ABSTRACT
The cytotoxic effect of trastuzumab in combination with oral fluoropyrimidine S-1 on human epidermal growth factor receptor 2 (HER2)-overexpressing human pancreatic cancer cell line TRG in vitro and in vivo was investigated. HER2 expression in TRG was analyzed by RT-PCR and flow cytometry. For in vitro experiments, 5-fluorouracil (5-FU) was used instead of S-1. In vivo studies were conducted with TRG xenografts in athymic mice. Trastuzumab (10 mg/kg) was administered intraperitoneally once a week for 4 weeks. S-1 (10 mg/kg) was administered orally 5 days a week for 4 weeks. The results showed that TRG cells were positive for HER2 mRNA and overexpressed HER2 protein. Either trastuzumab or 5-FU concentration-dependently inhibited the growth of TRG cells. The combination of trastuzumab and 5-FU resulted in a significant inhibition of growth of TRG cells compared to either agent alone (P<0.001). Incubation of TRG cells with peripheral blood mononuclear cells after treatment with trastuzumab enhanced the antiproliferative effect of trastuzumab, which could be the result of antibody-dependent cellular cytotoxicity. The combination of trastuzumab and S-1 resulted in a significant reduction in xenograft volume compared to each agent alone (P<0.0001). In conclusion, this study showed that combination therapy with trastuzumab and S-1 may be effective for HER2-overexpressing pancreatic cancer patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Receptor, ErbB-2/genetics , Xenograft Model Antitumor Assays , Administration, Oral , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Cell Line, Tumor , Cell Proliferation/drug effects , Coculture Techniques , Dose-Response Relationship, Drug , Drug Combinations , ErbB Receptors/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Oxonic Acid/administration & dosage , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, ErbB-3/genetics , Receptor, ErbB-4 , Reverse Transcriptase Polymerase Chain Reaction , Tegafur/administration & dosage , TrastuzumabABSTRACT
We evaluated the efficacy of IORT for unresectable Stage IVb (Japan Pancreas Society classification) pancreatic cancer. Twelve patients were treated with IORT, 17 with external beam radiotherapy (ERT) and 17 with chemotherapy (CHT, 8 patients doxorubicin-based, 7 patients 5-FU-based). Survival, hospital-free survival and pain relief were compared among the three groups. In the IORT group, 7 patients underwent bypass surgery, 3 celiac plexus blockade, 3 ERT, 2 hyperthermia and 2 CHT. In the ERT group, 1 patient underwent bypass surgery, 7 hyperthermia and 14 CHT. Distant metastases were more frequently found in the CHT group than in the IORT group. Median survival and median hospital-free survival were 208 and 79 days in the IORT group, 125 and 32 days in the ERT group and 76 and 9 days in the CHT group, respectively. Pain relief was obtained in 45% (5/11) of symptomatic patients after IORT and in 27% (4/15) after ERT. No patient (0/13) in the CHT group experienced pain relief. In conclusion, our experience suggests that IORT can reduce pain and improve QOL in patients with unresectable pancreatic cancer.
