Yi Taolin, Elson Paul, Mitsuhashi Masato, Jacobs Barbara, Hollovary Emese, Budd G Thomas, Spiro Timothy, Triozzi Pierre, Borden Ernest C
Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA.
Department of Immunology of Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.
Oncotarget. 2011 Dec;2(12):1155-1164. doi: 10.18632/oncotarget.563.
Since sodium stibogluconate (SSG) inhibited phosphatases including SHP-1 and augmented anti-tumor actions of IFN-α2b in vitro and in mice, two Phase I trials of SSG/IFN-α2b combination were undertaken to evaluate safety and target inhibition. Escalating doses of SSG (200-1200 mg/m2) and fixed doses of IFN-α2b (3x106 units/m2) with or without chemotherapy (dacarbazine, vinblastine, cisplatin) were evaluated for side effects and impact on SHP-1 phospho-substrates and IFNα-stimulated-genes (ISGs) in peripheral blood in 40 patients with metastatic melanoma, soft tissue sarcomas, gastrointestinal stromal tumors, and breast or colorectal carcinomas who did not have other established treatment options. Common adverse events were bone marrow suppression, fatigue, gastrointestinal upset, and asymptomatic lipase elevation (n=13); the latter was dose related and mostly after 10d of SSG/IFN-α2b in combination. Levels of SHP-1 substrates (pSTAT1, pSTAT3, pLck and pSlp76) were increased (up to 3x) in peripheral blood cells following SSG with no potentiation by combination with IFN-α2b. Representative ISGs in peripheral blood were induced after IFN-α2b at 4 and 24 hrs with selective modulations by combination. The median time on trials was 2.3 months (10-281d) with no objective regression of disease. Alive at 1y were 17/40 (43%) patients and after 2y were 8/40 (20%) following treatment initiation. These data demonstrate that SSG impacted signal molecules consistent with PTP inhibition and was tolerated in combination with IFN-α2b. Phase II investigations of SSG could safely utilize doses of up to 1200 mg/m2 of SSG for up to 10d alone or in combination with IFN-α2b with or without chemotherapy.
由于葡萄糖酸锑钠（SSG）可抑制包括SHP-1在内的磷酸酶，并在体外和小鼠体内增强IFN-α2b的抗肿瘤作用，因此开展了两项SSG/IFN-α2b联合用药的I期试验，以评估安全性和靶点抑制情况。对40例转移性黑色素瘤、软组织肉瘤、胃肠道间质瘤以及乳腺癌或结直肠癌患者（这些患者没有其他既定的治疗方案），评估递增剂量的SSG（200-1200mg/m²）和固定剂量的IFN-α2b（3×10⁶单位/m²）联合或不联合化疗（达卡巴嗪、长春碱、顺铂）的副作用，以及对外周血中SHP-1磷酸化底物和IFNα刺激基因（ISGs）的影响。常见的不良事件包括骨髓抑制、疲劳、胃肠道不适和无症状性脂肪酶升高（n = 13）；后者与剂量相关，且大多在SSG/IFN-α2b联合用药10天后出现。SSG给药后，外周血细胞中SHP-1底物（pSTAT1、pSTAT3、pLck和pSlp76）水平升高（最高达3倍），与IFN-α2b联合使用未增强这种升高。外周血中的代表性ISGs在IFN-α2b给药4小时和24小时后被诱导，联合用药有选择性调节作用。试验的中位时间为2.3个月（10-281天），疾病无客观缓解。治疗开始后1年存活的患者为17/40（43%），2年后为8/40（20%）。这些数据表明，SSG对信号分子的影响与蛋白酪氨酸磷酸酶抑制一致，并且与IFN-α2b联合使用时耐受性良好。SSG的II期研究可以安全地单独或与IFN-α2b联合使用高达1200mg/m²的SSG剂量，联合或不联合化疗，用药时间长达10天。
