公开(公告)号：US20110160146A1

公开(公告)日：2011-06-30

申请号：US12865692

申请日：2009-02-05

申请人： Paul Wender ,  Elena A. Dibikovskaya ,  Stephen H. Thorne ,  Christopher H. Contag

发明人： Paul Wender ,  Elena A. Dibikovskaya ,  Stephen H. Thorne ,  Christopher H. Contag

IPC分类号： A61K47/48 ,  C12N5/09 ,  C12N5/095 ,  C07K2/00 ,  C07K7/06 ,  C07K7/08 ,  A61P35/00

CPC分类号： A61K31/7048 ,  A61K31/337 ,  A61K47/645

摘要： Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp) mediated drug efflux. Here we provide compositions and methods that restore the efficacy of a therapeutic agent reduced by resistance by conjugation of the same agent to an oligoarginine transporter comprising from about 5 to about 25 guanidino or amidino moieties. We specifically show that the widely used chemotherapeutic agent taxol, ineffective against taxol-resistant human ovarian cancer cell lines, can be incorporated into an octaarginine conjugate that is effective against the same taxol-resistant cell lines. Significantly, the ability of the taxol conjugates to overcome taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with other Pgp substrate. This approach shows generality for overcoming the multidrug resistance elicited by small molecule cancer chemotherapeutics and could improve the prognosis for many cancer patients and fundamentally alter search strategies for novel therapeutic agents effective against resistant disease.

摘要翻译： 许多癌症治疗剂引起抗性，使其无效，并且经常产生与其它药物的交叉耐药性。 最常见的机制之一涉及P-糖蛋白（Pgp）介导的药物流出。 在这里，我们提供了通过将相同试剂与包含约5至约25个胍基或脒基部分的寡精氨酸转运蛋白缀合来恢复通过抗性降低的治疗剂的功效的组合物和方法。 我们具体表明，广泛使用的化疗药物紫杉醇对紫杉醇耐药的人类卵巢癌细胞系无效，可以掺入对抗相同抗紫杉醇细胞系有效的八氮精氨酸缀合物。 显着地，在细胞培养和卵巢癌的动物模型中观察到紫杉醇缀合物克服紫杉醇耐药性的能力。 还对其他Pgp底物进行了研究。 这种方法显示了克服小分子癌化学治疗引发的多药耐药性的一般性，并且可以改善许多癌症患者的预后，从根本上改变对抗性疾病有效的新型治疗剂的搜索策略。

公开(公告)号：US07687474B2

公开(公告)日：2010-03-30

申请号：US11643628

申请日：2006-12-20

申请人： A. C. Matin ,  Yoram Barak ,  Susan V. Lynch ,  David F. Ackerley ,  Stephen H. Thorne ,  Christopher H. Contag ,  Jianghong Rao

发明人： A. C. Matin ,  Yoram Barak ,  Susan V. Lynch ,  David F. Ackerley ,  Stephen H. Thorne ,  Christopher H. Contag ,  Jianghong Rao

IPC分类号： A61K48/00 ,  C12N5/00

CPC分类号： C12N9/0036 ,  G01N2333/90209

摘要： Compositions and methods are provided for the treatment of cancer.

摘要翻译： 提供用于治疗癌症的组合物和方法。

公开(公告)号：US11065286B2

公开(公告)日：2021-07-20

申请号：US16335515

申请日：2017-09-21

申请人： Stephen H. Thorne

发明人： Stephen H. Thorne

IPC分类号： A61K35/768 ,  A61K45/06 ,  A61K31/7088 ,  A61P35/00 ,  C07K14/47

摘要： Provided herein are oncolytic vaccinia viruses which have been modified to contain an exogenous nucleic acid that codes for a variant HMGB1 protein. Such vaccinia viruses modified to contain nucleic acid encoding variant HMGB1 and that express a variant HMGB1 or a fragment thereof can achieve a synergistic effect in combination with chemotherapy. Methods of using oncolytic vaccinia viruses modified to contain an exogenous nucleic acid that codes for a variant HMGB1 protein, in the treatment of various cancers, are also provided.