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

In vivo antitumor activity of S-222611 in patient-oriented preclinical models. (a–d) Luciferase-expressing human breast cancer cell line, BT474-luc, were implanted into the bone marrow of the left femur (a,b) or into the brain (c,d) of mice. (a,c) Tumor growth was monitored by the photons emitted from the tumor as an indicator, which was measured with an IVIS Imaging System 200 (Caliper Life Sciences). (b,d) Bioluminescent images at the last measurement. Tumor-bearing mice were orally administered vehicle or the indicated doses of S-222611 or lapatinib for 21 days (a,b) or 28 days (c,d). The photons were measured once or twice weekly and the mean photons/sec with SD are presented at each data point. a,b: n = 5, c,d: n = 7. In the experiment with intracranially implanted mice (c,d), 1 mouse treated with 200 mg/kg lapatinib died accidentally during the anesthesia for in vivo imaging at 13 days after the initial measurement. The death was not considered to be related to lapatinib treatment. Thus, the data points of the 200 mg/kg lapatinib group at 14 days after initial measurement represent the mean and SD of the data from 6 mice. ns: P ≥ 0.05, **: P < 0.01 (versus vehicle, Dunnett's test). #: P < 0.01 (50 mg/kg S-222611 vs 50 mg/kg lapatinib, Welch's t-test). (e) Human breast cancer cell line, BT474, were implanted into the brain of nude mice. After randomization at 36 days after implantation (n = 10), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily until death or the end of study (106 days after implantation). ns: P ≥ 0.05, **: P < 0.01 (log-rank test with Dunn–Šidák multiple test correction).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: In vivo antitumor activity of S-222611 in patient-oriented preclinical models. (a–d) Luciferase-expressing human breast cancer cell line, BT474-luc, were implanted into the bone marrow of the left femur (a,b) or into the brain (c,d) of mice. (a,c) Tumor growth was monitored by the photons emitted from the tumor as an indicator, which was measured with an IVIS Imaging System 200 (Caliper Life Sciences). (b,d) Bioluminescent images at the last measurement. Tumor-bearing mice were orally administered vehicle or the indicated doses of S-222611 or lapatinib for 21 days (a,b) or 28 days (c,d). The photons were measured once or twice weekly and the mean photons/sec with SD are presented at each data point. a,b: n = 5, c,d: n = 7. In the experiment with intracranially implanted mice (c,d), 1 mouse treated with 200 mg/kg lapatinib died accidentally during the anesthesia for in vivo imaging at 13 days after the initial measurement. The death was not considered to be related to lapatinib treatment. Thus, the data points of the 200 mg/kg lapatinib group at 14 days after initial measurement represent the mean and SD of the data from 6 mice. ns: P ≥ 0.05, **: P < 0.01 (versus vehicle, Dunnett's test). #: P < 0.01 (50 mg/kg S-222611 vs 50 mg/kg lapatinib, Welch's t-test). (e) Human breast cancer cell line, BT474, were implanted into the brain of nude mice. After randomization at 36 days after implantation (n = 10), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily until death or the end of study (106 days after implantation). ns: P ≥ 0.05, **: P < 0.01 (log-rank test with Dunn–Šidák multiple test correction).

Mentions: We evaluated S-222611 in patient-oriented models. Because bone metastasis is observed in more than 80% of advanced breast cancer patients with significant morbidity, we examined S-222611 using a model of luciferase-expressing human breast cancer cells implanted into the femur of nude mice.(30) S-222611 showed approximately four times more potent activity than lapatinib and completely inhibited the growth of cancer cells at 50 mg/kg (Fig. 3a,b).


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 of S-222611 in patient-oriented preclinical models. (a–d) Luciferase-expressing human breast cancer cell line, BT474-luc, were implanted into the bone marrow of the left femur (a,b) or into the brain (c,d) of mice. (a,c) Tumor growth was monitored by the photons emitted from the tumor as an indicator, which was measured with an IVIS Imaging System 200 (Caliper Life Sciences). (b,d) Bioluminescent images at the last measurement. Tumor-bearing mice were orally administered vehicle or the indicated doses of S-222611 or lapatinib for 21 days (a,b) or 28 days (c,d). The photons were measured once or twice weekly and the mean photons/sec with SD are presented at each data point. a,b: n = 5, c,d: n = 7. In the experiment with intracranially implanted mice (c,d), 1 mouse treated with 200 mg/kg lapatinib died accidentally during the anesthesia for in vivo imaging at 13 days after the initial measurement. The death was not considered to be related to lapatinib treatment. Thus, the data points of the 200 mg/kg lapatinib group at 14 days after initial measurement represent the mean and SD of the data from 6 mice. ns: P ≥ 0.05, **: P < 0.01 (versus vehicle, Dunnett's test). #: P < 0.01 (50 mg/kg S-222611 vs 50 mg/kg lapatinib, Welch's t-test). (e) Human breast cancer cell line, BT474, were implanted into the brain of nude mice. After randomization at 36 days after implantation (n = 10), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily until death or the end of study (106 days after implantation). ns: P ≥ 0.05, **: P < 0.01 (log-rank test with Dunn–Šidák multiple test correction).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: In vivo antitumor activity of S-222611 in patient-oriented preclinical models. (a–d) Luciferase-expressing human breast cancer cell line, BT474-luc, were implanted into the bone marrow of the left femur (a,b) or into the brain (c,d) of mice. (a,c) Tumor growth was monitored by the photons emitted from the tumor as an indicator, which was measured with an IVIS Imaging System 200 (Caliper Life Sciences). (b,d) Bioluminescent images at the last measurement. Tumor-bearing mice were orally administered vehicle or the indicated doses of S-222611 or lapatinib for 21 days (a,b) or 28 days (c,d). The photons were measured once or twice weekly and the mean photons/sec with SD are presented at each data point. a,b: n = 5, c,d: n = 7. In the experiment with intracranially implanted mice (c,d), 1 mouse treated with 200 mg/kg lapatinib died accidentally during the anesthesia for in vivo imaging at 13 days after the initial measurement. The death was not considered to be related to lapatinib treatment. Thus, the data points of the 200 mg/kg lapatinib group at 14 days after initial measurement represent the mean and SD of the data from 6 mice. ns: P ≥ 0.05, **: P < 0.01 (versus vehicle, Dunnett's test). #: P < 0.01 (50 mg/kg S-222611 vs 50 mg/kg lapatinib, Welch's t-test). (e) Human breast cancer cell line, BT474, were implanted into the brain of nude mice. After randomization at 36 days after implantation (n = 10), vehicle or multiple doses of S-222611 or lapatinib were orally administered daily until death or the end of study (106 days after implantation). ns: P ≥ 0.05, **: P < 0.01 (log-rank test with Dunn–Šidák multiple test correction).
Mentions: We evaluated S-222611 in patient-oriented models. Because bone metastasis is observed in more than 80% of advanced breast cancer patients with significant morbidity, we examined S-222611 using a model of luciferase-expressing human breast cancer cells implanted into the femur of nude mice.(30) S-222611 showed approximately four times more potent activity than lapatinib and completely inhibited the growth of cancer cells at 50 mg/kg (Fig. 3a,b).

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