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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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Related in: MedlinePlus

S-222611 inhibits the growth of various types of cancer in animal models. In all animal models, vehicle or indicated doses of S-222611 were orally administered daily. Multiple doses of lapatinib were also administered in the same experiment simultaneously and the ED50 value of both S-222611 and lapatinib were determined (Table S2). Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD is represented by each data point. (a,b) Human breast cancer cells, BT-474 (a) or MDA-MB-361 (b) were implanted orthotopically into the mammary fat pad of mice. Tumor-bearing mice were treated for 28 days. a: n = 7, b: n = 12. (c,d) Human epidermoid carcinoma cells, A431 (c), or human colon cancer cells, HT115 (d), were implanted subcutaneously into the back of mice. Tumor-bearing mice were treated for 11 and 21 days, respectively. c,d: n = 6. **: P < 0.01 (versus vehicle, Dunnett's test).
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fig02: S-222611 inhibits the growth of various types of cancer in animal models. In all animal models, vehicle or indicated doses of S-222611 were orally administered daily. Multiple doses of lapatinib were also administered in the same experiment simultaneously and the ED50 value of both S-222611 and lapatinib were determined (Table S2). Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD is represented by each data point. (a,b) Human breast cancer cells, BT-474 (a) or MDA-MB-361 (b) were implanted orthotopically into the mammary fat pad of mice. Tumor-bearing mice were treated for 28 days. a: n = 7, b: n = 12. (c,d) Human epidermoid carcinoma cells, A431 (c), or human colon cancer cells, HT115 (d), were implanted subcutaneously into the back of mice. Tumor-bearing mice were treated for 11 and 21 days, respectively. c,d: n = 6. **: P < 0.01 (versus vehicle, Dunnett's test).

Mentions: As EGFR and HER2 are expressed in many types of cancer, S-222611 was tested for its antitumor activity in various cancer models in vivo (Fig. 2a–d, Table S2). In HER2-overexpressing human breast cancer models, S-222611 showed remarkable antitumor activity in the BT474 tumor model (Fig. 2a) and complete growth inhibition at 50 mg/kg even in the relatively less sensitive MDA-MB-361 tumor model (Fig. 2b). The antitumor activity of lapatinib for EGFR-dominant cancer was limited compared with that for HER2-expressing cancer.(28,29) S-222611 showed potent antitumor activity even in EGFR-dominant tumor models (Fig. 2c,d and Table S2). Moreover, the treatment with a higher dose of S-222611 (>50 mg/kg) completely inhibited the growth of tumors or caused marked tumor regression in most of the models tested. These results indicate that S-222611 should be an effective treatment in a variety of tumor types.


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 various types of cancer in animal models. In all animal models, vehicle or indicated doses of S-222611 were orally administered daily. Multiple doses of lapatinib were also administered in the same experiment simultaneously and the ED50 value of both S-222611 and lapatinib were determined (Table S2). Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD is represented by each data point. (a,b) Human breast cancer cells, BT-474 (a) or MDA-MB-361 (b) were implanted orthotopically into the mammary fat pad of mice. Tumor-bearing mice were treated for 28 days. a: n = 7, b: n = 12. (c,d) Human epidermoid carcinoma cells, A431 (c), or human colon cancer cells, HT115 (d), were implanted subcutaneously into the back of mice. Tumor-bearing mice were treated for 11 and 21 days, respectively. c,d: n = 6. **: P < 0.01 (versus vehicle, Dunnett's test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: S-222611 inhibits the growth of various types of cancer in animal models. In all animal models, vehicle or indicated doses of S-222611 were orally administered daily. Multiple doses of lapatinib were also administered in the same experiment simultaneously and the ED50 value of both S-222611 and lapatinib were determined (Table S2). Tumor volume was measured twice or thrice weekly and the mean tumor volume with SD is represented by each data point. (a,b) Human breast cancer cells, BT-474 (a) or MDA-MB-361 (b) were implanted orthotopically into the mammary fat pad of mice. Tumor-bearing mice were treated for 28 days. a: n = 7, b: n = 12. (c,d) Human epidermoid carcinoma cells, A431 (c), or human colon cancer cells, HT115 (d), were implanted subcutaneously into the back of mice. Tumor-bearing mice were treated for 11 and 21 days, respectively. c,d: n = 6. **: P < 0.01 (versus vehicle, Dunnett's test).
Mentions: As EGFR and HER2 are expressed in many types of cancer, S-222611 was tested for its antitumor activity in various cancer models in vivo (Fig. 2a–d, Table S2). In HER2-overexpressing human breast cancer models, S-222611 showed remarkable antitumor activity in the BT474 tumor model (Fig. 2a) and complete growth inhibition at 50 mg/kg even in the relatively less sensitive MDA-MB-361 tumor model (Fig. 2b). The antitumor activity of lapatinib for EGFR-dominant cancer was limited compared with that for HER2-expressing cancer.(28,29) S-222611 showed potent antitumor activity even in EGFR-dominant tumor models (Fig. 2c,d and Table S2). Moreover, the treatment with a higher dose of S-222611 (>50 mg/kg) completely inhibited the growth of tumors or caused marked tumor regression in most of the models tested. These results indicate that S-222611 should be an effective treatment in a variety of tumor types.

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