Trifluridine/tipiracil increases survival rates in peritoneal dissemination mouse models of human colorectal and gastric cancer

Suzuki, Norihiko; Nakagawa, Fumio; Takechi, Teiji

doi:10.3892/ol.2017.6258

Cited by 6 publications

(3 citation statements)

References 31 publications

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“…Our study investigated the effects of sCEA on the pharmacokinetics of two anti-CEA antibodies: 15-1-32 and labetuzumab. We also prepared CEA-expressing tumor-bearing mice in which serum sCEA levels are maintained over 5 ng/ml (the reference value of sCEA as a cancer diagnostic marker) (Perkins et al, 2003;Suzuki et al, 2017). We compared the pharmacokinetics of the two anti-CEA antibodies between tumor-bearing mice and normal (non-tumor-bearing) mice.…”

Section: Introductionmentioning

confidence: 99%

Impact of Different Selectivity between Soluble and Membrane-bound Forms of Carcinoembryonic Antigen (CEA) on the Target-mediated Disposition of Anti-CEA Monoclonal Antibodies

Iwano¹,

Shinmi²,

Masuda³

et al. 2019

Drug Metab Dispos

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Carcinoembryonic antigen (CEA) is a tumor-specific antigen overexpressed in multiple cancers. CEA is expressed as a membrane protein, a part of which is cleaved from the cell membrane and secreted into blood. The soluble form of CEA (sCEA) has been shown to accelerate the clearance of anti-CEA antibody, which limits the antibody distribution in the tumor. To overcome this issue, we developed an anti-CEA monoclonal antibody, 15-1-32, which shows a strong affinity for membrane-bound CEA (mCEA) and relatively weak affinity for sCEA. In this study, we compared the effect of sCEA on the pharmacokinetics of 15-1-32 in mice with that of another anti-CEA monoclonal antibody, labetuzumab, showing less selectivity to mCEA than 15-1-32. As expected, the effect of sCEA on the serum concentration of 15-1-32 was much smaller than that of labetuzumab. The decrease in the area under the curve (AUC) of serum concentration was 22.5% for 15-1-32 when it was coadministered with sCEA, while that of labetuzumab was 79.9%. We also compared the pharmacokinetics of these two antibodies in CEA-positive tumor-bearing mice. The AUCs of 15-1-32 and labetuzumab were decreased in tumor-bearing mice compared with non-tumor-bearing mice to a similar extent (approximately 40% decrease). These results suggested that mCEA also contributes to the clearance of anti-CEA antibodies in CEA-positive tumor-bearing mice. Although the increased selectivity to mCEA minimized the effect of sCEA on the pharmacokinetics of 15-1-32, it may be insufficient to improve the pharmacokinetics in CEA-positive cancer patients. SIGNIFICANCE STATEMENT Because previous studies reported the rapid clearance of anti-CEA antibodies mediated by soluble CEA, we obtained a monoclonal antibody, 15-1-32, selective to membrane-bound CEA and evaluated the effects of CEA on its pharmacokinetics. Although the effect of soluble CEA on the serum concentration of 15-1-32 was very small, the clearance of 15-1-32 in CEA-positive tumor-bearing mice was still rapid, suggesting membrane-bound CEA also contributes to the clearance of anti-CEA antibodies. These results indicated that increasing selectivity to membrane-bound CEA is not enough to improve the pharmacokinetics of anti-CEA antibody.

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Section: Introductionmentioning

confidence: 99%

Impact of Different Selectivity between Soluble and Membrane-bound Forms of Carcinoembryonic Antigen (CEA) on the Target-mediated Disposition of Anti-CEA Monoclonal Antibodies

Iwano¹,

Shinmi²,

Masuda³

et al. 2019

Drug Metab Dispos

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“…The number of mice per group was set at 6, which was thought to be sufficient to evaluate the antitumor effect based on previous experiments [ 24 ]. FTD/TPI was administered on days 1–5, 8–12, and 15–19 for the HCT 116-xenograft model and on days 1–5, 8–12, and 15 for the SW48-xenograft model, respectively, according to the reported effective dose and schedule [ 25 , 26 ]. Fruquintinib was orally administered at the reported effective dose of 10 mg/kg [ 20 ] for 15 (SW48-xenograft model) or 21 (HCT 116-xenograft model) consecutive days.…”

Section: Methodsmentioning

confidence: 99%

“…This study protocol was reviewed and approved according to the guidelines for endpoints in animal study proposals by NIH [ 25 ] and with the approval of the Institutional Animal Care and Use Committee of Taiho Pharmaceutical Co., Ltd. (Approval number, 20TC11).…”

Section: Statement Of Ethicsmentioning

confidence: 99%

Evaluation of a Novel Combination Therapy, Based on Trifluridine/Tipiracil and Fruquintinib, against Colorectal Cancer

et al. 2023

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Introduction: Trifluridine/tipiracil hydrochloride (FTD/TPI, Lonsurf®) is an oral antineoplastic agent that has been approved as a late-stage chemotherapy for colorectal cancer. Its major mechanism of action is the dysfunction of tumoral DNA including DNA strand breaks and decreased replication. Fruquintinib (ELUNATE®) is a novel kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-1, -2, and -3. In this study, we evaluated the antitumor activity of combination therapy with FTD/TPI and fruquintinib in vivo. Methods: The enhancement of the antitumor effects with FTD/TPI and fruquintinib combination, compared to the single drugs given alone was evaluated using two human colorectal cancer xenografts in nude mouse models. FTD/TPI (200 mg/kg) was orally administered for 5 consecutive days followed by 2 days of rest in a 7-day period. Fruquintinib (10 mg/kg) was orally administered consecutively for 2 and 3 weeks in SW48 and HCT 116 tumor-bearing models, respectively. After treatment with these agents, the microvessel density was evaluated by CD31 immunohistochemical analyses. Results: In both models, FTD/TPI and fruquintinib significantly inhibited tumor growth, and the activity of the combined treatment was significantly superior to that of either monotherapy. Body weight loss of greater than 20% was not observed in any group. A histochemical analysis showed nuclei enlargement, abnormal mitosis and karyorrhexis in the FTD/TPI treatment group. The microvessel density in the HCT 116 tumors treated with FTD/TPI and fruquintinib was significantly lower than that in the control group. Conclusion: The combination of FTD/TPI and fruquintinib could be a promising treatment option for colorectal cancer.

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Discovery and Development of Trifluridine/Tipiracil (Lonsurf ™)

Suzuki

Ito

Takechi

2018

Successful Drug Discovery

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Trifluridine/tipiracil increases survival rates in peritoneal dissemination mouse models of human colorectal and gastric cancer

Cited by 6 publications

References 31 publications

Impact of Different Selectivity between Soluble and Membrane-bound Forms of Carcinoembryonic Antigen (CEA) on the Target-mediated Disposition of Anti-CEA Monoclonal Antibodies

Impact of Different Selectivity between Soluble and Membrane-bound Forms of Carcinoembryonic Antigen (CEA) on the Target-mediated Disposition of Anti-CEA Monoclonal Antibodies

Evaluation of a Novel Combination Therapy, Based on Trifluridine/Tipiracil and Fruquintinib, against Colorectal Cancer

Discovery and Development of Trifluridine/Tipiracil (Lonsurf ™)

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