PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model.
PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model.
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DOI：
10.1016/j.brainres.2008.06.122
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发表时间：
2008-09-16
期刊：
影响因子：
2.9
通讯作者：
Shu, Yan
中科院分区：
文献类型：
--
作者：
Black, Keith L.;Yin, Dali;Ong, John M.;Hu, Jinwei;Konda, Bindu M.;Wang, Xiao;Ko, MinHee K.;Bayan, Jennifer-Ann;Sacapano, Manuel R.;Espinoza, Andreas;Irvin, Dwain K.;Shu, Yan
关键词：
血脑肿瘤屏障(BTB)极大地限制了向脑肿瘤输送治疗浓度的化疗。一种选择性增加药物释放的新方法是对调节BTB通透性的信号分子进行药理学调节，例如cGMP信号转导中的那些分子。在这里，我们显示口服西地那非(伟哥)和伐地那非(Levitra)，cGMP特异性PDE5的抑制剂，选择性地增加9L胶质肉瘤荷瘤大鼠的肿瘤毛细血管通透性，而对正常脑毛细血管没有显著增加。化疗药物阿霉素与伐地那非联合治疗的荷瘤大鼠的存活时间明显长于单独使用阿霉素的大鼠。肿瘤毛细血管通透性的选择性增加似乎是由肿瘤cGMP水平的选择性增加和通过肿瘤毛细血管的囊泡运输增加所介导的，并可被作为cGMP信号转导效应的钙依赖钾(KCA)通道的选择性抑制剂iberiooxin所减弱。同时使用另一种BTB“开放剂”--缓激肽，可以进一步增强西地那非的作用。总的来说，这些数据表明，口服PDE5抑制剂选择性地增加了BTB的通透性，并增强了化疗药物的抗肿瘤效果。这些发现对于改善抗肿瘤药物对脑肿瘤的输送具有重要意义。
The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries. Tumor-bearing rats treated with the chemotherapy agent, adriamycin, in combination with vardenafil survived significantly longer than rats treated with adriamycin alone. The selective increase in tumor capillary permeability appears to be mediated by a selective increase in tumor cGMP levels and increased vesicular transport through tumor capillaries, and could be attenuated by iberiotoxin, a selective inhibitor for calcium-dependent potassium (KCa) channels, that are effectors in cGMP signaling. The effect by sildenafil could be further increased by simultaneously using another BTB “opener”, bradykinin. Collectively, this data demonstrates that oral administration of PDE5 inhibitors selectively increases BTB permeability and enhance anti-tumor efficacy for a chemotherapeutic agent. These findings have significant implications for improving delivery of anti-tumor agents to brain tumors.
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影响因子：
2.9
作者：
Matsukado, K;Sugita, M;Black, KL
通讯作者：
Black, KL
影响因子：
4.8
作者：
Matsukado, K;Inamura, T;Black, KL
通讯作者：
Black, KL
影响因子：
2.5
作者：
BROADWELL, RD;CHARLTON, HM;SALCMAN, M
通讯作者：
SALCMAN, M
DOI：
10.1161/01.atv.0000070546.16946.3a
发表时间：
2003-07-01
影响因子：
8.7
作者：
Frank, PG;Woodman, SE;Lisanti, MP
通讯作者：
Lisanti, MP
影响因子：
1.9
作者：
Liu, YH;Hashizume, K;Black, KL
通讯作者：
Black, KL