞和其他癌细胞中TRPM-2的量，从而增强化学敏感性的这些细胞对化疗药物和辐射。因此，例如，可以通过将肾细胞癌细胞暴露于化疗剂和减少肾细胞癌细胞中TRPM-2的量的试剂来增加肾细胞癌细胞对化疗剂的敏感性。这提供了治疗肾细胞癌的改进方法，其通常对已知化疗剂的治疗具有抗性。

8. 发明授权

US06900187B2 TRPM-2 antisense therapy using an oligonucleotide having 2′-O-(2-methoxy)ethyl modifications 失效
标题翻译：使用具有2'-O-（2-甲氧基）乙基修饰的寡核苷酸的TRPM-2反义治疗
公开(公告)号：US06900187B2
公开(公告)日：2005-05-31
申请号：US10080794
申请日：2002-02-22
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson , Brett P. Monia
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson , Brett P. Monia
IPC分类号： C12N15/09 , A61K31/00 , A61K31/136 , A61K31/337 , A61K31/66 , A61K31/704 , A61K31/7125 , A61K38/00 , A61K41/00 , A61K45/00 , A61K45/06 , A61K48/00 , A61P43/00 , C07H21/00 , C07K14/775 , C12N15/113 , A61K31/70
CPC分类号： C12N15/113 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/0038 , A61K45/06 , A61K48/00 , C07H21/00 , C07K14/775 , C12N15/1135 , C12N2310/315 , C12N2310/321 , C12N2310/3341 , C12N2310/341 , C12N2310/346 , C12N2310/3525 , A61K2300/00
摘要： A compound consisting of an oligonucleotide of sequence CAGCAGCAGAGTCTTCATCAT, where the oligonucleotide has a phosphorothioate backbone throughout, the sugar moieties of nucleotides 1-4 and 18-21 bear 2′-O-methoxyethyl modifications, and the remaining nucleotides (nucleotides 5-17) are 2′-deoxynucleotides, and where the cytosines of nucleotides 1, 4 and 19 are 5-methylcytosines. The compound has increased stability in vivo and improved in vitro and in vivo antitumor activity.
摘要翻译：由序列CAGCAGCAGAGTCTTCATCAT的寡核苷酸组成的化合物，其寡核苷酸全部具有硫代磷酸酯主链，核苷酸1-4和18-21的糖部分具有2'-O-甲氧基乙基修饰，剩余的核苷酸（核苷酸5-17）是2'-脱氧核苷酸，其中核苷酸1,4和19的胞嘧啶是5-甲基胞嘧啶。该化合物具有增加的体内稳定性和改善的体外和体内抗肿瘤活性。

9. 发明授权

US09074209B2 TRPM-2 antisense therapy 有权
标题翻译： TRPM-2反义治疗
公开(公告)号：US09074209B2
公开(公告)日：2015-07-07
申请号：US14027693
申请日：2013-09-16
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
IPC分类号： C12N15/113 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/00 , A61K45/06 , C07H21/00 , C07K14/775 , A61K48/00
CPC分类号： C12N15/1135 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/0038 , A61K45/06 , A61K48/00 , C07H21/00 , C07K14/775 , C12N15/113 , C12N2310/315 , C12N2310/321 , C12N2310/3341 , C12N2310/341 , C12N2310/346 , A61K2300/00 , C12N2310/3525
摘要： A method for treating an individual suffering from a cancer comprising administering to the individual i) a chemotherapeutic agent, and ii) one antisense oligonucleotide having nucleotides in the sequence set forth in Seq. ID No. 4 and which antisense oligonucleotide has a phosphorothioate modification that increases the stability thereof in vivo, wherein the cancer expresses testosterone-repressed prostate message-2 (TRPM-2), thereby treating said individual.
摘要翻译：一种用于治疗患有癌症的个体的方法，包括向个体施用i）化学治疗剂，和ii）一种具有Seq。所列序列中具有核苷酸的反义寡核苷酸。 ID No.4，反义寡核苷酸具有增加其在体内的稳定性的硫代磷酸酯修饰，其中癌症表达睾丸激素抑制前列腺消息-2（TRPM-2），从而治疗所述个体。

10. 发明授权

US08536149B2 TRPM-2 antisense therapy 失效
标题翻译： TRPM-2反义治疗
公开(公告)号：US08536149B2
公开(公告)日：2013-09-17
申请号：US13464670
申请日：2012-05-04
申请人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
发明人： Martin Gleave , Paul S. Rennie , Hideaki Miyake , Colleen Nelson
IPC分类号： C12N15/113 , C07H21/04
CPC分类号： C12N15/1135 , A61K31/00 , A61K31/337 , A61K31/66 , A61K31/704 , A61K41/0038 , A61K45/06 , A61K48/00 , C07H21/00 , C07K14/775 , C12N15/113 , C12N2310/315 , C12N2310/321 , C12N2310/3341 , C12N2310/341 , C12N2310/346 , A61K2300/00 , C12N2310/3525
摘要： It has now been determined that antisense therapy which reduces the expression of TRPM-2 provides therapeutic benefits in the treatment of cancer. Addition of antisense TRPM-2 ODN to prostatic tumor cells in vivo is effective for delaying the onset of androgen independence. Combined use of antisense TRPM-2 and taxanes synergistically enhances cytotoxic chemosensitivity of androgen-independent prostate cancer. In addition, it has also been found that antisense TRPM-2 has beneficial effect for other cancer types. Specifically, antisense TRPM-2 ODN enhances chemosensitivity in human Renal cell cancer, a normally chemoresistant disease with no active chemotherapeutic agent having an objective response rate higher than 10%. Radiation sensitivity is also enhanced when cells expressing TRPM-2 are treated with antisense TRPM-2 ODN. Thus, the antisense TRPM-2 ODNs can be used to enhance hormone sensitivity, chemosensitivity and radiation sensitivity of a variety of cancer types in which expression of TRPM-2 has been observed.
摘要翻译：现在已经确定减少TRPM-2表达的反义治疗在治疗癌症方面提供了治疗益处。反义TRPM-2 ODN在体内向前列腺肿瘤细胞的添加对于延缓雄激素独立性的发生是有效的。结合使用反义TRPM-2和紫杉烷类物质协同增强雄激素依赖性前列腺癌的细胞毒性化学敏感性。此外，还已经发现反义TRPM-2对其他癌症类型具有有益的作用。具体地，反义TRPM-2 ODN增强了人肾细胞癌的化学敏感性，这是一种没有活性化学治疗剂的客观反应率高于10％的正常化疗耐药性疾病。当用反义TRPM-2 ODN处理表达TRPM-2的细胞时，放射敏感性也增强。因此，反义TRPM-2 ODN可用于增强已经观察到TRPM-2表达的各种癌症类型的激素敏感性，化学敏感性和辐射敏感性。

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