公开(公告)号：EP1728510A2

公开(公告)日：2006-12-06

申请号：EP06012623.2

申请日：2000-11-13

申请人： The Johns Hopkins University, School of Medicine, Office of Technology Licencing

发明人： Pizer, Ellen S. ,  Townsend, Craig A. ,  Kuhajda, Francis P.

IPC分类号： A61K31/365 ,  A61K31/341 ,  A61K45/06 ,  G01N33/50 ,  A61K31/00

CPC分类号： G01N33/5011 ,  A61K31/00 ,  A61K31/34 ,  A61K31/365 ,  A61K45/06 ,  G01N2510/00 ,  A61K2300/00

摘要： This invention describes a method to kill cancer cells by acute elevation of cellular malonyl Coenzyme A (Malonyl CoA) which leads to apoptosis. Elevation of malonyl CoA may be induced by inhibition of fatty acid synthase (FAS), or by other manipulation of fatty acid metabolism tht does not involve inhibition of FAS. Alternatively, growth of tumor cells may be induced by a combination of effects including FAS inhibition in conjunction with other interventions which affect fatty acid metabolism, including inhibition of camitine palmitoyltransferase-1 (CPT-1). Any combination of drugs which produces an analogous physiologic effect(s) may be expected to lead to the same effect on susceptible tumor cells. For example, combination therapy with drug(s) that inhibit the fatty acid synthesis by inhibiting acetyl CoA carboxylase (the first enzyme in the fatty acid synthesis pathway) and drug(s) that inhibit CPT-1 may be expected to induce apoptosis in tumor cells. Therefore, this invention encompasses any method to systemically modify fatty acid metabolism in cancer cells including but not limited to direct inhibition of CPT-1 through small molecule inhibitors such as etomoxir, as well as inhibition of CPT-1 incidental to increasing the level of malonyl CoA in cancer cells.

摘要翻译： 本发明描述了通过促进细胞凋亡的细胞丙二酰辅酶A（丙二酰辅酶A）的急性升高来杀死癌细胞的方法。 丙二酰辅酶A的升高可以通过抑制脂肪酸合成酶（FAS）或通过脂肪酸代谢的其它操作来诱导，不涉及FAS的抑制。 或者，肿瘤细胞的生长可以通过包括FAS抑制与影响脂肪酸代谢的其它干预措施（包括抑制camitine palmitoyltransferase-1（CPT-1））的作用的组合来诱导。 产生类似生理作用的药物的任何组合可能预期对易感的肿瘤细胞产生相同的作用。 例如，通过抑制乙酰辅酶A羧化酶（脂肪酸合成途径中的第一个酶）抑制脂肪酸合成的药物和抑制CPT-1的药物的组合疗法可以预期诱导肿瘤细胞凋亡 细胞。 因此，本发明包括用于系统地修饰癌细胞中的脂肪酸代谢的任何方法，包括但不限于通过小分子抑制剂如依托莫司直接抑制CPT-1，以及抑制CPT-1附带增加丙二酰的水平 CoA在癌细胞中。