GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

Breen Danna M.; Kim Hanna; Bennett Donald; Calle Roberto A.; Collins Susie; Esquejo Ryan M.; He Tao; Joaquim Stephanie; Joyce Alison; Lambert Matthew; Lin Laura; Pettersen Betty; Qiao Shuxi; Rossulek Michelle; Weber Gregory; Wu Zhidan; Zhang Bei B.; Birnbaum Morris J.

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GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

机译：GDF-15中和减轻了小鼠和非人的衰减铂的化疗诱导的呕吐物，厌食症和减肥

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Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life.

机译：以铂为基础的癌症治疗受到剂量限制性副作用的限制，并与生长分化因子15（GDF-15）的升高有关。但这种升高是否会导致此类副作用尚不清楚。在此，我们在小鼠和/或非人灵长类动物模型中探讨了GDF-15阻断剂对铂类化疗诱导的呕吐、厌食和体重减轻的影响。我们发现，接受铂类化疗的癌症患者的循环GDF-15水平较高，并且与结直肠癌患者的体重减轻呈正相关（NCT00609622）。此外，与高临床呕吐评分相关的化疗药物可诱导小鼠循环GDF-15和体重减轻。在GDF-15基因敲除小鼠中，以铂为基础的治疗诱导的厌食症和体重减轻得到缓解，而用单克隆抗体mAB1中和GDF-15可提高存活率。在非人灵长类动物中，mAB1治疗可减轻厌食和呕吐。这些结果表明，GDF-15中和是一种潜在的治疗方法，可以减轻化疗引起的副作用，提高生活质量。

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《Cell metabolism》 |2020年第6期|共20页
作者
Breen Danna M.; Kim Hanna; Bennett Donald; Calle Roberto A.; Collins Susie; Esquejo Ryan M.; He Tao; Joaquim Stephanie; Joyce Alison; Lambert Matthew; Lin Laura; Pettersen Betty; Qiao Shuxi; Rossulek Michelle; Weber Gregory; Wu Zhidan; Zhang Bei B.; Birnbaum Morris J.;
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Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Early Clin Dev Biostat 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer R&

D UK Ltd Early Clin Dev Biostat Ramsgate Rd Sandwich Kent England;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Biomed Design 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Biomed Design 1 Burtt Rd Andover MA USA;

Pfizer Inc Biomed Design 1 Portland St Cambridge MA USA;

Pfizer Inc Biomed Design 1 Portland St Cambridge MA USA;

Pfizer Inc Drug Safety Res &

Dev 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Biomed Design 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

Pfizer Inc Internal Med Res Unit 1 Portland St Cambridge MA USA;

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正文语种 eng
中图分类内分泌腺疾病及代谢病;
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2. Weight Loss and Gastrointestinal Symptoms in Advanced Cancer Patients Treated with Platinum-based Chemotherapy [J] . Hui Gao, Dong Bo Liu, Jin Tong, 肿瘤营养学杂志(英文) . 2020,第002期
3. Weight Loss and Gastrointestinal Symptoms in Advanced Cancer Patients Treated with Platinum-based Chemotherapy [J] . Hui Gao, Qiang Fu, Dong Bo Liu, 肿瘤营养学杂志（英文） . 2020,第002期
4. Ganoderic acid alleviates chemotherapy-induced fatigue in mice bearing colon tumor [J] . Abudumijiti Abulizi, Jing Li, Hong Zhou, 中国药理学报：英文版 . 2021,第010期
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6. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates [J] . Mullican Shannon E., Lin-Schmidt Xiefan, Chin Chen-Ni, Nature medicine . 2017,第10期

机译：Gfral是GDF15的受体，配体促进小鼠和非人的重量丧失
7. A DNA Vaccine against Chikungunya Virus Is Protective in Mice and Induces Neutralizing Antibodies in Mice and Nonhuman Primates [J] . Karthik Mallilankaraman, Devon J. Shedlock, Huihui Bao, PLOS Neglected Tropical Diseases . 2011,第1期

机译：针对基孔肯雅病毒的DNA疫苗对小鼠具有保护作用，并在小鼠和非人类灵长类动物中诱导中和抗体。
8. Induction of neutralizing antibodies to influenza A virus H7N9 by inactivated whole virus in mice and nonhuman primates [J] . Weiqi Pan, Ling Han, Zhenyuan Dong, Antiviral Research . 2014,第Null期

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9. A DNA Vaccine against Chikungunya Virus Is Protective in Mice and Induces Neutralizing Antibodies in Mice and Nonhuman Primates [O] . Karthik Mallilankaraman, Devon J. Shedlock, Huihui Bao, 2011

机译：针对基孔肯雅病毒的DNA疫苗对小鼠具有保护作用并在小鼠和非人类灵长类动物中诱导中和抗体。
10. A DNA vaccine against chikungunya virus is protective in mice and induces neutralizing antibodies in mice and nonhuman primates. [O] . Karthik Mallilankaraman, Devon J Shedlock, Huihui Bao, 2011

机译：针对基孔肯雅病毒的DNa疫苗在小鼠中具有保护作用，并在小鼠和非人灵长类动物中诱导中和抗体。
11. Hantaan/Andes virus DNA Vaccine Elicits a Broadly Cross-Reactive Neutralizing Antibody Response in Nonhuman Primates [R] . Hooper, J. W. , Custer, D. M. , Smith, J. , 2006

机译：汉坦/安第斯山脉病毒DNa疫苗在非人类灵长类动物中引发广泛的交叉反应中和抗体反应

GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

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