Sex-Specific Differences in Toxicity Following Systemic Paclitaxel Treatment and Localized Cardiac Radiotherapy.
Sex-Specific Differences in Toxicity Following Systemic Paclitaxel Treatment and Localized Cardiac Radiotherapy.
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DOI：
10.3390/cancers13163973
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发表时间：
2021-08-06
期刊：
影响因子：
5.2
通讯作者：
Vozenin MC
中科院分区：
文献类型：
--
作者：
Chmielewski-Stivers N;Petit B;Ollivier J;Monceau V;Tsoutsou P;Quintela Pousa A;Lin X;Limoli C;Vozenin MC
本研究的目的是调查性别对全身紫杉醇治疗和心脏照射后癌症幸存者长期毒性发展的影响，这些毒性影响生活质量。性别特异性差异可能影响肿瘤生物学、药物药代动力学和动力学，以及对局部治疗（如放射治疗（RT））的反应。然而，在进行癌症治疗时很少考虑性别因素。有趣的是，雌性小鼠免受紫杉醇诱导的神经毒性以及放射治疗诱导的心脏毒性的影响，并且小GTdR RhoB的缺乏逆转了雌性小鼠的保护作用，但在雄性小鼠中没有。总之，我们的研究结果是第一个确定性别和器官特异性反应的全身紫杉醇管理和局部RT。这些结果可能有重要意义的癌症患者的管理和实施个性化治疗的肿瘤学。性别在影响癌症幸存者生活质量的长期毒性发展中的影响尚未进行实验研究。为了解决这个问题，一系列神经和心脏终点被用来研究紫杉醇治疗和放疗暴露引发的性别差异。雄性和雌性野生型（WT）小鼠接受紫杉醇（150和300 mg/kg）治疗，每周给药一次，持续6周，或暴露于19戈伊心脏照射。分析队列的行为和神经生物学终点以评估紫杉醇的全身毒性或心血管终点以评估放疗毒性。有趣的是，与雄性WT小鼠相比，雌性WT小鼠表现出增强的耐受性，无论治疗方案如何。为了深入了解可能的性别特异性保护机制，使用rhoB缺陷动物和老年小鼠（22个月），重点关注性激素（包括雌激素）的可能作用。在女性中，RhoB缺乏和高龄对紫杉醇诱导的神经认知障碍没有影响，但增强了心脏对放疗的敏感性。相反，rhoB缺乏保护男性免受辐射毒性。总之，RhoB被确定为驱动雌性小鼠雌激素依赖性心脏保护作用的分子决定簇，而神经保护作用不依赖于性激素。据我们所知，这项研究首次揭示了紫杉醇和放疗的性别和器官特异性反应。
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. 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.
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影响因子：
4.5
作者：
Jenkins, VA;Bloomfield, DJ;Edginton, TL
通讯作者：
Edginton, TL
影响因子：
51.1
作者：
Darby, SC;McGale, P;Peto, R
通讯作者：
Peto, R
影响因子：
3.5
作者：
Anderson, GD
通讯作者：
Anderson, GD
DOI：
10.1186/bcr3377
发表时间：
2013-01-22
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Médale-Giamarchi C;Lajoie-Mazenc I;Malissein E;Meunier E;Couderc B;Bergé Y;Filleron T;Keller L;Marty C;Lacroix-Triki M;Dalenc F;Doisneau-Sixou SF;Favre G
通讯作者：
Favre G
DOI：
10.1016/j.mrrev.2016.07.003
发表时间：
2016-10
期刊：
Mutation research. Reviews in mutation research
影响因子：
--
作者：
Boerma M;Sridharan V;Mao XW;Nelson GA;Cheema AK;Koturbash I;Singh SP;Tackett AJ;Hauer-Jensen M
通讯作者：
Hauer-Jensen M