Sex-Specific Differences in Toxicity Following Systemic Paclitaxel Treatment and Localized Cardiac Radiotherapy

SIMPLE SUMMARY: The objective of the present study was to investigate the impact of sex in the development of long-term toxicities affecting quality of life in cancer survivors after systemic paclitaxel treatment and cardiac irradiation. Sex-specific differences may affect tumor biology, drug pharmacokinetics and dynamics, and response to local treatment such as radiation therapy (RT). However, sex is rarely taken into consideration when administering cancer therapies. Interestingly, female mice are protected from paclitaxel-induced neurotoxicity as well as from radiotherapy-induced cardiotoxicity, and deficiency in the small GTPase RhoB reversed the protection in females but not in males. In conclusion, our results are the first to identify sex- and organ-specific responses to systemic paclitaxel administration and localized RT. These results may have important implications for the management of cancer patients and implementation of personalized medicine in oncology. ABSTRACT: The impact of sex in the development of long-term toxicities affecting the quality of life of cancer survivors has not been investigated experimentally. To address this issue, a series of neurologic and cardiologic endpoints were used to investigate sex-based differences triggered by paclitaxel treatment and radiotherapy exposure. Male and female wild-type (WT) mice were treated with paclitaxel (150 and 300 mg/kg) administered weekly over 6 weeks or exposed to 19 Gy cardiac irradiation. Cohorts were analyzed for behavioral and neurobiologic endpoints to assess systemic toxicity of paclitaxel or cardiovascular endpoints to assess radiotherapy toxicity. Interestingly, female WT mice exhibited enhanced tolerance compared to male WT mice regardless of the treatment regimen. To provide insight into the possible sex-specific protective mechanisms, rhoB-deficient animals and elderly mice (22 months) were used with a focus on the possible contribution of sex hormones, including estrogen. In females, RhoB deficiency and advanced age had no impact on neurocognitive impairment induced by paclitaxel but enhanced cardiac sensitivity to radiotherapy. Conversely, rhoB-deficiency protected males from radiation toxicity. In sum, RhoB was identified as a molecular determinant driving estrogen-dependent cardioprotection in female mice, whereas neuroprotection was not sex hormone dependent. To our knowledge, this study revealed for the first time sex- and organ-specific responses to paclitaxel and radiotherapy.