Abstract P151: Differential Effects of Concurrent and Sequential Combined Lapatinib and Doxorubicin Treatment on Cardiac Function in Mice
Background: Clinical studies showed that Trastuzumab, a monoclonal antibody that blocks the HER2 receptor, exacerbated chemotherapy drug doxorubicin (DOX)-induced heart failure. Lapatinib, a small molecule inhibitor of HER2 and EGF receptor (EGFR), is currently studied in clinical trials for cancer therapy, in combination with DOX, concurrently and sequentially. Therefore, it is important to assess the cardiac effect of the combination treatment using lapatinib and DOX.
Methods: Two mouse models were used. In the first model, mice were treated with a single dose of DOX (20 mg/kg, i.p.), concurrently with lapatinib (100 mg/kg, oral gavage, daily). In the second model, mice were treated with DOX (2 mg/kg, i.p. twice a week) for seven weeks, followed by lapatinib (100 mg/kg, oral gavage, daily) for three weeks. Survival was analyzed by the Kaplan-Meier method. Cardiac function was monitored by hemodynamic measurements.
Results: When mice were treated concurrently with lapatinib and DOX, ten-day 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/group]; however, these indices were maintained in DOX mice (LVSP: 99 ±4 mmHg; dP/dtmin: 7787 ± 965 mmHg/sec; CO: 2315 ± 366 unit/min, P=NS vs. control, n=5–6/ group). On the other hand, when mice were treated sequentially with DOX and lapatinib, seventy-day survival was higher in DOX+lapatinib vs. DOX mice (63 vs. 43 %, n=7–8/ group). Cardiac output was decreased in DOX vs. control mice (1733±135 vs. 3438±268 unit/min, P<0.05, n=4–5/group). However, cardiac output was less depressed in DOX+lapatinib mice (2817±559 unit/min, P=NS vs. control, n=4/group).
Conclusions: These results showed that concurrent and sequential combined lapatinib and DOX treatment produced opposite effects on survival and cardiac function in mice. This study suggests that the cardiac safety of lapatinib and DOX combination therapy depends on the specific treatment regimen.
- © 2011 by American Heart Association, Inc.