Abstract P3-08-08: Establishment of a Breast Cancer Rat Model of Chemotherapy-Induced Cardiotoxicity

Abstract

Abstract Establishment of a Breast Cancer Rat Model of Chemotherapy-Induced Cardiotoxicity Katherine Wallis, Marjan Boerma, Antiño Allen, Joseph Su, Sam Makhoul, Ping-Ching Hsu Background. Doxorubicin (DOX) is a highly effective chemotherapy agent that is commonly used in combination with precision medicine to treat a wide range of cancers, including 32% of breast cancer (BC) cases. Although the treatment has greatly increased the number of long-term cancer survivors, it has also increased the number of patients experiencing DOX-induced cardiotoxicity (DIC). Animal models have played a vital role in the development of basic and translational breast cancer research in humans, and rat is a preferred animal to study breast cancer for the similarity to human neoplasms and metabolism. However, most studies were established using mouse models, male rats and commonly non-cancer bearing animals. Currently no single universal cancer-bearing female rat model is utilized for DOX-induced chronic cardiotoxicity. The number of cancer cells to be injected to mimic human experience is not known. Large numbers of injected cancer cells grow quickly and kill the animal before the investigators have the time to assess for cardiac toxicity. Here we aimed to identify the minimal number of cancer cell injections to mimic tumor growth of BC patients and to achieve chemotherapy-induced toxicities. Methods. Various numbers (5 × 104 – 1 × 106) of MAT B III adenocarcinoma cancer cells derived from Fischer 344 (F344) rats were injected in the mammary fat pad of female F344 rats, followed by six intraperitoneal (IP) injections of either DOX (1.25mg/kg per dose) or saline post tumor cell injection. The treatments were administered on day 4 from cell injection, and every third day after for a total of six injections. Echocardiography (Vevo 3100, VisualSonics) was conducted before and after the end of chemotherapy. Results. Tumor burden reduced significantly among rats treated with DOX compared with the saline group. In the Kaplan-Meier survival curve, an injection of 5 × 104 cancer cells was associated with tumor growth but the tumor burden was low enough to allow long-term follow-up of both DOX and saline treated rats and assess signs of cardiotoxicity. At 4 days after the final DOX administration, increased left ventricular ejection fraction and fractional shortening in the absence of increased stroke volume were an indication of adverse cardiac effects in the DOX animals but not the saline-treated rats. Plasma was collected from the animals to be subjected to metabolomics testing so that a preliminary assessment of metabolites associated with DIC could be gathered. Conclusion. We have established a breast cancer rat model in which DIC can be studied. Research in this model can aid in identifying mechanisms of DIC and testing novel interventions. Citation Format: Katherine Wallis, Marjan Boerma, Antino Allen, Joseph Su, Sam Makhoul, Ping-Ching Hsu. Establishment of a Breast Cancer Rat Model of Chemotherapy-Induced Cardiotoxicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-08.