Tumor priming by Apo2L/TRAIL reduces interstitial fluid pressure and enhances efficacy of liposomal gemcitabine in a patient derived xenograft tumor model

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• 作者：Bonnie L. Hylander^a ; ¹ ; ^{Bonnie.Hylander@roswellpark.org" class="auth_mail" title="E-mail the corresponding author} ; Arindam Sen^a ; ¹ ; Sarah H. Beachy^b ; ² ; Rose Pitoniak^a ; Soumya Ullas^b ; John F. Gibbs^c ; ³ ; Jingxin Qiu^d ; Joshua D. Prey^e ; Gerald J. Fetterly^e ; ⁴ ; Elizabeth A. Repasky^a ; ^{Elizabeth.Repasky@roswellpark.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Apo2L/TRAIL ; Patient tumor xenograft ; Interstitial fluid pressure ; Gemcitabine ; Liposomes ; Drug uptake
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：10 November 2015
• 年：2015
• 卷：217
• 期：Complete
• 页码：160-169
• 全文大小：2347 K

文摘

Interstitial fluid pressure (IFP) is elevated in tumors and high IFP, a negative cancer prognosticator, is known to limit the uptake and efficacy of anti-tumor therapeutics. Approaches that alter the tumor microenvironment and enhance uptake of therapeutics are collectively referred to as tumor “priming”. Here we show that the cytotoxic biological therapy Apo2L/TRAIL can prime the tumor microenvironment and significantly lower IFP in three different human tumor xenograft models (Colo205, MiaPaca-2 and a patient gastrointestinal adenocarcinoma tumor xenograft). We found that a single dose of Apo2L/TRAIL resulted in a wave of apoptosis which reached a maximum at 8 h post-treatment. Apoptotic debris subsequently disappeared concurrent with an increase in macrophage infiltration. By 24 h post-treatment, treated tumors appeared less condensed with widening of the stromal areas which increased at 48 and 72 h. Analysis of tumor vasculature demonstrated a significant increase in overall vessel size at 48 and 72 h although the number of vessels did not change. Notably, IFP was significantly reduced in these tumors by 48 h after Apo2L/TRAIL treatment. Administration of gemcitabine at this time resulted in increased tumor uptake of both gemcitabine and liposomal gemcitabine and significantly improved anti-tumor efficacy of liposomal gemcitabine. These results suggest that Apo2L/TRAIL has a potential as a tumor priming agent and provides a rationale for developing a sequencing schema for combination therapy such that an initial dose of Apo2L/TRAIL would precede administration of gemcitabine or other therapies.