Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment.
Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment.
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作者：
血管破坏剂通过选择性地破坏肿瘤相关的血管系统，有望对实体肿瘤产生显著的治疗效果。在给予磷酸前药ox6197后，动态生物发光成像显示MDA-MB-231人乳腺肿瘤异种移植物和小鼠RENCA肾肿瘤的剂量反应性血管关闭。血管快速破裂，持续24 h以上。组织学表现为血管充血、出血、坏死。每周两次剂量的OXi6197导致MDA-MB-231乳腺肿瘤和许多RENCA肾肿瘤在小鼠原位生长的显著生长延迟。在乳腺脂肪垫原位生长的MDA-MB-231人乳腺肿瘤异种移植物和肾脏原位生长的同源RENCA肾肿瘤中，一种有前途的微管蛋白结合剂（ox6196）在小鼠中显示了血管破坏活性。为了提高水溶性，ox6196被衍生为相应的磷酸前药盐ox6197，便于有效递送。ox6197在水中稳定，但在碱性磷酸酶的存在下迅速释放。在低纳摩尔浓度下，ox6196引起MDA-MB-231乳腺癌细胞的G2/M细胞周期阻滞和凋亡，快速生长的huvec单层细胞的形态发生浓度依赖性变化。观察到微管结构的丧失和丝状肌动蛋白在应力纤维中的捆绑增加，随后细胞崩溃，变圆和起泡。ox6196 （100 nM）破坏了预先在Matrigel®上用HUVECs建立的毛细血管样内皮网络。当前药OXi6197给予原位MDA-MB-231-luc肿瘤小鼠时，动态生物发光成像（BLI）显示剂量依赖性血管关闭，剂量≥30 mg/kg时，2小时内>信号丢失80%，剂量≥35 mg/kg时，6小时后>信号关闭90%，24小时后仍有至少70%的抑制。每周两次前药OXi6197 （20 mg/kg）治疗导致肿瘤生长明显延迟，但没有总体生存益处。在原位RENCA-luc肿瘤中首次观察到类似的疗效，24 h后出现大量出血和坏死。每周两次给药前药ox6197 （35 mg/kg）导致大多数原位RENCA肿瘤生长延迟。免疫组化显示广泛坏死，但周围组织存活。这些结果表明，与最有效的血管破坏剂（VDAs）相当的剂量可以有效地破坏血管，这表明有进一步开发的机会。
Vascular-disrupting agents promise significant therapeutic efficacy against solid tumors by selectively damaging tumor-associated vasculature. Following administration of the phosphate prodrug OXi6197, dynamic bioluminescence imaging revealed dose-responsive vascular shutdown in MDA-MB-231 human breast tumor xenografts and for the first time murine RENCA kidney tumors. Rapid vascular disruption was observed, which continued over 24 h. Histology showed vascular congestion, hemorrhage and necrosis. Twice-weekly doses of OXi6197 caused a significant growth delay in MDA-MB-231 breast tumors and many RENCA kidney tumors growing orthotopically in mice. The vascular disrupting activity of a promising tubulin-binding agent (OXi6196) was demonstrated in mice in MDA-MB-231 human breast tumor xenografts growing orthotopically in mammary fat pad and syngeneic RENCA kidney tumors growing orthotopically in the kidney. To enhance water solubility, OXi6196, was derivatized as its corresponding phosphate prodrug salt OXi6197, facilitating effective delivery. OXi6197 is stable in water, but rapidly releases OXi6196 in the presence of alkaline phosphatase. At low nanomolar concentrations OXi6196 caused G2/M cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells and monolayers of rapidly growing HUVECs underwent concentration-dependent changes in their morphology. Loss of the microtubule structure and increased bundling of filamentous actin into stress fibers followed by cell collapse, rounding and blebbing was observed. OXi6196 (100 nM) disrupted capillary-like endothelial networks pre-established with HUVECs on Matrigel®. When prodrug OXi6197 was administered to mice bearing orthotopic MDA-MB-231-luc tumors, dynamic bioluminescence imaging (BLI) revealed dose-dependent vascular shutdown with >80% signal loss within 2 h at doses ≥30 mg/kg and >90% shutdown after 6 h for doses ≥35 mg/kg, which remained depressed by at least 70% after 24 h. Twice weekly treatment with prodrug OXi6197 (20 mg/kg) caused a significant tumor growth delay, but no overall survival benefit. Similar efficacy was observed for the first time in orthotopic RENCA-luc tumors, which showed massive hemorrhage and necrosis after 24 h. Twice weekly dosing with prodrug OXi6197 (35 mg/kg) caused tumor growth delay in most orthotopic RENCA tumors. Immunohistochemistry revealed extensive necrosis, though with surviving peripheral tissues. These results demonstrate effective vascular disruption at doses comparable to the most effective vascular-disrupting agents (VDAs) suggesting opportunities for further development.
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2-Aryl-3-芳酰吲哚盐（OXI8007）的合成类似于Combretastatin A-4，并用作血管破坏剂。
影响因子：
5.1
作者：
Hadimani MB;Macdonough MT;Ghatak A;Strecker TE;Lopez R;Sriram M;Nguyen BL;Hall JJ;Kessler RJ;Shirali AR;Liu L;Garner CM;Pettit GR;Hamel E;Chaplin DJ;Mason RP;Trawick ML;Pinney KG
通讯作者：
Pinney KG
影响因子：
5.7
作者：
Ellis L;Shah P;Hammers H;Lehet K;Sotomayor P;Azabdaftari G;Seshadri M;Pili R
通讯作者：
Pili R
影响因子：
3.6
作者：
Inglis, Daniel J.;Lavranos, Tina C.;Kremmidiotis, Gabriel
通讯作者：
Kremmidiotis, Gabriel
DOI：
10.3390/molecules26092551
发表时间：
2021-04-27
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Liu L;O'Kelly D;Schuetze R;Carlson G;Zhou H;Trawick ML;Pinney KG;Mason RP
通讯作者：
Mason RP
影响因子：
11.2
作者：
Gallego-Yerga, Laura;de la Torre, Cristina;Cena, Valentin
通讯作者：
Cena, Valentin