Effect of melanocortin-4 receptor antagonist TCMCB07 on chemotherapy-induced anorexia and weight loss in rats.

Abstract

e15196 Background: We previously reported that peripheral administration of TCMCB07, a synthetic antagonist of the type 4 melanocortin receptor (MC4R), ameliorates cancer- and chronic kidney disease-associated cachexia in rats. In this study, we used a rat model of cisplatin and 5-FU to evaluate the efficacy of TCMCB07 in alleviating chemotherapy-induced anorexia, weight loss and muscle wasting. Methods: Two separate experiments were performed in a total of 58 rats. 1) Cisplatin (Cis)/TCMCB07 experiment with 3 groups: Cis/saline (n = 11), Cis/TCMCB07 (n = 11), Saline/saline (n = 6). 2) 5-FU/TCMCB07 experiment with 3 groups: 5-FU/saline (n = 12), 5-FU/TCMCB07 (n = 12), Saline/saline (n = 6). Rats were treated with Cis (2.5mg/kg), 5-FU (70 mg/kg), or saline via IP injection once weekly for 3 weeks. Rats were also treated with TCMCB07 (3 mg/kg/day) or saline via daily SC injection for 21 days. Food intake and body weight were measured daily. Body composition was analyzed pre- and post-treatment by MRI. Heart and gastrocnemius were dissected and weighed after euthanasia. Results: Total food intake over 21 days was significantly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0006) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0134), and decreased in Cis/saline vs Saline/saline group (p = 0.001), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/saline or 5-FU/TCMCB07 vs Saline/saline group. Body weight was robustly increased in Cis/TCMCB07 vs Cis/saline group (p = 0.0007) and 5-FU/TCMCB07 vs 5-FU/saline group (p = 0.0013), and decreased in Cis/saline vs Saline/saline group (p = 0.0001) and 5-FU/saline vs Saline/saline group (p = 0.0041), but was no significant change in Cis/TCMCB07 vs Saline/saline group and 5-FU/TCMCB07 vs Saline/saline group. Cardiac and skeletal muscle loss was markedly attenuated in Cis/TCMCB07 vs Cis/saline (cardiac: 3.12% vs -11.95%, p < 0.0001; skeletal: -3.88% vs -9.02%, p = 0.0259). Cardiac muscle loss was significantly attenuated in 5-FU/TCMCB07 vs 5-FU/saline group (1.40% vs -6.09%, p = 0.0131) and skeletal muscle was modestly changed (-4.17% vs -7.24%, p = 0.1782). While Cis/saline and 5-FU/saline groups lost 91.33% and 52.61% of fat mass respectively compared to Saline/saline group, Cis/TCMCB07 and 5-FU/TCMCB07 groups gained 37.68% (p = 0.0002) and 70.19% (p < 0.0001). Conclusions: This preclinical trial provides evidence supporting peripheral TCMCB07 antagonism of central melanocortin signaling, increasing food intake and anabolism, ultimately alleviating anorexia, weight loss and muscle wasting over multiple cycles of cisplatin or 5-FU chemotherapy.