Klin Padiatr 2013; 225 - A12
DOI: 10.1055/s-0033-1343629

Continuous but not intermittent long-term exposure to the tyrosine kinase inhibitor (TKI) dasatinib causes cardiac failure in juvenile rats

P Geidel 1, JT Tauer 1, N Steinbronn 2, R Jung 3, E Bonifacio 4, I Leuschner 5, RH Strasser 2, M Suttorp 1
  • 1Dept. of Pediatrics, Div. of Hemato-Oncology, University Hospital, TU Dresden
  • 2Dept. of Internal Medicine and Cardiology, Heart Centre, University Hospital, TU Dresden
  • 3Experimental Centre of the Medical Faculty, TU Dresden
  • 4Center of Regenerative Therapies, Custer of Excellence of the TU Dresden
  • 5Inst. of Pathology, Div. of Paidopatholgy, University of Schleswig-Holstein, Campus Kiel, Germany

* these authors contributed equally to the work

Background: TKI treatment can result in cardiac failure as these drugs exert off-target effects via so far ill-defined mechanisms. Long-term exposure is of great concern in pediatric patients which may require life-long treatment for diseases like chronic myeloid leukemia. We here investigated the impact of prolonged dasatinib exposure on the growing heart in juvenile rodents.

Methods: 4-week old male Wistar rats were exposed via the drinking water to dasatinib at a standard dose (cohort S: 50µM) and a high dose (cohort H: 100µM) continuously, and also at the high dose intermittently (cohort I; Mon.-Wed. "on"; Thu.-Sun. "off"), respectively, over 10 weeks. Each cohort comprised 10 animals; controls (cohort K) received water only. Thus, the animals' development was covered from shortly after weaning (3 weeks old) over puberty (6 – 8 weeks old) until young adolescence (12 weeks old). Animals' behaviour, development, and body weight gain was monitored 3 x weekly while echocardiography using a dedicated small device as well as analysis of blood serums markers indicating cardiac impairment (BNP, IL-6, TNF-alpha, Troponin I) by Luminex assay (Milipore, USA) were performed every two weeks. Surviving animals were sacrificed at the end of the experiment. In all animals total heart weight and histopathological changes were examined.

Results: Dose-dependently animals died spontaneously (8/10 in cohort H) if exposed at a high dose continuously, but not if exposed intermittently. For ethical reason the experiment was terminated in cohort H after 5 weeks of drug exposure. Details on survival are presented for each cohort by Kaplan-Meier-Plots (see below). In concordance to survival data animals also exhibited impaired left ventricular ejection fraction, elevated serum BNP and increased heart weight with structural changes at necropsy.

Conclusion: Exposure to dasatinib at a high dosage continuously is life-threatening to juvenile rats. Interrupting the exposure for a period comparable to the treatment interval will avoid cardiac failure. Cardiac function in still growing individuals should be carefully monitored if treated with dasatinib in the long-term.