Antifibrotic effects of pentoxifylline improve the efficacy of gemcitabine in human pancreatic tumor xenografts

• Published in: Cancer science Vol. 108; no. 12; pp. 2470 - 2477
• Main Authors: Kim, Jung Ho, Shin, Byung Cheol, Park, Won Sang, Lee, Jaehwi, Kuh, Hyo‐Jeong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2017; John Wiley and Sons Inc
• Subjects: Actin; Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Cancer therapies; Chemotherapy; Collagen; Collagen (type I); Connective tissue growth factor; Connective tissues; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; desmoplasia; Doxorubicin; Drug delivery; Drug resistance; Drug Synergism; Fibroblasts; Gemcitabine; Growth factors; Growth rate; Humans; Immunoglobulins; Mice; Mice, Inbred BALB C; Mice, Nude; Original; Pancreas; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - pathology; pentoxifylline; Pentoxifylline - pharmacology; Pharmaceuticals; Phosphodiesterase Inhibitors - pharmacology; Smooth muscle; Stroma; Studies; Tissue Distribution; Tumors; Xenograft Model Antitumor Assays; Xenografts; United States > US; Connective tissue growth factor; pentoxifylline; gemcitabine; desmoplasia; pancreatic ductal adenocarcinoma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13405

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. The combinatorial effects of pentoxifylline (PTX) on the efficacy of gemcitabine (GEM) was investigated in a human pancreatic tumor xenograft model. PTX improved the efficacy of GEM, which was shown to be associated with the antifibrotic effects of PTX, and mediated by suppressed expression of CTGF and subsequent reduction in the collagen matrix in the PDAC stroma.