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    Methods for modulation and inhibition of telomerase
    1.
    发明授权
    Methods for modulation and inhibition of telomerase 失效
    调节和抑制端粒酶的方法

    公开(公告)号：US6004939A

    公开(公告)日：1999-12-21

    申请号：US879457

    申请日：1997-06-20

    申请人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

    发明人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

    IPC分类号： A61K31/70 ,  C07H19/14

    CPC分类号： A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  A61K31/708 ,  C07H19/14

    摘要： It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deazanucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer.

    摘要翻译： 发现正常的人类干细胞产生调节的非进程性端粒酶活性，而癌细胞产生进行性的端粒酶活性。 发现核苷酸类似物，如7-脱氮-2'-脱氧鸟苷-5'-三磷酸（7-脱氮-dGTP）是进行性端粒酶的底物并掺入端粒序列。 该核苷酸的并入随后影响端粒酶的进程，将进程性端粒酶转化为非进程性端粒酶。 还发现该核苷酸类似物的掺入通过端粒序列抑制G四重奏的形成。 将癌症进程性端粒酶转化为更良性非进程性端粒酶的其他方法包括部分切割端粒酶RNA。 发现核苷类似物具有多种活性，包括介导端粒酶的变构类似的抑制，早期终止和端粒DNA的缩短，端粒结构和功能的不稳定以及最终的细胞死亡。 了解7-脱氮核苷酸端粒酶调节的机制使得设计了新的端粒酶抑制剂，调节剂和药剂来影响端粒结构和功能。 这些发现可用于治疗癌症。

    Methods for modulation and inhibition of telomerase
    2.
    发明授权
    Methods for modulation and inhibition of telomerase 失效
    调节和抑制端粒酶的方法

    公开(公告)号：US06593306B1

    公开(公告)日：2003-07-15

    申请号：US09467932

    申请日：1999-12-21

    申请人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

    发明人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

    IPC分类号： A61K3170

    CPC分类号： A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  A61K31/708 ,  C07H19/14

    摘要： It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2′-deoxyquanosine-5′-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deaza-nucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer.

    摘要翻译： 发现正常的人类干细胞产生调节的非进程性端粒酶活性，而癌细胞产生进行性的端粒酶活性。 发现核苷酸类似物，如7-脱氮-2'-脱氧鸟苷-5'-三磷酸（7-脱氮-dGTP）是进行性端粒酶的底物并掺入端粒序列。 该核苷酸的并入随后影响端粒酶的进程，将进程性端粒酶转化为非进程性端粒酶。 还发现该核苷酸类似物的掺入通过端粒序列抑制G四重奏的形成。 将癌症进程性端粒酶转化为更良性非进程性端粒酶的其他方法包括部分切割端粒酶RNA。 发现核苷类似物具有多种活性，包括介导端粒酶的变构类似的抑制，早期终止和端粒DNA的缩短，端粒结构和功能的不稳定以及最终的细胞死亡。 了解7-脱氮核苷酸端粒酶调节机制使得设计了新的端粒酶抑制剂，调节剂和药剂来影响端粒结构和功能。 这些发现可用于治疗癌症。

    Methods and compositions for modulation and inhibition of telomerase in vitro
    3.
    发明授权
    Methods and compositions for modulation and inhibition of telomerase in vitro 失效
    用于调节和抑制端粒酶的方法和组合物

    公开(公告)号：US6054442A

    公开(公告)日：2000-04-25

    申请号：US675119

    申请日：1996-07-03

    申请人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miguel Salazar ,  Blain Mamiya ,  Bradford E. Windle ,  Makoto Wajima

    发明人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miguel Salazar ,  Blain Mamiya ,  Bradford E. Windle ,  Makoto Wajima

    IPC分类号： A61K31/70 ,  C07H19/14

    CPC分类号： A61K31/7076 ,  A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/708 ,  C07H19/14

    摘要： It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deaza-nucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer.

    摘要翻译： 发现正常的人类干细胞产生调节的非进程性端粒酶活性，而癌细胞产生进行性的端粒酶活性。 发现核苷酸类似物，如7-脱氮-2'-脱氧鸟苷-5'-三磷酸（7-脱氮-dGTP）是进行性端粒酶的底物并掺入端粒序列。 该核苷酸的并入随后影响端粒酶的进程，将进程性端粒酶转化为非进程性端粒酶。 还发现该核苷酸类似物的掺入通过端粒序列抑制G四重奏的形成。 将癌症进程性端粒酶转化为更良性非进程性端粒酶的其他方法包括部分切割端粒酶RNA。 发现核苷类似物具有多种活性，包括介导端粒酶的变构类似的抑制，早期终止和端粒DNA的缩短，端粒结构和功能的不稳定以及最终的细胞死亡。 了解7-脱氮核苷酸端粒酶调节机制使得设计了新的端粒酶抑制剂，调节剂和药剂来影响端粒结构和功能。 这些发现可用于治疗癌症。

    Use of adenosine A3 receptor antagonists to inhibit tumor growth
    5.
    发明授权
    Use of adenosine A3 receptor antagonists to inhibit tumor growth 失效
    使用腺苷A3受体拮抗剂抑制肿瘤生长

    公开(公告)号：US06326390B1

    公开(公告)日：2001-12-04

    申请号：US09377271

    申请日：1999-08-19

    申请人： Edward Leung ,  Pier Giovanni Baraldi ,  Pier Andrea Borea ,  Shih-Fong Chen

    发明人： Edward Leung ,  Pier Giovanni Baraldi ,  Pier Andrea Borea ,  Shih-Fong Chen

    IPC分类号： A61K3141

    CPC分类号： A61K31/7076 ,  A61K31/00 ,  A61K31/519 ,  A61K45/06

    摘要： Tumor growth and metastasis can be inhibited by administration of adenosine A1 and/or A3 antagonists, preferably A3 antagonists, to a patient. The antagonists can be, and preferably are, administered in combination with other anti-tumor agents, such as anti-angiogenic agents (including adenosine A2a antagonists) and/or cytotoxic agents. Because the cytotoxic agents attack the tumor cells themselves, and the anti-angiogenic agents prevent the growth of vasculature which would otherwise support the growth of the tumor cells.

    摘要翻译： 通过向患者施用腺苷A1和/或A3拮抗剂，优选A3拮抗剂，可以抑制肿瘤生长和转移。 拮抗剂可以并且优选与其它抗肿瘤剂如抗血管生成剂（包括腺苷A2a拮抗剂）和/或细胞毒性剂组合施用。 因为细胞毒性剂本身攻击肿瘤细胞，并且抗血管生成剂阻止脉管系统的生长，否则其将支持肿瘤细胞的生长。

    Unsymmetrically linked bisnaphthalimides as antitumor agents
    7.
    发明授权
    Unsymmetrically linked bisnaphthalimides as antitumor agents 失效
    不对称连接的双萘二甲酰胺作为抗肿瘤剂

    公开(公告)号：US5604095A

    公开(公告)日：1997-02-18

    申请号：US279173

    申请日：1994-07-22

    申请人： Alexander L. Weis ,  Shih-Fong Chen ,  Peech S. Reedy ,  Mallaiah Mittakanti ,  Daniel L. Dexter

    发明人： Alexander L. Weis ,  Shih-Fong Chen ,  Peech S. Reedy ,  Mallaiah Mittakanti ,  Daniel L. Dexter

    IPC分类号： C07D221/14 ,  C07F15/00 ,  C12Q1/68 ,  A61K31/44

    CPC分类号： C07D221/14 ,  C07F15/0093

    摘要： The present invention provides novel bis-naphthalimides characterized by having a linker containing a heteroatom, their preparation, pharmaceutical compositions thereof, and various methods of using the bis-naphthalimides. Particularly preferred bis-naphthalimides have a linker of about 8-16 atoms where the heteroatom is oxygen, sulfur, sulfur oxide or sulfur dioxide. The bis-naphthalimides provided herein have exceptional DNA binding properties and demonstrate cytotoxicity in both in vitro and in vivo tumor models, in particular, against melanoma.

    摘要翻译： 本发明提供新型的双 - 萘二酰亚胺，其特征在于具有含有杂原子的接头，其制备方法，药物组合物，以及使用双 - 萘二酰亚胺的各种方法。 特别优选的双 - 萘二酰亚胺具有约8-16个原子的接头，其中杂原子是氧，硫，硫氧化物或二氧化硫。 本文提供的双萘二酰胺具有特殊的DNA结合性质，并在体外和体内肿瘤模型，特别是针对黑素瘤中表现出细胞毒性。

    Diamine platinum naphthalimide complexes as antitumor agents
    9.
    发明授权
    Diamine platinum naphthalimide complexes as antitumor agents 失效
    二胺铂萘二胺配合物作为抗肿瘤剂

    公开(公告)号：US5561042A

    公开(公告)日：1996-10-01

    申请号：US380841

    申请日：1995-01-30

    申请人： Alexander L. Weis ,  Shih-Fong Chen ,  Peech S. Reddy ,  Mallaiah Mittakanti ,  Daniel L. Dexter ,  Jan M. Woynarowski

    发明人： Alexander L. Weis ,  Shih-Fong Chen ,  Peech S. Reddy ,  Mallaiah Mittakanti ,  Daniel L. Dexter ,  Jan M. Woynarowski

    IPC分类号： C07D221/14 ,  C07F15/00 ,  C12Q1/68

    CPC分类号： C07D221/14 ,  C07F15/0093

    摘要： The present invention provides novel bis-naphthalimides characterized by having a linker containing a heteroatom, their preparation, pharmaceutical compositions thereof, and various methods of using the bis-naphthalimides. Particularly preferred bis-naphthalimides have a linker of about 8-16 atoms where the heteroatom is oxygen, sulfur, sulfur oxide or sulfur dioxide. The bis-naphthalimides provided herein have exceptional DNA binding properties and demonstrate cytotoxicity in both in vitro and in vivo tumor models, in particular, against melanoma. Also provided a novel mono-naphthalimides linked to a DNA alkylating agent. These agents are shown to have conformational effects on double stranded DNA and to form covalent adducts after an extended incubation period.

    摘要翻译： 本发明提供新型的双 - 萘二酰亚胺，其特征在于具有含有杂原子的接头，其制备方法，药物组合物，以及使用双 - 萘二酰亚胺的各种方法。 特别优选的双 - 萘二酰亚胺具有约8-16个原子的接头，其中杂原子是氧，硫，硫氧化物或二氧化硫。 本文提供的双萘二酰胺具有特殊的DNA结合性质，并在体外和体内肿瘤模型，特别是针对黑素瘤中表现出细胞毒性。 还提供了与DNA烷基化剂连接的新型单 - 萘二酰亚胺。 显示这些试剂对双链DNA具有构象影响，并在延长的潜伏期后形成共价加成物。