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Targeting interleukin-4 receptor alpha by hybrid Peptide for novel biliary tract cancer therapy.

Seto K, Shoda J, Horibe T, Warabi E, Kohno M, Yanagawa T, Bukawa H, Nakanuma Y, Kawakami K - Int J Hepatol (2014)

Bottom Line: It is known that the interleukin-4 receptor α (IL-4R α ) is highly expressed on the surface of various human solid tumors.We also showed that IL-4R α -lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro.In addition, intravenous administration of IL-4R α -lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Surgery, Clinical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan ; Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

ABSTRACT
It is known that the interleukin-4 receptor α (IL-4R α ) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4R α -lytic hybrid peptide composed of binding peptide to IL-4R α and cell-lytic peptide and reported that the designed IL-4R α -lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4R α . Here, we evaluated the antitumor activity of the IL-4R α -lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4R α -lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5  μ M. We also showed that IL-4R α -lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4R α -lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4R α -lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC.

No MeSH data available.


Related in: MedlinePlus

Antitumor activity of IL-4Rα-lytic hybrid peptide in tumor xenograft model in vivo. TGBC-44-TKB were implanted subcutaneously into athymic nude mice. Intravenous injection of saline and IL-4Rα-lytic hybrid peptide (2 mg/kg or 5 mg/kg) is indicated by the arrows. Data are expressed as mean ± SD (n = 6 animals in each group).
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fig4: Antitumor activity of IL-4Rα-lytic hybrid peptide in tumor xenograft model in vivo. TGBC-44-TKB were implanted subcutaneously into athymic nude mice. Intravenous injection of saline and IL-4Rα-lytic hybrid peptide (2 mg/kg or 5 mg/kg) is indicated by the arrows. Data are expressed as mean ± SD (n = 6 animals in each group).

Mentions: Following the observation that IL-4Rα-lytic hybrid peptide was remarkably cytotoxic to BTC cell lines in vitro (Figure 2), the antitumor activity of the hybrid peptide was assessed in a xenograft model of human BTC. TGBC-44-TKB cells were inoculated subcutaneously into athymic nude mice and then the animals were treated with IL-4Rα-lytic hybrid peptide by intravenous injection. As shown in Figure 4, tumors grew aggressively in control mice injected with saline alone, reaching a volume of 1285 mm3 by day 22. In contrast, mice treated with IL-4Rα-lytic hybrid peptide showed significant tumor regression at both dosages: mean tumor volumes were 1025 mm3 (2 mg/kg) and 594 mm3 (5 mg/kg) on day 22. The tumor volume was inhibited significantly at a dose of 5 mg/kg (P < 0.05). No other abnormalities, such as loss of appetite and body weight, were observed in mice injected with IL-4Rα-lytic hybrid peptide (data not shown). The number of leukocytes (the mean (×103) and SD values) after the experiments is as follows: control group: 5.1 ± 2.1, 2 mg/kg group: 5.6 ± 4.0, and 5 mg/kg group: 6.6 ± 4.7, and there are no significant differences in each group. Histological analysis also showed no side effects in tissue from the major organs, including liver and kidney, which were obtained from mice treated with intravenous administration of IL-4Rα-lytic hybrid peptide (data not shown). These results demonstrated that IL-4Rα-lytic hybrid peptide induced an effective antitumor activity in a mouse xenograft model of BTC.


Targeting interleukin-4 receptor alpha by hybrid Peptide for novel biliary tract cancer therapy.

Seto K, Shoda J, Horibe T, Warabi E, Kohno M, Yanagawa T, Bukawa H, Nakanuma Y, Kawakami K - Int J Hepatol (2014)

Antitumor activity of IL-4Rα-lytic hybrid peptide in tumor xenograft model in vivo. TGBC-44-TKB were implanted subcutaneously into athymic nude mice. Intravenous injection of saline and IL-4Rα-lytic hybrid peptide (2 mg/kg or 5 mg/kg) is indicated by the arrows. Data are expressed as mean ± SD (n = 6 animals in each group).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: Antitumor activity of IL-4Rα-lytic hybrid peptide in tumor xenograft model in vivo. TGBC-44-TKB were implanted subcutaneously into athymic nude mice. Intravenous injection of saline and IL-4Rα-lytic hybrid peptide (2 mg/kg or 5 mg/kg) is indicated by the arrows. Data are expressed as mean ± SD (n = 6 animals in each group).
Mentions: Following the observation that IL-4Rα-lytic hybrid peptide was remarkably cytotoxic to BTC cell lines in vitro (Figure 2), the antitumor activity of the hybrid peptide was assessed in a xenograft model of human BTC. TGBC-44-TKB cells were inoculated subcutaneously into athymic nude mice and then the animals were treated with IL-4Rα-lytic hybrid peptide by intravenous injection. As shown in Figure 4, tumors grew aggressively in control mice injected with saline alone, reaching a volume of 1285 mm3 by day 22. In contrast, mice treated with IL-4Rα-lytic hybrid peptide showed significant tumor regression at both dosages: mean tumor volumes were 1025 mm3 (2 mg/kg) and 594 mm3 (5 mg/kg) on day 22. The tumor volume was inhibited significantly at a dose of 5 mg/kg (P < 0.05). No other abnormalities, such as loss of appetite and body weight, were observed in mice injected with IL-4Rα-lytic hybrid peptide (data not shown). The number of leukocytes (the mean (×103) and SD values) after the experiments is as follows: control group: 5.1 ± 2.1, 2 mg/kg group: 5.6 ± 4.0, and 5 mg/kg group: 6.6 ± 4.7, and there are no significant differences in each group. Histological analysis also showed no side effects in tissue from the major organs, including liver and kidney, which were obtained from mice treated with intravenous administration of IL-4Rα-lytic hybrid peptide (data not shown). These results demonstrated that IL-4Rα-lytic hybrid peptide induced an effective antitumor activity in a mouse xenograft model of BTC.

Bottom Line: It is known that the interleukin-4 receptor α (IL-4R α ) is highly expressed on the surface of various human solid tumors.We also showed that IL-4R α -lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro.In addition, intravenous administration of IL-4R α -lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Surgery, Clinical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan ; Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.

ABSTRACT
It is known that the interleukin-4 receptor α (IL-4R α ) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4R α -lytic hybrid peptide composed of binding peptide to IL-4R α and cell-lytic peptide and reported that the designed IL-4R α -lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4R α . Here, we evaluated the antitumor activity of the IL-4R α -lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4R α -lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5  μ M. We also showed that IL-4R α -lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4R α -lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4R α -lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC.

No MeSH data available.


Related in: MedlinePlus