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Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant
Background Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproduci...
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| Published in: | Breast cancer (Tokyo, Japan) Japan), 2021, Vol.28 (1), p.99-109 |
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| container_issue | 1 |
| container_start_page | 99 |
| container_title | Breast cancer (Tokyo, Japan) |
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| creator | Secombe, Kate R. Ball, Imogen A. Shirren, Joseph Wignall, Anthony D. Keefe, Dorothy M. Bowen, Joanne M. |
| description | Background
Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats.
Methods
At first, male rats were treated with neratinib at 15, 30 or 50 mg/kg or vehicle control via oral gavage for 28 days (total
n
= 12). Secondly, we compared outcomes of male (
n
= 7) and female (
n
= 8) rats, treated with 50 mg/kg neratinib.
Results
Rats treated with a 50 mg/kg daily dose of neratinib had a reproducible and clinically relevant level of diarrhea and therefore was confirmed as an appropriate dose. Male rats treated with neratinib had significant changes to their gut microbiome. This included neratinib-induced increases in
Ruminococcaceae
(
P
= 0.0023) and
Oscillospira
(
P
= 0.026), and decreases in
Blautia
(
P
= 0.0002). On average, female rats experienced more significant neratinib-induced diarrhea (mean grade 1.526) compared with male rats (mean grade 1.182) (
P
|
| doi_str_mv | 10.1007/s12282-020-01133-9 |
| format | article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_2425589870</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A712280303</galeid><sourcerecordid>A712280303</sourcerecordid><originalsourceid>FETCH-LOGICAL-c438t-c11ef1c639251a6853ced2f65487a240debe4c5ec1395db504261e6d870c5ac03</originalsourceid><addsrcrecordid>eNp9kU-PFCEQxYnRuOvqF_BgSLx46bWAbpr2ttn4L9lED3omNFTPsOmGEejDfPtlplcTE2M4UCl-r1K8R8hrBtcMoH-fGeeKN8ChAcaEaIYn5JIpBU3LhXhaa9FCI5VUF-RFzvcArehBPicXgkslJMhLUr6bso-H_TH7OMfdkcaJBkym-ODHxge3WnTUeZPSHg31gS5mRmqCoxOey8rmD3TxNsXRm5mauZz1MWRq6CEWDOXUd1j7iw8mlJfk2WTmjK8e7yvy89PHH7dfmrtvn7_e3tw1thWqNJYxnJiVYuAdM1J1ou7CJ9m1qje8BYcjtrZDy8TQubGDlkuG0qkebGcsiCvybpt7SPHXirnoxWeL82wCxjVr3vKuU0PlK_p2Q3f1T9qHKZZk7AnXN_3JZxAgKnX9D6oeh9WAGHDytf-XgG-C6k7OCSd9SH4x6agZ6FOIegtR1xD1OUQ9VNGbx7XXcUH3R_I7tQqIDcj1Keww6fu4plCt_N_YB1Xlp5g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2425589870</pqid></control><display><type>article</type><title>Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant</title><source>Springer Nature</source><creator>Secombe, Kate R. ; Ball, Imogen A. ; Shirren, Joseph ; Wignall, Anthony D. ; Keefe, Dorothy M. ; Bowen, Joanne M.</creator><creatorcontrib>Secombe, Kate R. ; Ball, Imogen A. ; Shirren, Joseph ; Wignall, Anthony D. ; Keefe, Dorothy M. ; Bowen, Joanne M.</creatorcontrib><description>Background
Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats.
Methods
At first, male rats were treated with neratinib at 15, 30 or 50 mg/kg or vehicle control via oral gavage for 28 days (total
n
= 12). Secondly, we compared outcomes of male (
n
= 7) and female (
n
= 8) rats, treated with 50 mg/kg neratinib.
Results
Rats treated with a 50 mg/kg daily dose of neratinib had a reproducible and clinically relevant level of diarrhea and therefore was confirmed as an appropriate dose. Male rats treated with neratinib had significant changes to their gut microbiome. This included neratinib-induced increases in
Ruminococcaceae
(
P
= 0.0023) and
Oscillospira
(
P
= 0.026), and decreases in
Blautia
(
P
= 0.0002). On average, female rats experienced more significant neratinib-induced diarrhea (mean grade 1.526) compared with male rats (mean grade 1.182) (
P
< 0.0001). Neratinib caused a reduction in percentage weight gain after 28 days of treatment in females (
P
= 0.0018) compared with vehicle controls. Females and males both showed instances of villus atrophy and fusion, most severely in the distal ileum. Serum neratinib concentration was higher in female rats compared to male rats (
P
= 0.043).
Conclusions
A reproducible diarrhea model was developed in both female and male rats, which indicated that diarrhea pathogenesis is multifactorial, including anatomical disruption particularly evident in the distal ileum, and alterations in microbial composition.</description><identifier>ISSN: 1340-6868</identifier><identifier>EISSN: 1880-4233</identifier><identifier>DOI: 10.1007/s12282-020-01133-9</identifier><identifier>PMID: 32683606</identifier><language>eng</language><publisher>Tokyo: Springer Japan</publisher><subject>Adjuvant treatment ; Cancer ; Cancer Research ; Comparative analysis ; Complications and side effects ; Diarrhea ; Drug approval ; Drug therapy ; Medicine ; Medicine & Public Health ; Oncology ; Original Article ; Surgery ; Surgical Oncology ; Tyrosine</subject><ispartof>Breast cancer (Tokyo, Japan), 2021, Vol.28 (1), p.99-109</ispartof><rights>The Japanese Breast Cancer Society 2020</rights><rights>COPYRIGHT 2021 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-c11ef1c639251a6853ced2f65487a240debe4c5ec1395db504261e6d870c5ac03</citedby><cites>FETCH-LOGICAL-c438t-c11ef1c639251a6853ced2f65487a240debe4c5ec1395db504261e6d870c5ac03</cites><orcidid>0000-0003-0716-238X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32683606$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Secombe, Kate R.</creatorcontrib><creatorcontrib>Ball, Imogen A.</creatorcontrib><creatorcontrib>Shirren, Joseph</creatorcontrib><creatorcontrib>Wignall, Anthony D.</creatorcontrib><creatorcontrib>Keefe, Dorothy M.</creatorcontrib><creatorcontrib>Bowen, Joanne M.</creatorcontrib><title>Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant</title><title>Breast cancer (Tokyo, Japan)</title><addtitle>Breast Cancer</addtitle><addtitle>Breast Cancer</addtitle><description>Background
Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats.
Methods
At first, male rats were treated with neratinib at 15, 30 or 50 mg/kg or vehicle control via oral gavage for 28 days (total
n
= 12). Secondly, we compared outcomes of male (
n
= 7) and female (
n
= 8) rats, treated with 50 mg/kg neratinib.
Results
Rats treated with a 50 mg/kg daily dose of neratinib had a reproducible and clinically relevant level of diarrhea and therefore was confirmed as an appropriate dose. Male rats treated with neratinib had significant changes to their gut microbiome. This included neratinib-induced increases in
Ruminococcaceae
(
P
= 0.0023) and
Oscillospira
(
P
= 0.026), and decreases in
Blautia
(
P
= 0.0002). On average, female rats experienced more significant neratinib-induced diarrhea (mean grade 1.526) compared with male rats (mean grade 1.182) (
P
< 0.0001). Neratinib caused a reduction in percentage weight gain after 28 days of treatment in females (
P
= 0.0018) compared with vehicle controls. Females and males both showed instances of villus atrophy and fusion, most severely in the distal ileum. Serum neratinib concentration was higher in female rats compared to male rats (
P
= 0.043).
Conclusions
A reproducible diarrhea model was developed in both female and male rats, which indicated that diarrhea pathogenesis is multifactorial, including anatomical disruption particularly evident in the distal ileum, and alterations in microbial composition.</description><subject>Adjuvant treatment</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Comparative analysis</subject><subject>Complications and side effects</subject><subject>Diarrhea</subject><subject>Drug approval</subject><subject>Drug therapy</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Surgery</subject><subject>Surgical Oncology</subject><subject>Tyrosine</subject><issn>1340-6868</issn><issn>1880-4233</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kU-PFCEQxYnRuOvqF_BgSLx46bWAbpr2ttn4L9lED3omNFTPsOmGEejDfPtlplcTE2M4UCl-r1K8R8hrBtcMoH-fGeeKN8ChAcaEaIYn5JIpBU3LhXhaa9FCI5VUF-RFzvcArehBPicXgkslJMhLUr6bso-H_TH7OMfdkcaJBkym-ODHxge3WnTUeZPSHg31gS5mRmqCoxOey8rmD3TxNsXRm5mauZz1MWRq6CEWDOXUd1j7iw8mlJfk2WTmjK8e7yvy89PHH7dfmrtvn7_e3tw1thWqNJYxnJiVYuAdM1J1ou7CJ9m1qje8BYcjtrZDy8TQubGDlkuG0qkebGcsiCvybpt7SPHXirnoxWeL82wCxjVr3vKuU0PlK_p2Q3f1T9qHKZZk7AnXN_3JZxAgKnX9D6oeh9WAGHDytf-XgG-C6k7OCSd9SH4x6agZ6FOIegtR1xD1OUQ9VNGbx7XXcUH3R_I7tQqIDcj1Keww6fu4plCt_N_YB1Xlp5g</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Secombe, Kate R.</creator><creator>Ball, Imogen A.</creator><creator>Shirren, Joseph</creator><creator>Wignall, Anthony D.</creator><creator>Keefe, Dorothy M.</creator><creator>Bowen, Joanne M.</creator><general>Springer Japan</general><general>Springer</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0716-238X</orcidid></search><sort><creationdate>2021</creationdate><title>Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant</title><author>Secombe, Kate R. ; Ball, Imogen A. ; Shirren, Joseph ; Wignall, Anthony D. ; Keefe, Dorothy M. ; Bowen, Joanne M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-c11ef1c639251a6853ced2f65487a240debe4c5ec1395db504261e6d870c5ac03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adjuvant treatment</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Comparative analysis</topic><topic>Complications and side effects</topic><topic>Diarrhea</topic><topic>Drug approval</topic><topic>Drug therapy</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Surgery</topic><topic>Surgical Oncology</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Secombe, Kate R.</creatorcontrib><creatorcontrib>Ball, Imogen A.</creatorcontrib><creatorcontrib>Shirren, Joseph</creatorcontrib><creatorcontrib>Wignall, Anthony D.</creatorcontrib><creatorcontrib>Keefe, Dorothy M.</creatorcontrib><creatorcontrib>Bowen, Joanne M.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Breast cancer (Tokyo, Japan)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Secombe, Kate R.</au><au>Ball, Imogen A.</au><au>Shirren, Joseph</au><au>Wignall, Anthony D.</au><au>Keefe, Dorothy M.</au><au>Bowen, Joanne M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant</atitle><jtitle>Breast cancer (Tokyo, Japan)</jtitle><stitle>Breast Cancer</stitle><addtitle>Breast Cancer</addtitle><date>2021</date><risdate>2021</risdate><volume>28</volume><issue>1</issue><spage>99</spage><epage>109</epage><pages>99-109</pages><issn>1340-6868</issn><eissn>1880-4233</eissn><abstract>Background
Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats.
Methods
At first, male rats were treated with neratinib at 15, 30 or 50 mg/kg or vehicle control via oral gavage for 28 days (total
n
= 12). Secondly, we compared outcomes of male (
n
= 7) and female (
n
= 8) rats, treated with 50 mg/kg neratinib.
Results
Rats treated with a 50 mg/kg daily dose of neratinib had a reproducible and clinically relevant level of diarrhea and therefore was confirmed as an appropriate dose. Male rats treated with neratinib had significant changes to their gut microbiome. This included neratinib-induced increases in
Ruminococcaceae
(
P
= 0.0023) and
Oscillospira
(
P
= 0.026), and decreases in
Blautia
(
P
= 0.0002). On average, female rats experienced more significant neratinib-induced diarrhea (mean grade 1.526) compared with male rats (mean grade 1.182) (
P
< 0.0001). Neratinib caused a reduction in percentage weight gain after 28 days of treatment in females (
P
= 0.0018) compared with vehicle controls. Females and males both showed instances of villus atrophy and fusion, most severely in the distal ileum. Serum neratinib concentration was higher in female rats compared to male rats (
P
= 0.043).
Conclusions
A reproducible diarrhea model was developed in both female and male rats, which indicated that diarrhea pathogenesis is multifactorial, including anatomical disruption particularly evident in the distal ileum, and alterations in microbial composition.</abstract><cop>Tokyo</cop><pub>Springer Japan</pub><pmid>32683606</pmid><doi>10.1007/s12282-020-01133-9</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-0716-238X</orcidid></addata></record> |
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| source | Springer Nature |
| subjects | Adjuvant treatment Cancer Cancer Research Comparative analysis Complications and side effects Diarrhea Drug approval Drug therapy Medicine Medicine & Public Health Oncology Original Article Surgery Surgical Oncology Tyrosine |
| title | Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant |
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