Antitumor activity of a combination of trastuzumab (Herceptin) and oral fluoropyrimidine S-1 on human epidermal growth factor receptor 2-overexpressing pancreatic cancer

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 antibodydependent 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.

A review of clinical and molecular prognostic factors in osteosarcoma

“…On the basis of these mixed Wndings, there is some evidence for ErbB-2 as a prognostic indicator, although future studies with larger sample numbers are required to conWrm this. Furthermore, drugs blocking ErbB-2 like herceptin, used successfully in breast cancer clinically (Lin and Rugo 2007) and other cancers in vitro (Saeki et al 2007), may be beneWcial if patients with osteosarcoma were found to over express ErbB-2.…”

Pancreatic cancer: from molecular pathogenesis to targeted therapy

“…Significant synergism was found as well with transuzumab and the fluopyrimidines, on pancreatic cancer cell lines, both in vivo and in vitro (5-fluorouracil was used in vitro and S-1, an oral compound, in vivo) [108]. The examined pancreatic cancer cell lines TRG were overexpressing the HER2/neu receptor and treatment with the antibody and the cytotoxic drug significantly inhibited the tumor volume and growth [108].…”

“…The examined pancreatic cancer cell lines TRG were overexpressing the HER2/neu receptor and treatment with the antibody and the cytotoxic drug significantly inhibited the tumor volume and growth [108].…”

Monoclonal Antibodies in the Treatment of Pancreatic Cancer

“…Additive effects were observed when trastuzumab was combined with fluoropyrimidine S-1 both in vitro and in vivo (fluoropyrimidine S-1 is an oral preparation of 5-fluorouracil [5-FU] that consists of tegafur [a prodrug of 5-FU], 5-chloro-2,4-dihydoxypyridine and potassium oxonate, where the latter two can inhibit degradation of 5-FU and reduce gastrointestinal toxicity). In addition to the inhibition of the HER2 signal transduction pathway, antibody-dependent cellular cytotoxicity (ADCC) induced by trastuzumab contributed to cell growth inhibition [30]. Many effector cells in the immune system express IgG Fc receptors, which may activate the effector cells upon binding with specific antibodies.…”