Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas.
Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas.
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DOI：
10.1007/s11060-010-0502-4
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发表时间：
2011-08
影响因子：
3.9
通讯作者：
Kieran MW
中科院分区：
文献类型：
--
作者：
Chaponis D;Barnes JW;Dellagatta JL;Kesari S;Fast E;Sauvageot C;Panagrahy D;Greene ER;Ramakrishna N;Wen PY;Kung AL;Stiles C;Kieran MW
恶性神经胶质瘤是对当前疗法具有抗性的高致死性肿瘤。这些肿瘤的标准治疗方式，手术切除后放射治疗和同时替莫唑胺，已被证明是有效的，但耐药性和疾病进展的发展是常见的。虽然致癌Ras突变在神经胶质瘤中并不常见，但已发现Ras通过上游信号通路的作用被组成性激活，这表明法尼基转移酶抑制剂可能对这些肿瘤显示出活性。我们现在报告在体外和原位在体内的结果，使用放射，替莫唑胺和洛那法尼（SCH 66336），口服法尼基转移酶抑制剂，在胶质母细胞瘤的小鼠模型的联合治疗。我们在体外检测了联合处理的U87细胞的活力、增殖、H-Ras的法尼基化和下游信号的激活。单独使用洛那法尼或与放射和替莫唑胺联合使用在体外对肿瘤细胞的细胞毒性有限，尽管它确实表现出对肿瘤细胞增殖的显着抑制。在体内，单独的洛那法尼具有适度的抑制原位U87肿瘤的能力，放射和替莫唑胺表现出更好的抑制作用，而同时使用洛那法尼、放射和替莫唑胺发现了显著的抗肿瘤活性，大多数动物表现出肿瘤体积的减小。使用来自新鲜切除的成人胶质母细胞瘤组织的肿瘤神经球对替莫唑胺和放射治疗相对耐受。洛那法尼对这些神经球具有显著的抑制活性，并且可以增强替莫唑胺和辐射的活性。这些数据支持继续研究法尼基转移酶抑制剂、替莫唑胺和放射疗法的高级别胶质瘤治疗组合。
Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy.