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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.

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In vivo antitumor activity and toxicity profile of S-222611, neratinib and afatinib in the NCI-N87 model. (a) Human gastric cancer cells, NCI-N87, were implanted subcutaneously into nude mice. After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611, neratinib or afatinib were orally administered daily for 21 days. Mean tumor volume with SD at the last measurement (the day following the last administration) is represented in each bar graph. ns: P ≥ 0.05, *: P < 0.05 (Welch's t-test with Dunn–Šidák multiple test correction). (b,c) Representative histopatholgical images of the colon (b) and eyeball (c) of mice treated with vehicle, S-222611 (25 mg/kg), neratinib (25 mg/kg) and afatinib (12.5 mg/kg). Regeneration in the colonic epithelium (b) and atrophy in the corneal epithelium were observed in neratinib-treated and afatinib-treated mice. No remarkable changes were observed in vehicle-treated and S-222611-treated mice. Stained with H&E. Bar: 100 μm.
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fig04: In vivo antitumor activity and toxicity profile of S-222611, neratinib and afatinib in the NCI-N87 model. (a) Human gastric cancer cells, NCI-N87, were implanted subcutaneously into nude mice. After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611, neratinib or afatinib were orally administered daily for 21 days. Mean tumor volume with SD at the last measurement (the day following the last administration) is represented in each bar graph. ns: P ≥ 0.05, *: P < 0.05 (Welch's t-test with Dunn–Šidák multiple test correction). (b,c) Representative histopatholgical images of the colon (b) and eyeball (c) of mice treated with vehicle, S-222611 (25 mg/kg), neratinib (25 mg/kg) and afatinib (12.5 mg/kg). Regeneration in the colonic epithelium (b) and atrophy in the corneal epithelium were observed in neratinib-treated and afatinib-treated mice. No remarkable changes were observed in vehicle-treated and S-222611-treated mice. Stained with H&E. Bar: 100 μm.

Mentions: Recently, several irreversible EGFR/HER2 inhibitors have been evaluated in clinical trials and shown promising efficacy.(9)– (15) We compared the antitumor activity of S-222611 with irreversible inhibitors neratinib and afatinib (Fig. 4a). If we simply compared these drugs at the same dose, the efficacy of S-2322611 was weaker than those of both irreversible inhibitors, although statistical significance was observed only between 25 mg/kg S-222611 and 25 mg/kg afatinib. Generally, irreversible inhibitors are more potent in kinase inhibition and antitumor activity than reversible inhibitors, but the clinical trials of these irreversible inhibitors revealed that the frequency and degree of the adverse effect are also significantly increased.(10)– (15,32,33) To assess the toxicity profile, we conducted a histopathological examination with mice used in the antitumor efficacy studies and observed the pivotal toxicity in the colon and eyeball in neratinib-treated and afatinib-treated mice. In the colon, mucosal regeneration was observed in 2/9 mice of the 25 mg/kg neratinib-treated group and 4/9 mice of the 12.5 mg/kg afatinib-treated group (Fig. 4b). These findings indicated prior injuries in the colon intestine. In the eyeball, atrophy in the corneal epithelium was observed in 1/9 mouse of the 6.25 and 25 mg/kg neratinib-treated groups, and 5/9 mice of the 6.25 and 12.5 mg/kg afatinib-treated groups (Fig. 4c). Neither of these toxicological findings was observed with 12.5 and 25 mg/kg S-222611-treated mice. These results indicated that S-222611 should be more effective than irreversible inhibitors when compared at doses that are not associated with toxic changes.


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)

In vivo antitumor activity and toxicity profile of S-222611, neratinib and afatinib in the NCI-N87 model. (a) Human gastric cancer cells, NCI-N87, were implanted subcutaneously into nude mice. After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611, neratinib or afatinib were orally administered daily for 21 days. Mean tumor volume with SD at the last measurement (the day following the last administration) is represented in each bar graph. ns: P ≥ 0.05, *: P < 0.05 (Welch's t-test with Dunn–Šidák multiple test correction). (b,c) Representative histopatholgical images of the colon (b) and eyeball (c) of mice treated with vehicle, S-222611 (25 mg/kg), neratinib (25 mg/kg) and afatinib (12.5 mg/kg). Regeneration in the colonic epithelium (b) and atrophy in the corneal epithelium were observed in neratinib-treated and afatinib-treated mice. No remarkable changes were observed in vehicle-treated and S-222611-treated mice. Stained with H&E. Bar: 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: In vivo antitumor activity and toxicity profile of S-222611, neratinib and afatinib in the NCI-N87 model. (a) Human gastric cancer cells, NCI-N87, were implanted subcutaneously into nude mice. After randomization at 3 days after implantation (n = 9), vehicle or multiple doses of S-222611, neratinib or afatinib were orally administered daily for 21 days. Mean tumor volume with SD at the last measurement (the day following the last administration) is represented in each bar graph. ns: P ≥ 0.05, *: P < 0.05 (Welch's t-test with Dunn–Šidák multiple test correction). (b,c) Representative histopatholgical images of the colon (b) and eyeball (c) of mice treated with vehicle, S-222611 (25 mg/kg), neratinib (25 mg/kg) and afatinib (12.5 mg/kg). Regeneration in the colonic epithelium (b) and atrophy in the corneal epithelium were observed in neratinib-treated and afatinib-treated mice. No remarkable changes were observed in vehicle-treated and S-222611-treated mice. Stained with H&E. Bar: 100 μm.
Mentions: Recently, several irreversible EGFR/HER2 inhibitors have been evaluated in clinical trials and shown promising efficacy.(9)– (15) We compared the antitumor activity of S-222611 with irreversible inhibitors neratinib and afatinib (Fig. 4a). If we simply compared these drugs at the same dose, the efficacy of S-2322611 was weaker than those of both irreversible inhibitors, although statistical significance was observed only between 25 mg/kg S-222611 and 25 mg/kg afatinib. Generally, irreversible inhibitors are more potent in kinase inhibition and antitumor activity than reversible inhibitors, but the clinical trials of these irreversible inhibitors revealed that the frequency and degree of the adverse effect are also significantly increased.(10)– (15,32,33) To assess the toxicity profile, we conducted a histopathological examination with mice used in the antitumor efficacy studies and observed the pivotal toxicity in the colon and eyeball in neratinib-treated and afatinib-treated mice. In the colon, mucosal regeneration was observed in 2/9 mice of the 25 mg/kg neratinib-treated group and 4/9 mice of the 12.5 mg/kg afatinib-treated group (Fig. 4b). These findings indicated prior injuries in the colon intestine. In the eyeball, atrophy in the corneal epithelium was observed in 1/9 mouse of the 6.25 and 25 mg/kg neratinib-treated groups, and 5/9 mice of the 6.25 and 12.5 mg/kg afatinib-treated groups (Fig. 4c). Neither of these toxicological findings was observed with 12.5 and 25 mg/kg S-222611-treated mice. These results indicated that S-222611 should be more effective than irreversible inhibitors when compared at doses that are not associated with toxic changes.

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