Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer.
Cetuximab delivery and antitumor effects are enhanced by mild hyperthermia in a xenograft mouse model of pancreatic cancer.
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DOI：
10.1111/cas.12888
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发表时间：
2016-04
期刊：
影响因子：
5.7
通讯作者：
Ohkohchi N
中科院分区：
文献类型：
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作者：
Miyamoto R;Oda T;Hashimoto S;Kurokawa T;Inagaki Y;Shimomura O;Ohara Y;Yamada K;Akashi Y;Enomoto T;Kishimoto M;Yanagihara H;Kita E;Ohkohchi N
即使使用目前有希望的抗肿瘤抗体，它们对富含基质的实体癌的抗肿瘤作用也是不够的。我们使用轻度热疗，目的是通过打破基质屏障来改善药物递送。在这里，我们提供了西妥昔单抗+轻度热疗治疗的临床前证据。我们使用了四种具有不同基质量的体内胰腺癌异种移植小鼠模型（稀少，MIAPaCa-2;中等，BxPC-3;和丰富，Capan-1和Ope-xeno）。全身给予西妥昔单抗（1 mg/kg），同时使用水浴法在三种不同温度下加热小鼠腿部肿瘤30 min，25°C（对照）、37°C（腹腔内器官水平）或41°C（轻度高热）（n = 4，每组）。评价的变量为抗肿瘤作用（以肿瘤体积表示）和体内西妥昔单抗蓄积（使用抗人IgG Fc抗体通过免疫组织化学荧光强度值/细胞间接定量）。在25°C时，抗肿瘤作用充分，西妥昔单抗蓄积值（荧光强度/细胞）在MIAPaCa-2模型中为1632，在BxPC-3模型中为中度（1063），在Capan-1和Ope-xeno模型中为阴性（760，461）。通过施加37°C或41°C的热量，抗肿瘤效果增强，表现为肿瘤体积减小。这些增强效应伴随着西妥昔单抗蓄积增加，在BxPC-3模型中增加2.8倍（2980，3015），在Capan-1模型中增加2.5或4.8倍（1881，3615），在Ope-xeno模型中增加3.2或4.2倍（1469，1922）。西妥昔单抗在治疗甚至间质丰富和k-ras突变胰腺癌小鼠模型中也是有效的，当药物递送通过与轻度热疗组合来改善时。
Even with current promising antitumor antibodies, their antitumor effects on stroma‐rich solid cancers have been insufficient. We used mild hyperthermia with the intent of improving drug delivery by breaking the stromal barrier. Here, we provide preclinical evidence of cetuximab + mild hyperthermia therapy. We used four in vivo pancreatic cancer xenograft mouse models with different stroma amounts (scarce, MIAPaCa‐2; moderate, BxPC‐3; and abundant, Capan‐1 and Ope‐xeno). Cetuximab (1 mg/kg) was given systemically, and the mouse leg tumors were concurrently heated using a water bath method for 30 min at three different temperatures, 25°C (control), 37°C (intra‐abdominal organ level), or 41°C (mild hyperthermia) (n = 4, each group). The evaluated variables were the antitumor effects, represented by tumor volume, and in vivo cetuximab accumulation, indirectly quantified by the immunohistochemical fluorescence intensity value/cell using antibodies against human IgG Fc. At 25°C, the antitumor effects were sufficient, with a cetuximab accumulation value (florescence intensity/cell) of 1632, in the MIAPaCa‐2 model, moderate (1063) in the BxPC‐3 model, and negative in the Capan‐1 and Ope‐xeno models (760, 461). By applying 37°C or 41°C heat, antitumor effects were enhanced shown in decreased tumor volumes. These enhanced effects were accompanied by boosted cetuximab accumulation, which increased by 2.8‐fold (2980, 3015) in the BxPC‐3 model, 2.5‐ or 4.8‐fold (1881, 3615) in the Capan‐1 model, and 3.2‐ or 4.2‐fold (1469, 1922) in the Ope‐xeno model, respectively. Cetuximab was effective in treating even stroma‐rich and k‐ras mutant pancreatic cancer mouse models when the drug delivery was improved by combination with mild hyperthermia.