Abstract 1209: Concurrent administration of doxorubicin and lapatinib worsens doxorubicin-induced cardiac dysfunction in mice

Abstract

Abstract Background: Concurrent use of chemotherapy drug doxorubicin (DOX) and Trastuzumab, a monocloncal antibody that blocks HER2, induced cardiac dysfunction in 27% of patients. Clinical trials have shown that the incidence of symptomatic heart failure was much lower (0.3%) in patients sequentially treated with DOX and lapatinib, an EGFR and HER2 tyrosine kinase inhibitor. More studies are necessary to determine the safety of concurrent DOX and lapatinib treatment, which is important for developing more effective cancer therapy. Here, we tested the effect of concurrent DOX and lapatinib administration on cardiac function in mice. Methods: A well-established subacute murine DOX heart failure model was used. 10-12 week old C57BL/6 mice were treated with a single dose of DOX (20 mg/kg, i.p.), or DOX concurrently with lapatinib (100 mg/kg, oral gavage, daily). Survival was analyzed by the Kaplan-Meier method. Cardiac function was monitored by hemodynamic measurements. Results: Ten days after the treatment, survival was significantly lower in DOX+lapatinib vs. DOX mice (13 vs. 0 %, n=7-8 /group, P<0.001). Five to seven days after the treatment, cardiac contractile function was significantly lower in DOX+lapatinib vs. control mice [left ventricular systolic pressure (LVSP): 83 ± 2 vs. 93 ± 2 mmHg, P<0.05; dP/dtmin: 4020 ± 360 vs. 7112 ± 580 mmHg/sec, P<0.05; cardiac output (CO): 1236 ± 266 vs. 2734 ± 209 unit/min, P<0.05, n=5 per group]; however, these indices were maintained in DOX mice at this point (LVSP: 99 ±4 mmHg; dP/dtmin: 7787 ± 965 mmHg/sec; CO: 2315 ± 366 unit/min, P=NS vs. control, n=5-6 per group). Conclusions: These results have shown that concurrent DOX and lapatinib administration exacerbates DOX-induced cardiac dysfunction in mice, suggesting that concurrent use of DOX and lapatanib may not be safe in patients. This study strongly suggests that cardiac function must be closely monitored in patients treated with DOX and HER2 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1209. doi:10.1158/1538-7445.AM2011-1209