Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice.
Novel lysyl oxidase inhibitors attenuate hallmarks of primary myelofibrosis in mice.
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DOI：
10.1007/s12185-019-02751-6
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发表时间：
2019-12
影响因子：
2.1
通讯作者：
Ravid K
中科院分区：
文献类型：
--
作者：
Leiva O;Ng SK;Matsuura S;Chitalia V;Lucero H;Findlay A;Turner C;Jarolimek W;Ravid K
原发性骨髓纤维化（PMF）是一种慢性骨髓增生性肿瘤（MPN），通常预示着预后不良，治疗选择有限。目前，只有同种异体干细胞移植对那些候选人是治愈性的，而JAK 1/2抑制剂ruxolitonib的给药具有恶化血细胞减少症的风险。有限的治疗选择突出了开发PMF新治疗方法的必要性。赖氨酰氧化酶（LOX），一种对胶原交联和细胞外基质硬化至关重要的酶，已被发现在PMF中上调。在此，我们评价了两种新型LOX抑制剂PXS-LOX_1和PXS-LOX_2在两种PMF动物模型（GATA 1 low和JAK 2 V617 F突变小鼠）中的作用。具体地，将PXS-LOX_1或载体以15 mg/kg的剂量通过腹膜内注射给予15-16周龄的GATA 1低小鼠，每周4次，持续9周。在雄性和雌性GATA 1 low小鼠中，发现PXS-LOX_1与媒介物相比显著降低骨髓纤维化负荷和巨核细胞数量。鉴于这些结果，然后在15-17周龄JAK 2 V617 F突变小鼠中以30 mg/kg的剂量每周四次持续八周测试PXS-LOX_1。我们再次观察到骨髓纤维化负荷显著降低。PXS-LOX_2是一种具有改善的口服生物利用度的LOX抑制剂，接下来在15至17周龄JAK 2 V617 F突变小鼠中以5 mg/kg p.o.一周四次，持续八周该抑制剂还导致骨髓纤维化显著减少，尽管雌性小鼠中的改善更明显。综合以上结果，PXS-LOX_1和PXS-LOX_2有望成为治疗PMF纤维化的新候选药物。
Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) that usually portends a poor prognosis with limited therapeutic options available. Currently only allogeneic stem cell transplantation is curative in those who are candidates, while administration of the JAK1/2 inhibitor ruxolitonib carries a risk of worsening cytopenia. The limited therapeutic options available highlight the need for the development of novel treatments for PMF. Lysyl oxidase (LOX), an enzyme vital for collagen cross-linking and extracellular matrix stiffening, has been found to be up-regulated in PMF. Herein, we evaluate two novel LOX inhibitors, PXS-LOX_1 and PXS-LOX_2, in two animal models of PMF (GATA1low and JAK2V617F-mutated mice). Specifically, PXS-LOX_1 or vehicle was given to 15-16-week-old GATA1low mice via intraperitoneal injection at a dose of 15 mg/kg four times a week for nine weeks. PXS-LOX_1 was found to significantly decrease the bone marrow fibrotic burden and megakaryocyte number compared to vehicle in both male and female GATA1low mice. Given these results, PXS-LOX_1 was then tested in 15-17-week-old JAK2V617F-mutated mice at a dose of 30 mg/kg four times a week for eight weeks. Again, we observed a significant decrease in bone marrow fibrotic burden. PXS-LOX_2, a LOX inhibitor with improved oral bioavailability, was next evaluated in 15 to 17-week-old JAK2V617F-mutated mice at a dose of 5 mg/kg p.o. four times a week for eight weeks. This inhibitor also resulted in a significant decrease in bone marrow fibrosis, albeit with a more pronounced amelioration in female mice. Taking these results together, PXS-LOX_1 and PXS-LOX_2 appear to be promising new candidates for the treatment of fibrosis in PMF.
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影响因子：
4.8
作者：
Eliades, Alexia;Papadantonakis, Nikolaos;Ravid, Katya
通讯作者：
Ravid, Katya
影响因子：
11.4
作者：
Tefferi, A.;Lasho, T. L.;Pardanani, A.
通讯作者：
Pardanani, A.
影响因子：
158.5
作者：
Klampfl, Thorsten;Gisslinger, Heinz;Kralovics, Robert
通讯作者：
Kralovics, Robert
DOI：
10.1056/nejmoa1110557
发表时间：
2012-03-01
期刊：
The New England journal of medicine
影响因子：
--
作者：
Verstovsek S;Mesa RA;Gotlib J;Levy RS;Gupta V;DiPersio JF;Catalano JV;Deininger M;Miller C;Silver RT;Talpaz M;Winton EF;Harvey JH Jr;Arcasoy MO;Hexner E;Lyons RM;Paquette R;Raza A;Vaddi K;Erickson-Viitanen S;Koumenis IL;Sun W;Sandor V;Kantarjian HM
通讯作者：
Kantarjian HM
影响因子：
--
作者：
Chang J;Lucas MC;Leonte LE;Garcia-Montolio M;Singh LB;Findlay AD;Deodhar M;Foot JS;Jarolimek W;Timpson P;Erler JT;Cox TR
通讯作者：
Cox TR