Kim Jung Ho, Shin Byung Cheol, Park Won Sang, Lee Jaehwi, Kuh Hyo-Jeong
Department of Biomedicine & Health Science, The Catholic University of Korea, Seoul, Korea.
Bio/Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Korea.
Cancer Sci. 2017 Dec;108(12):2470-2477. doi: 10.1111/cas.13405. Epub 2017 Oct 31.
We investigated the combinatorial effects of pentoxifylline (PTX) on the efficacy of gemcitabine (GEM) in a human pancreatic tumor xenograft model. PTX significantly improved the efficacy of GEM, as shown by a 50% reduction in tumor growth rate at 4 weeks of treatment compared with that in animals given GEM alone. The fluorescent drug doxorubicin (DOX) was used to test whether drug delivery was improved by PTX, contributing to the improved efficacy of GEM. PTX given for 2 weeks prior to giving DOX improved drug distribution by 1.8- to 2.2-fold with no changes in vessel density, suggesting that improvement in drug delivery was not related to the vascular mechanism. Instead, collagen I content in tumor stroma was significantly reduced, as was the expression of alpha-smooth muscle actin of cancer-associated fibroblasts and connective tissue growth factor (CTGF) by PTX pretreatment. Overall, our data demonstrated that increased efficacy of GEM by PTX was associated with improved drug delivery to tumor tissue, which may be attributed to decreased expression of CTGF and subsequent reduction in the stromal collagen matrix in the pancreatic ductal adenocarcinoma tumor. These results support the usefulness of PTX in combination with chemotherapy for targeting drug delivery barriers associated with the stromal matrix, which should be further evaluated for clinical development.
我们在人胰腺肿瘤异种移植模型中研究了己酮可可碱（PTX）对吉西他滨（GEM）疗效的联合作用。PTX显著提高了GEM的疗效，与单独给予GEM的动物相比，治疗4周时肿瘤生长速率降低了50%。使用荧光药物阿霉素（DOX）来测试PTX是否改善了药物递送，这有助于提高GEM的疗效。在给予DOX前2周给予PTX，药物分布提高了1.8至2.2倍，而血管密度没有变化，这表明药物递送的改善与血管机制无关。相反，PTX预处理显著降低了肿瘤基质中I型胶原蛋白的含量，以及癌相关成纤维细胞的α-平滑肌肌动蛋白和结缔组织生长因子（CTGF）的表达。总体而言，我们的数据表明，PTX提高GEM的疗效与改善肿瘤组织的药物递送有关，这可能归因于CTGF表达降低以及随后胰腺导管腺癌肿瘤基质胶原基质减少。这些结果支持PTX联合化疗对靶向与基质相关的药物递送障碍的有用性，应进一步评估其临床开发价值。
