Interstitial chemotherapy with ricin-loaded thermosensitive hydrogel in pancreatic cancer xenograft

• Published in: Hepatobiliary & pancreatic diseases international 2009-08, Vol.8 (4), p.418-423
• Main Authors: Chen, Zhi-Kui, Lin, Li-Wu, Weng, Xiu-Hua, Xue, En-Sheng, Lin, Yong-Hua
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Apoptosis - drug effects; bcl-2-Associated X Protein - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; delivery; Dose-Response Relationship, Drug; drug; Drug Carriers; Feasibility Studies; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; hydrogel; Hydrogels; Injections, Intralesional; Mice; Mice, Inbred BALB C; Mice, Nude; Necrosis; neoplasm; pancreatic; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Polyethylene Glycols - chemistry; Polyglactin 910 - chemistry; Proto-Oncogene Proteins c-bcl-2 - genetics; Reverse Transcriptase Polymerase Chain Reaction; ricin; Ricin - administration & dosage; RNA, Messenger - metabolism; system; Temperature; therapeutics; Time Factors; Xenograft Model Antitumor Assays
• ISSN: 1499-3872

BACKGROUND:Pancreatic cancer is one of the most aggressive malignancies,and has a poor prognosis. Despite efforts made in multiple fields,there has been little success in improving the disease-free survival rate of patients.This study was undertaken to investigate the effectiveness and feasibility of using intra-tumoral injection of ricin-loaded thermosensitive hydrogel for treatment of pancreatic cancer xenografts,attempting to develop a new treatment for human pancreatic cancer. METHODS:BALB/c-(nu/nu)nude mice were inoculated subcutaneously in the right flank with the human pancreatic cancer cells,SW1990.Fourteen days after inoculation,32 mice,bearing tumors of volume 1.5-2.0 cm 3 ,were randomly assigned to one of four groups,and given an intra-tumoral injection of:(1)saline;(2)23% w/w thermosensitive hydrogel alone;(3)ricin,10μg/kg;or (4)10μg/kg ricin loaded in thermosensitive hydrogel.On day 14 after administration,the tumors were excised to calculate the inhibition rate of tumor growth and perform histopathological examination.Tumor cell apoptosis was detected by flow cytometry,and RT-PCR was performed to evaluate the mRNA expression levels of Bcl2 and Bax. RESULTS:Intra-tumoral injection of ricin-loaded thermo- sensitive hydrogel resulted in remarkable control of tumor growth.The tumor became necrotic by day 14 after administration.The histological results clearly confirmed that the tumor cells were lysed.The percentage of apoptotic cells detected by flow cytometry was higher in the ricin hydrogel group than in the other groups.Semi-quantitative RT-PCR revealed that the mRNA expression level of Bcl2 was down-regulated whereas Bax was upregulated.CONCLUSIONS:Intra-tumoral injection of ricin-loaded thermosensitive hydrogel may provide an effective approach for interstitial chemotherapy in pancreatic cancer. Inducing apoptosis by downregulating Bcl2 expression and upregulating Bax expression may be a key molecular mechanism.