Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer.
Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer.
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DOI：
10.1111/cas.13309
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发表时间：
2017-09
期刊：
影响因子：
5.7
通讯作者：
Okamoto I
中科院分区：
文献类型：
--
作者：
Otsubo K;Nosaki K;Imamura CK;Ogata H;Fujita A;Sakata S;Hirai F;Toyokawa G;Iwama E;Harada T;Seto T;Takenoyama M;Ozeki T;Mushiroda T;Inada M;Kishimoto J;Tsuchihashi K;Suina K;Nagano O;Saya H;Nakanishi Y;Okamoto I
CD44剪接变异体(CD44v)是实体瘤中肿瘤干细胞的标志物。它们稳定转运蛋白系统XC(-)的XCT亚单位，从而促进抗氧化剂谷胱甘肽的合成。Salazosulfapyridine(SASP)是XCT的一种抑制剂，能抑制CD44v阳性癌细胞的增殖。化疗初治的晚期非鳞状非小细胞肺癌患者参加了SASP联合顺铂和培美曲塞的剂量递增研究(标准3+3设计)。主要终点是经历剂量限制毒性的患者的百分比。15名患者参加了这项研究。剂量限制性毒性发生在6名患者中的1名，剂量为1.5g/d(天冬氨酸和丙氨酸氨基转移酶水平升高，各为3级)，5名患者中的2名，每天3 g(低血压或肺炎，各为3级)，以及3名患者中的2名，剂量为4.5g/d(3级厌食)。因此，最大耐受量为3克/天，推荐剂量为1.5克/天。总有效率为26.7%，中位无进展生存期为11.7个月，远长于以往研究中单用顺铂-培美曲塞的时间。根据ABCG2和NAT2基因型别，暴露于SASP的个体之间存在显著差异。第一周期治疗后血清游离CD44v蛋白浓度升高，可能反映了肿瘤干细胞的死亡。因此，沙拉唑磺胺吡啶与顺铂-培美曲塞联合使用是安全的，加上SASP有延长无进展生存期的趋势。这项试验在UMIN临床试验注册中心注册为UMIN000017854。
Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(–) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v‐positive cancer cells. Chemotherapy‐naïve patients with advanced non‐squamous non‐small‐cell lung cancer were enrolled in a dose‐escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end‐point was the percentage of patients who experience dose‐limiting toxicity. Fifteen patients were enrolled in the study. Dose‐limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression‐free survival was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin–pemetrexed, with the addition of SASP tending to prolong progression‐free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
45.3
作者：
Scagliotti, Giorgio Vittorio;Parikh, Purvish;Gandara, David
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影响因子：
50.3
作者：
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通讯作者：
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影响因子：
51.1
作者：
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通讯作者：
Gridelli, Cesare
影响因子：
7.4
作者：
Shitara, Kohei;Doi, Toshihiko;Ohtsu, Atsushi
通讯作者：
Ohtsu, Atsushi