Limits...
Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2.

Tanaka H, Hirata M, Shinonome S, Wada T, Iguchi M, Dohi K, Inoue M, Ishioka Y, Hojo K, Yamada T, Sugimoto T, Masuno K, Nezasa K, Sato N, Matsuo K, Yonezawa S, Frenkel EP, Shichijo M - Cancer Sci. (2014)

Bottom Line: In evaluations with two patient-oriented models, the intrafemoral implantation model and the intracranial implantation model, S-222611 exhibited excellent activity and could be effective against bone and brain metastasis.Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S-222611 showed equivalent or slightly weaker antitumor activity but a safer profile.These results indicated that S-222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses.

View Article: PubMed Central - PubMed

Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.

Show MeSH

Related in: MedlinePlus

S-222611 inhibits the growth of NCI-N87 tumor and phosphorylation of epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2) in the tumor. The animal model was prepared by subcutaneous implantation of human gastric cancer cells, NCI-N87 into the back of nude mice. (a) After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily for 21 days. To avoid visual complexity, only two doses of lapatinib are depicted in this graph. The four full doses of lapatinib are presented in Figure S1. Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD was represented at each data point. **P < 0.01 (versus vehicle, Dunnett's test). (b–e) After randomization at 12 days after implantation (n = 5), vehicle or multiple doses of S-222611 or lapatinib were administered orally. The relative phosphorylations of EGFR (b,d) and HER2 (c,e) were calculated and the mean with SD is presented in each bar graph. In b and c, the relative phosphorylations of EGFR (b) and HER2 (c) in tumor collected 24 h after administration of the indicated doses of S-222611 or lapatinib are shown. In d and e, the relative phosphorylation levels of EGFR (d) and HER2 (e) in the tumor collected 6 and 24 h after administration of 50 mg/kg of S-222611 or lapatinib are shown. ns: P ≥ 0.05, **: P < 0.01 (Tukey's multiple comparison). (f) The fold increase of the IC50 of each short-time pulse treatment compared to that of 72-h treatment was calculated and the mean with SD is presented in each bar graph (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4317859&req=5

fig01: S-222611 inhibits the growth of NCI-N87 tumor and phosphorylation of epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2) in the tumor. The animal model was prepared by subcutaneous implantation of human gastric cancer cells, NCI-N87 into the back of nude mice. (a) After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily for 21 days. To avoid visual complexity, only two doses of lapatinib are depicted in this graph. The four full doses of lapatinib are presented in Figure S1. Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD was represented at each data point. **P < 0.01 (versus vehicle, Dunnett's test). (b–e) After randomization at 12 days after implantation (n = 5), vehicle or multiple doses of S-222611 or lapatinib were administered orally. The relative phosphorylations of EGFR (b,d) and HER2 (c,e) were calculated and the mean with SD is presented in each bar graph. In b and c, the relative phosphorylations of EGFR (b) and HER2 (c) in tumor collected 24 h after administration of the indicated doses of S-222611 or lapatinib are shown. In d and e, the relative phosphorylation levels of EGFR (d) and HER2 (e) in the tumor collected 6 and 24 h after administration of 50 mg/kg of S-222611 or lapatinib are shown. ns: P ≥ 0.05, **: P < 0.01 (Tukey's multiple comparison). (f) The fold increase of the IC50 of each short-time pulse treatment compared to that of 72-h treatment was calculated and the mean with SD is presented in each bar graph (n = 3).

Mentions: The in vivo antitumor activity of S-222611 was evaluated. Nude mice bearing NCI-N87 xenograft were treated orally with S-222611 or lapatinib. The changes of tumor volume over time are shown in Figure 1(a) (Fig. S1). S-222611 significantly inhibited the tumor growth in a dose-dependent manner. Comparison of ED50 between S-222611 and lapatinib (10.2 and 57.7 mg/kg, respectively, Table S2) indicated that the in vivo antitumor activity of S-222611 was approximately six times more potent than that of lapatinib. No body weight loss and no macroscopic toxicity were observed in the S-222611-treated mice.


Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2.

Tanaka H, Hirata M, Shinonome S, Wada T, Iguchi M, Dohi K, Inoue M, Ishioka Y, Hojo K, Yamada T, Sugimoto T, Masuno K, Nezasa K, Sato N, Matsuo K, Yonezawa S, Frenkel EP, Shichijo M - Cancer Sci. (2014)

S-222611 inhibits the growth of NCI-N87 tumor and phosphorylation of epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2) in the tumor. The animal model was prepared by subcutaneous implantation of human gastric cancer cells, NCI-N87 into the back of nude mice. (a) After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily for 21 days. To avoid visual complexity, only two doses of lapatinib are depicted in this graph. The four full doses of lapatinib are presented in Figure S1. Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD was represented at each data point. **P < 0.01 (versus vehicle, Dunnett's test). (b–e) After randomization at 12 days after implantation (n = 5), vehicle or multiple doses of S-222611 or lapatinib were administered orally. The relative phosphorylations of EGFR (b,d) and HER2 (c,e) were calculated and the mean with SD is presented in each bar graph. In b and c, the relative phosphorylations of EGFR (b) and HER2 (c) in tumor collected 24 h after administration of the indicated doses of S-222611 or lapatinib are shown. In d and e, the relative phosphorylation levels of EGFR (d) and HER2 (e) in the tumor collected 6 and 24 h after administration of 50 mg/kg of S-222611 or lapatinib are shown. ns: P ≥ 0.05, **: P < 0.01 (Tukey's multiple comparison). (f) The fold increase of the IC50 of each short-time pulse treatment compared to that of 72-h treatment was calculated and the mean with SD is presented in each bar graph (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317859&req=5

fig01: S-222611 inhibits the growth of NCI-N87 tumor and phosphorylation of epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2) in the tumor. The animal model was prepared by subcutaneous implantation of human gastric cancer cells, NCI-N87 into the back of nude mice. (a) After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily for 21 days. To avoid visual complexity, only two doses of lapatinib are depicted in this graph. The four full doses of lapatinib are presented in Figure S1. Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD was represented at each data point. **P < 0.01 (versus vehicle, Dunnett's test). (b–e) After randomization at 12 days after implantation (n = 5), vehicle or multiple doses of S-222611 or lapatinib were administered orally. The relative phosphorylations of EGFR (b,d) and HER2 (c,e) were calculated and the mean with SD is presented in each bar graph. In b and c, the relative phosphorylations of EGFR (b) and HER2 (c) in tumor collected 24 h after administration of the indicated doses of S-222611 or lapatinib are shown. In d and e, the relative phosphorylation levels of EGFR (d) and HER2 (e) in the tumor collected 6 and 24 h after administration of 50 mg/kg of S-222611 or lapatinib are shown. ns: P ≥ 0.05, **: P < 0.01 (Tukey's multiple comparison). (f) The fold increase of the IC50 of each short-time pulse treatment compared to that of 72-h treatment was calculated and the mean with SD is presented in each bar graph (n = 3).
Mentions: The in vivo antitumor activity of S-222611 was evaluated. Nude mice bearing NCI-N87 xenograft were treated orally with S-222611 or lapatinib. The changes of tumor volume over time are shown in Figure 1(a) (Fig. S1). S-222611 significantly inhibited the tumor growth in a dose-dependent manner. Comparison of ED50 between S-222611 and lapatinib (10.2 and 57.7 mg/kg, respectively, Table S2) indicated that the in vivo antitumor activity of S-222611 was approximately six times more potent than that of lapatinib. No body weight loss and no macroscopic toxicity were observed in the S-222611-treated mice.

Bottom Line: In evaluations with two patient-oriented models, the intrafemoral implantation model and the intracranial implantation model, S-222611 exhibited excellent activity and could be effective against bone and brain metastasis.Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S-222611 showed equivalent or slightly weaker antitumor activity but a safer profile.These results indicated that S-222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses.

View Article: PubMed Central - PubMed

Affiliation: Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.

Show MeSH
Related in: MedlinePlus