Effect of dna topoisomerase II inhibitor – doxorubicin on capsule formati̇on due to silicone implant application in rats

Introduction and Objective: Capsular contracture is an abnormal and severe foreign body reaction that develops around silicone implants used in breast augmentation and breast reconstruction after mastectomy. It's one of the most common complications leading to re-operation in these patient groups. Although many studies have been carried out on the prevention and treatment of this clinical entity, which was defined and classified in the 1970s, its pathophysiology has not yet been clearly revealed and, in parallel, satisfactory treatment methods have not been found. Therefore, there is a need to investigate new protective and therapeutic agents through experimental and clinical studies. Doxorubicin; DNA topoisomerase II inhibitor is a chemotherapeutic agent used in the treatment of oncological diseases such as breast cancer, bladder cancer, Kaposi sarcoma, lymphoma, and leukemia. Additionally, it inhibits the enzyme prolyl 4-hydroxylase, an essential enzyme in collagen synthesis. Our aim in this study is to examine the effect of Doxorubicin on capsule formation following silicone implant placement. Material and Methods: 24 female Wistar - Albino rats, aged 4-6 months and weighing between 250 and 300 g, were divided into 3 different groups. Group 1 (n=8) is the control group and no invasive procedure was performed. Group 2 (n=8) was the experimental control group and a silicone implant was placed under the panniculus carnosus in the back region and was followed up without any additional drug treatment. Group 3 (n=8) was the Doxorubicin group and was followed similarly after the implant was placed by injecting Doxorubicin hydrochloride at a dose of 4 mg/kg/week once a week for four weeks, starting from day 0, into the pocket where the implant was placed. On the 28th day of the experiment, the subjects were sacrificed and the samples taken were evaluated by light microscopy. Tumor Necrosis Factor - alpha (TNF-α), Interleukin-6 (IL-6), Collagen I and alpha-Smooth Muscle Actin (α-SMA) levels were evaluated using immunohistochemical methods. Results: In light microscopic examination, capsule formation was observed in the experimental control and Doxorubicin groups. In the experimental control group, it was observed that the collagen fibers forming the capsule were in a dispersed structure and their integrity was disrupted. Additionally, the presence of inflammatory cell infiltration was detected. It was observed that collagen fibers showed a more uniform distribution in the Doxorubicin group. However, the presence of any inflammatory cell infiltration was not observed. In immunohistochemical examination, COL-1, α-SMA, TNF-α and IL-6 immunoreactivities were observed to be more significantly positive in the experimental control group compared to the Doxorubicin group. The difference between both groups was found to be statistically significant. (p<0.05) Conclusion: In this study, it was observed that Doxorubicin was protective against capsule formation around the silicone implant and subsequent capsule contracture, and this effect was histopathologically supported. Significant inflammation and capsule formation were observed in the experimental control group. In parallel, COL-1, α-SMA, TNF-α and IL-6 levels were found to be significantly lower in the Doxorubicin group. These findings indicate that Doxorubicin may prevent capsular contracture by reducing the severity of inflammation after silicone breast implant placement. Key Words: Doxorubicin, Capsule Contracture, Breast Implant