背景：多柔比星（阿霉素）是具有廣譜抗癌作用的最有效藥物之一。然而，多柔比星引起的心臟毒性成為累積劑量受限的主要因素。谷氨酰胺和ω-3多不飽和脂肪酸（PUFA）在應(yīng)對(duì)各種應(yīng)激過程中具有明確的心臟保護(hù)作用，同時(shí)對(duì)腫瘤化療具有增敏效應(yīng)。

　　方法：通過使用多柔比星（累積劑量為12mg/kg）治療大鼠MatBIII乳腺癌移植瘤模型評(píng)估多柔比星治療的抗腫瘤活性和心臟毒性?；熼_始之前6天至該研究結(jié)束（50天）過程中每隔一天單獨(dú)或聯(lián)合給予谷氨酰胺（0.35g/kg）和ω-3PUFA（0.19g/kg EPA和0.18g/kg DHA）治療。

　　結(jié)果：?jiǎn)为?dú)應(yīng)用谷氨酰胺可以明顯預(yù)防多柔比星相關(guān)性心臟功能衰退，降低血清心肌肌鈣蛋白Ⅰ的水平，同時(shí)減輕心臟脂質(zhì)過氧化，而不影響腫瘤抑制動(dòng)力學(xué)。單獨(dú)應(yīng)用ω-3PUFA可以通過增強(qiáng)腫瘤內(nèi)的氧化應(yīng)激和多柔比星濃度明顯增強(qiáng)多柔比星的抗瘤活性，同時(shí)不伴有心臟功能障礙的加重和心臟氧化應(yīng)激的加強(qiáng)。有趣的是，聯(lián)合應(yīng)用谷氨酰胺和ω-3PUFA時(shí)并不會(huì)有更大的效益；相反，對(duì)心臟毒性的保護(hù)和化療增敏作用有所減弱或者完全消失。

　　結(jié)論：與單獨(dú)應(yīng)用谷氨酰胺和ω-3PUFA相比，對(duì)于聯(lián)合用藥我們的數(shù)據(jù)得出了有趣的區(qū)分或者甚至可以說是對(duì)腫瘤和宿主出現(xiàn)極端效應(yīng)。觀察到的谷氨酰胺×ω-3PUFA有趣的相互作用使我們對(duì)營(yíng)養(yǎng)素的聯(lián)合應(yīng)用會(huì)對(duì)人體產(chǎn)生疊加益處的認(rèn)識(shí)產(chǎn)生質(zhì)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