Cardiovascular differentiation of imatinib and bosutinib in the rat

• Published in: International journal of hematology Vol. 98; no. 5; pp. 597 - 607
• Main Authors: Heyen, Jonathan R., Hu, Wenyue, Jamieson, Joseph, Thibault, Stephane, Batugo, Minerva, Loi, Cho-Ming, Burns-Naas, Leigh Ann, McHarg, Aileen D., Jessen, Bart
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.11.2013; Springer; Springer Nature B.V
• Subjects: Aniline Compounds - administration & dosage; Aniline Compounds - adverse effects; Aniline Compounds - pharmacokinetics; Animals; Benzamides - administration & dosage; Benzamides - adverse effects; Benzamides - pharmacokinetics; Biological and medical sciences; Cardiomyopathy, Hypertrophic - chemically induced; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - pathology; Cardiovascular System - drug effects; Cardiovascular System - pathology; Echocardiography; Female; Gene Expression; Gene Knockdown Techniques; Heart - drug effects; Heart - physiopathology; Hematologic and hematopoietic diseases; Hematology; Imatinib Mesylate; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Medicine; Medicine & Public Health; Myocardium - metabolism; Myocardium - pathology; Nitriles - administration & dosage; Nitriles - adverse effects; Nitriles - pharmacokinetics; Oncology; Organ Size; Original Article; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - pharmacokinetics; Proto-Oncogene Proteins c-abl - genetics; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - pharmacokinetics; Rats; Sex Factors; Chronic myelogenous leukemia; Imatinib; Echocardiography; Cardiotoxicity; Bosutinib; Sonography; Antineoplastic agent; Hematology; Rat; Enzyme; Tyrosine kinase inhibitor; Transferases; Rodentia; Enzyme inhibitor; Cardiovascular disease; Malignant hemopathy; Cell differentiation; Myeloproliferative syndrome; Vertebrata; Mammalia; Animal; Circulatory system; Protein-tyrosine kinase; Cancer
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-013-1453-2

Imatinib and bosutinib were administered to rats for up to 6 months at clinically relevant exposures to investigate the effects on the cardiovascular system. Imatinib treatment resulted in increased volume, wall thickness and mass suggesting a hypertrophic heart in male and female rats at one and fivefold clinical exposures, respectively. Bosutinib treatment resulted in milder cardiac hypertrophy in female rats only at fivefold clinical exposures. Analysis of excised hearts and cultured myocytes demonstrated increased expression of hypertrophic genes with imatinib or analogs, but not bosutinib or c-Abl RNAi treatment. The current dataset suggests that cardiovascular liability of imatinib and bosutinib are differentiated preclinically and c-Abl independent.