Hoch Ute, Lynch Jennifer, Sato Yuji, Kashimoto Shigeki, Kajikawa Fumie, Furutani Yasuji, Silverman Jeffrey A
Sunesis Pharmaceuticals Inc, South San Francisco, CA, USA.
Cancer Chemother Pharmacol. 2009 Jun;64(1):53-65. doi: 10.1007/s00280-008-0850-3. Epub 2008 Oct 19.
Voreloxin, formerly known as SNS-595 or AG-7352, is a novel naphthyridine analog currently under investigation for the treatment of ovarian and hematologic malignancies. Voreloxin mechanism of action includes DNA intercalation and inhibition of topoisomerase II that causes selective DNA damage. In this study, we describe the anti-proliferative activity of voreloxin in a wide range of in vitro and in vivo models of human cancers.
The cytotoxicity of voreloxin in vitro was examined by MTT assay in 15 cell lines, including 4 drug-resistant lines. Activation of caspase in cell lines and tumors was evaluated by immunohistochemistry. Anti-tumor activity was assessed in 16 xenograft and 3 syngeneic tumor models in mice. Tumors were allowed to grow to approximately 150 mm(3) prior to treatment with voreloxin or comparator drugs. Activity of the anti-cancer agents was determined by calculating the inhibition rate (IR = [1 - (average tumor weight treated/average tumor weight control)] x 100%) and survival ratio (number surviving mice/number of mice per group at start of study) for each agent and dose and schedule tested.
In vitro studies demonstrated voreloxin has broad anti-proliferative activity in 11 tumor cell lines, with IC(50) values ranging from 0.04 to 0.97 muM. Similar activity was observed in vitro in drug-resistant cell lines, including those that overexpress P-glycoprotein and have reduced topoisomerase levels. After a single intravenous dose, voreloxin concentrations in tumor were correlated with induction of the apoptosis marker caspase-3. The optimal dose and schedule was established using a KB nasopharyngeal carcinoma xenograft model. Administration of voreloxin at 20 mg/kg weekly for five doses effectively inhibited tumor growth (86%). Voreloxin demonstrated strong dose-dependent tumor growth inhibition (63-88%) in 10 of 11 solid tumor (breast, ovarian, colon, lung, gastric, and melanoma) xenograft models, 2 hematologic tumor xenograft models, 3 multidrug resistant tumor models and 3 murine syngeneic tumor models (Colon 26, Lewis Lung carcinoma, M5076 Ovarian Sarcoma).
These data demonstrate that voreloxin is a broadly active anti-tumor agent in vitro and in vivo, with potent activity in aggressive and drug-resistant tumor models.
沃洛昔星，曾称为SNS - 595或AG - 7352，是一种新型萘啶类似物，目前正在进行治疗卵巢癌和血液系统恶性肿瘤的研究。沃洛昔星的作用机制包括DNA嵌入和抑制拓扑异构酶II，从而导致选择性DNA损伤。在本研究中，我们描述了沃洛昔星在多种人类癌症的体外和体内模型中的抗增殖活性。
通过MTT法检测沃洛昔星在15种细胞系（包括4种耐药细胞系）中的体外细胞毒性。通过免疫组织化学评估细胞系和肿瘤中半胱天冬酶的激活情况。在16种异种移植和3种同基因肿瘤小鼠模型中评估抗肿瘤活性。在用沃洛昔星或对照药物治疗前，使肿瘤生长至约150 mm³。通过计算每种药物、剂量和给药方案的抑制率（IR = [1 - （治疗组平均肿瘤重量/对照组平均肿瘤重量）]×100%）和存活率（存活小鼠数量/研究开始时每组小鼠数量）来确定抗癌药物的活性。
体外研究表明，沃洛昔星在11种肿瘤细胞系中具有广泛的抗增殖活性，IC₅₀值范围为0.04至0.97 μM。在耐药细胞系中也观察到类似活性，包括那些过表达P - 糖蛋白且拓扑异构酶水平降低的细胞系。单次静脉给药后，肿瘤中的沃洛昔星浓度与凋亡标志物半胱天冬酶 - 3的诱导相关。使用KB鼻咽癌异种移植模型确定了最佳剂量和给药方案。每周以20 mg/kg给药5次的沃洛昔星有效抑制肿瘤生长（86%）。在11种实体瘤（乳腺癌、卵巢癌、结肠癌、肺癌、胃癌和黑色素瘤）异种移植模型中的10种、2种血液系统肿瘤异种移植模型、3种多药耐药肿瘤模型和3种小鼠同基因肿瘤模型（结肠26、刘易斯肺癌、M5076卵巢肉瘤）中，沃洛昔星表现出强烈的剂量依赖性肿瘤生长抑制（63 - 88%）。
这些数据表明，沃洛昔星在体外和体内均为广泛有效的抗肿瘤药物，在侵袭性和耐药肿瘤模型中具有强大活性。
