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    • 1. 发明申请
    • IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS
    • 改进组合治疗肿瘤的微生物治疗
    • WO2005039492A2
    • 2005-05-06
    • PCT/US2004/034625
    • 2004-10-21
    • THE JOHN HOPKINS UNIVERSITYDANG, LongBETTEGOWDA, ChetanKINZLER, Kenneth, W.VOGELSTEIN, Bert
    • DANG, LongBETTEGOWDA, ChetanKINZLER, Kenneth, W.VOGELSTEIN, Bert
    • A61K
    • A61K35/742A61K31/337A61K31/427A61K45/06Y10S435/842A61K2300/00
    • Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that spores of anaerobic bacteria in combination with agents which interact with microtubules can cause the destruction of both the vascular and avascular compartments of tumors. Two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with spores. In contrast, agents that stabilized microtubules, such as the taxane docetaxel, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by sponzlated bacteria. Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which spores could germinate. A single intravenous injection of spores plus selected microtubule-interacting agents was able to cause regressions of several tumors in the absence of excessive toxicity.
    • 目前用于治疗癌症的方法在一定程度上受到药物不能影响肿瘤血管不足的区域的限制。 我们已经发现,厌氧细菌的孢子与与微管相互作用的药物组合可能导致肿瘤的血管和非血管性腔室的破坏。 发现两类微管抑制剂发挥显着不同的作用。 抑制微管合成的一些药物,如长春瑞滨,当与孢子结合使用时,引起快速,大规模的出血性坏死。 相比之下,稳定微管(如紫杉烷多西紫杉醇)的药物导致肿瘤消退缓慢,导致大多数肿瘤细胞死亡。 肿瘤不良灌注区域中的剩余细胞可以被杂音细菌消灭。 机理研究表明,微管不稳定剂,而不是微管稳定剂,从根本上减少了流向肿瘤的血液,从而扩大了孢子可以发芽的缺氧生态位。 在没有过量毒性的情况下,单次静脉注射孢子加选择的微管相互作用剂能够引起几种肿瘤的回归。
    • 2. 发明申请
    • CERTAIN IMPROVED COMBINATION BACTERIOLYTIC THERAPY FOR THE TREATMENT OF TUMORS
    • 某些改进的联合用于治疗肿瘤的细菌疗法治疗
    • WO2005039491A2
    • 2005-05-06
    • PCT/US2004/034624
    • 2004-10-21
    • THE JOHN HOPKINS UNIVERSITYDANG, LongBETTEGOWDA, ChetanKINZLER, Kenneth, W.VOGELSTEIN, Bert
    • DANG, LongBETTEGOWDA, ChetanKINZLER, Kenneth, W.VOGELSTEIN, Bert
    • A61K
    • A61K35/742A61K31/195A61K31/4045A61K38/06A61K2300/00
    • Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that spores of anaerobic bacteria in combination with agents which interact with microtubules can cause the destruction of both the vascular and avascular compartments of tumors. Two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis such as HTI-286 and vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with spores. In contrast, agents that stabilized microtubules, such as the taxanes docetaxel and MAC-321, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by sporulated bacteria Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which spores could germinate. A single intravenous injection of spores plus selected microtubule-interacting agents was able to cause regressions of several tumors in the absence of excessive toxicity.
    • 目前用于治疗癌症的方法部分地由于药物不能影响肿瘤血管化程度差的区域而受到限制。 我们发现厌氧菌的孢子与微管相互作用的药物联合使用会导致肿瘤血管和血管腔的破坏。 发现两类微管抑制剂发挥显着不同的作用。 一些抑制微管合成的药物如HTI-286和长春瑞滨,当与孢子结合使用时会引起快速,大量的出血性坏死。 相反,稳定微管的药物,如紫杉类多西他赛和MAC-321,导致缓慢的肿瘤消退,从而杀死大多数肿瘤细胞。 机体研究表明,微管去稳定剂,但不是微管稳定剂,从根本上减少了血液流向肿瘤,从而扩大了孢子可能发芽的低氧生态位。 单次静脉注射孢子加选定的微管相互作用剂能够在没有过量毒性的情况下引起几种肿瘤的消退。