通过谷氨酰胺和ω-3多不饱和脂肪酸对多柔比星（阿霉素）化疗相关心脏毒性和抗癌功效进行营养调控
背景：多柔比星（阿霉素）是具有广谱抗癌作用的最有效药物之一。然而，多柔比星引起的心脏毒性成为累积剂量受限的主要因素。谷氨酰胺和ω-3多不饱和脂肪酸（PUFA）在应对各种应激过程中具有明确的心脏保护作用，同时对肿瘤化疗具有增敏效应。
方法：通过使用多柔比星（累积剂量为12mg/kg）治疗大鼠MatBIII乳腺癌移植瘤模型评估多柔比星治疗的抗肿瘤活性和心脏毒性。化疗开始之前6天至该研究结束（50天）过程中每隔一天单独或联合给予谷氨酰胺（0.35g/kg）和ω-3PUFA（0.19g/kg EPA和0.18g/kg DHA）治疗。
结果：单独应用谷氨酰胺可以明显预防多柔比星相关性心脏功能衰退，降低血清心肌肌钙蛋白Ⅰ的水平，同时减轻心脏脂质过氧化，而不影响肿瘤抑制动力学。单独应用ω-3PUFA可以通过增强肿瘤内的氧化应激和多柔比星浓度明显增强多柔比星的抗瘤活性，同时不伴有心脏功能障碍的加重和心脏氧化应激的加强。有趣的是，联合应用谷氨酰胺和ω-3PUFA时并不会有更大的效益；相反，对心脏毒性的保护和化疗增敏作用有所减弱或者完全消失。
结论：与单独应用谷氨酰胺和ω-3PUFA相比，对于联合用药我们的数据得出了有趣的区分或者甚至可以说是对肿瘤和宿主出现极端效应。观察到的谷氨酰胺×ω-3PUFA有趣的相互作用使我们对营养素的联合应用会对人体产生叠加益处的认识产生质疑。
JPEN J Parenter Enteral Nutr. 2016;40(1):52-66.
Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω-3 Polyunsaturated Fatty Acids.
Xue H, Ren W, Denkinger M, Schlotzer E, Wischmeyer PE.
Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado; Fresenius Kabi, Bad Homburg, Germany.
BACKGROUND: Doxorubicin (DOX) has been one of the most effective antitumor agents against a broad spectrum of malignancies. However, DOX-induced cardiotoxicity forms the major cumulative dose-limiting factor. Glutamine and ω-3 polyunsaturated fatty acids (PUFAs) are putatively cardioprotective during various stresses and/or have potential chemosensitizing effects during cancer chemotherapy.
METHODS: Antitumor activity and cardiotoxicity of DOX treatment were evaluated simultaneously in a MatBIII mammary adenocarcinoma tumor-bearing rat model treated with DOX (cumulative dose 12 mg/kg). Single or combined treatment of parenteral glutamine (0.35 g/kg) and ω-3 PUFAs (0.19 g/kg eicosapentaenoic acid and 0.18 g/kg docosahexaenoic acid) was administered every other day, starting 6 days before chemotherapy initiation until the end of study (day 50).
RESULTS: Glutamine alone significantly prevented DOX-related deterioration of cardiac function, reduced serum cardiac troponin I levels, and diminished cardiac lipid peroxidation while not affecting tumor inhibition kinetics. Single ω-3 PUFA treatment significantly enhanced antitumor activity of DOX associated with intensified tumoral oxidative stress and enhanced tumoral DOX concentration while not potentiating cardiac dysfunction or increasing cardiac oxidative stress. Intriguingly, providing glutamine and ω-3 PUFAs together did not consistently confer a greater benefit; conversely, individual benefits on cardiotoxicity and chemosensitization were mostly attenuated or completely lost when combined.
CONCLUSIONS: Our data demonstrate an interesting differentiality or even dichotomy in the response of tumor and host to single parenteral glutamine and ω-3 PUFA treatments. The intriguing glutamine × ω-3 PUFA interaction observed draws into question the common assumption that there are additive benefits of combinations of nutrients that are beneficial on an individual basis.
KEYWORDS: amino acids; breast cancer; cardiotoxicity; doxorubicin; fatty acids; glutamine; oncology; research and diseases
PMID: 25888676
DOI: 10.1177/0148607115581838
