Torosian M H, Mullen J L, Miller E E, Zinnser K R, Buzby G P
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia.
Cancer. 1988 May 1;61(9):1731-5. doi: 10.1002/1097-0142(19880501)61:9<1731::aid-cncr2820610902>3.0.co;2-a.
The administration of chemotherapy in clinical situations is limited frequently because of the associated toxicity to normal bone marrow cells, gastrointestinal epithelium, and other host tissues. Although nutritional support has been advocated to reduce chemotherapy-related toxicity in cancer patients, few studies substantiate this clinical impression. The current study was performed to determine the role of nutritional status and enteral nutrient intake as determinants of methotrexate (MTX) toxicity in a well-controlled, tumor-bearing animal model. After subcutaneous mammary tumor (AC-33) inoculation, 56 female Lewis/Wistar rats were assigned randomly to one of the following two nutritional regimens for 14 days: (1) protein-depleted chow (PC) (0.03% protein; 4.27 kcal/g) or (2) standard chow (RC) (22.0% protein; 3.50 kcal/g). After 7 days of dietary control, all animals received one of three weight-adjusted doses of MTX (5, 10, or 20 mg/kg intramuscularly [IM] ) or placebo. All animals received leucovorin rescue (0.6 mg IM) at 6 and 24 hours after MTX injection. Improved nutritional status was associated with a significant reduction in objective measures of MTX-related morbidity and mortality. At low doses of MTX (5 and 10 mg/kg), the mean duration of clinical signs of toxicity (i.e., hair loss, lethargy, and diarrhea) and severity of leukopenia were greater in protein-depleted (PD) animals. With high-dose MTX (20 mg/kg), mortality was increased significantly in PD animals (100%) compared with well-nourished animals (0%). Equivalent tumor response was observed in PD and well-nourished animals. Thus, improved nutritional status by enteral nutrition reduced the morbidity and mortality associated with MTX significantly in this tumor-bearing animal model.
在临床情况下，化疗的应用常常受到限制，因为它会对正常骨髓细胞、胃肠道上皮及其他宿主组织产生毒性。尽管有人主张通过营养支持来降低癌症患者化疗相关的毒性，但很少有研究能证实这一临床观点。本研究旨在一个严格控制的荷瘤动物模型中，确定营养状况和肠内营养摄入作为甲氨蝶呤（MTX）毒性决定因素的作用。皮下接种乳腺肿瘤（AC - 33）后，56只雌性Lewis/Wistar大鼠被随机分为以下两种营养方案之一，持续14天：（1）低蛋白饲料（PC）（0.03%蛋白质；4.27千卡/克）或（2）标准饲料（RC）（22.0%蛋白质；3.50千卡/克）。饮食控制7天后，所有动物接受三种按体重调整剂量之一的MTX（5、10或20毫克/千克肌肉注射[IM]）或安慰剂。所有动物在MTX注射后6小时和24小时接受亚叶酸钙解救（0.6毫克IM）。营养状况改善与MTX相关发病率和死亡率的客观指标显著降低相关。在低剂量MTX（5和10毫克/千克）时，低蛋白（PD）动物的毒性临床症状（即脱发、嗜睡和腹泻）平均持续时间和白细胞减少的严重程度更高。使用高剂量MTX（20毫克/千克）时，与营养良好的动物（0%）相比，PD动物的死亡率显著增加（100%）。在PD动物和营养良好的动物中观察到等效的肿瘤反应。因此，在这个荷瘤动物模型中，通过肠内营养改善营养状况可显著降低与MTX相关的发病率和死亡率。
