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Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea.

ABSTRACT: Orally administered small molecule receptor tyrosine kinase inhibitors (RTKIs) are increasingly common treatments for cancer, both alone and in combination with chemotherapy. However, their side effect profiles and the underlying mechanisms of such are not yet fully elucidated. Management of their most common dose limiting side effect, diarrhea, has been hampered by a lack of suitable animal models. We aimed to develop a clinically relevant rat model of RTKI-induced diarrhea that could be utilized for investigating supportive care interventions and pharmacokinetics. Albino Wistar rats were treated daily for 4 weeks with various concentrations of lapatinib to determine the optimal dose for development of diarrhea. This was then followed by an experiment with addition of paclitaxel once weekly for 4 weeks to observe effects of combination drug treatment on diarrhea. Data regarding animal tolerance to the treatment, organ weights, circulating lapatinib concentration and histopathology were collected weekly. Lapatinib caused diarrhea in rats that was dose-dependent. Diarrhea occurred without causing significant intestinal histopathology. Follow up experiments are currently underway to determine the exact pathogenesis and mechanisms of lapatinib-induced diarrhea and potential protective strategies.

SUBMITTER: Bowen JM

PROVIDER: S-EPMC3493434 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea.

Bowen Joanne M JM Mayo Bronwen J BJ Plews Erin E Bateman Emma E Stringer Andrea M AM Boyle Frances M FM Finnie John W JW Keefe Dorothy M K DM

Cancer biology & therapy 20120816 13

Orally administered small molecule receptor tyrosine kinase inhibitors (RTKIs) are increasingly common treatments for cancer, both alone and in combination with chemotherapy. However, their side effect profiles and the underlying mechanisms of such are not yet fully elucidated. Management of their most common dose limiting side effect, diarrhea, has been hampered by a lack of suitable animal models. We aimed to develop a clinically relevant rat model of RTKI-induced diarrhea that could be utiliz ...[more]

PMID: 22895076

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Project description:One of the most clinically relevant molecular aberrations in breast cancer is overexpression of human epidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog (125/131I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. Methods: The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. 125/131I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of 131I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal 125I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of 125/131I-IBA-CP toward HER2 in vitro and in vivo. Additionally, 125/131I-ICP was prepared by direct radioiodination of CP724,714 for comparison with 125/131I-IBA-CP. Results: IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. 125/131I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of 125I-IBA-CP than of 125I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of 125I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. Conclusion: The radiolabeled HER2-selective inhibitor 125/131I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.

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Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea.

Publications

Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea.

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