Departments of Surgery, The University ofKansas Medical Center, KansasCity, KS, USA.
JAMA Otolaryngol Head Neck Surg. 2013 Apr;139(4):382-7. doi: 10.1001/jamaoto.2013.214.
Treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) uses a multidisciplinary approach often limited by the toxicity and drug resistance of platinum agents.
To test whether a nanocarrier-conjugated cisplatin boosting locoregional drug delivery improves tumor efficacy while decreasing systemic toxicity over systemic cisplatin in a murine model of locally advanced HNSCC.
A randomized, controlled, in vivo study compared standard cisplatin with nanocarrier (hyaluronan [HA])-conjugated cisplatin (HA-cisplatin) each at 50% of the maximum tolerated doses in a murine model of locally advanced HNSCC (10 mice/arm, each injected with 1 × 106 MDA-1986 HNSCC cells, with phosphate-buffered saline and HA-only control arms). Mice were treated for 3 weeks and observed for 3 additional weeks.
Academic medical center.
Forty female Nu/Nu mice. Randomization and treatment arms were initiated once tumor volumes reached 30 mm3.
Injection with MDA-1986 HNSCC cells followed by 3 weeks of treatment with cisplatin, HA-cisplatin, phosphate-buffered saline, or HA only.
Animal weights and tumor volumes were measured 3 times each week (modified RECIST [Response Evaluation Criteria in Solid Tumors]). At necropsy, animal kidneys were examined for nephrotoxic effects and cochleae were examined for ototoxic effects.
The mice treated with HA-cisplatin showed superior tumor efficacy (1 with complete clinical response, 3 with partial response, 1 with stable disease, and 5 with progressive disease) compared with standard cisplatin (no animals with complete clinical response, 1 with partial response, 1 with stable disease, and 8 with progressive disease), which was statistically significant (P = .003). All control animals developed progressive disease. Weight loss and body score were surrogate measures of treatment toxicity. The HA-cisplatin group had the least weight loss (mean [SD], 10.8% [4.7%]) compared with the cisplatin group (13.6% [5.6%]; P = .25). Body score dropped to 2 or less in all cisplatin-treated mice but not in any HA-cisplatin-treated mice, which also lacked any histologic signs of nephrotoxic or ototoxic effects.
Nanoconjugated HA-cisplatin significantly improves tumor efficacy with lower toxicity compared with standard cisplatin in locally advanced HNSCC in vivo, justifying additional translational studies.
重要性：局部晚期头颈部鳞状细胞癌（HNSCC）的治疗采用多学科方法，但常常受到铂类药物毒性和耐药性的限制。
目的：在局部晚期 HNSCC 的小鼠模型中，通过测试纳米载体结合顺铂是否能改善肿瘤疗效，同时降低系统毒性，来检验局部递增强效药物治疗是否优于全身顺铂。
设计：一项随机、对照、体内研究比较了标准顺铂和纳米载体（透明质酸[HA]）结合顺铂（HA-顺铂），均以局部晚期 HNSCC 小鼠模型中的最大耐受剂量的 50%（每组 10 只小鼠，每只注射 1×106 MDA-1986 HNSCC 细胞，磷酸缓冲盐水和仅 HA 对照臂）进行治疗。小鼠治疗 3 周，观察 3 周。
地点：学术医疗中心。
参与者：40 只雌性 Nu/Nu 小鼠。一旦肿瘤体积达到 30mm3，即开始进行随机分组和治疗臂。
干预：注射 MDA-1986 HNSCC 细胞，然后用顺铂、HA-顺铂、磷酸缓冲盐水或仅 HA 治疗 3 周。
主要观察指标：每周测量 3 次动物体重和肿瘤体积（改良的 RECIST [实体瘤反应评价标准]）。解剖时，检查动物肾脏是否有肾毒性作用，检查耳蜗是否有耳毒性作用。
结果：与标准顺铂相比，HA-顺铂治疗的小鼠具有更好的肿瘤疗效（1 只完全临床缓解，3 只部分缓解，1 只稳定，5 只进展），这具有统计学意义（P =.003）。所有对照动物均发生进展性疾病。体重减轻和身体评分是治疗毒性的替代指标。HA-顺铂组的体重减轻最少（平均[标准差]，10.8%[4.7%]），而顺铂组为 13.6%[5.6%]；P =.25）。所有顺铂治疗的小鼠的身体评分降至 2 分或以下，但没有一只 HA-顺铂治疗的小鼠出现这种情况，而且也没有任何组织学上的肾毒性或耳毒性迹象。
结论和相关性：在局部晚期 HNSCC 的体内模型中，与标准顺铂相比，纳米载体结合 HA-顺铂显著提高了肿瘤疗效，且毒性更低，这证明了进一步的转化研究是合理的。
