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Despite its therapeutic advantages, chemotherapy with anti-cancer drugs can cause adverse effects, including anorexia and weight loss. Although most patients with cancer suffer from anorexia during chemotherapy, resulting in the need to suspend or cease treatment and thereby worsening prognosis, treatment options for anorexia remain limited. Ghrelin is an orexigenic hormone that has been proposed to prevent anorexia. To investigate the potential of ghrelin receptor agonists, synthetic small-molecule compounds, as preventive therapies for chemotherapy-induced anorexia, we studied the effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, in cisplatin- and 5-fluorouracil (5-FU)-induced anorexia animal models. The agonistic activity of Z-505 was examined using calcium flux assays in Chinese hamster ovary (CHO-K1) cells stably expressing rat or mouse GHSR1a. Z-505 showed agonistic activity for rat GHSR1a and mouse GHSR1a, with a half maximal effective concentration (EC 50 ) of 2.08 nM and 5.46 nM, respectively. In a cisplatin-induced anorexia rat model, administration of Z-505 (30, 100 or 300 mg/kg, p.o., once daily) significantly improved the cisplatin-induced reduction in food intake and body weight. In addition, treatment with Z-505 (100 or 300 mg/kg, p.o., once daily) prevented the 5-FU-induced decrease in food intake and body weight in the 5-FU-induced mouse model. Our results demonstrate that Z-505 ameliorates cisplatin- and 5-FU-induced anorexia through the activation of the ghrelin receptor, GHSR1a, suggesting its usefulness in the preventive treatment of anorexia during chemotherapy. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300 mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC 50 ) value of 0.45 nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a. [ABSTRACT FROM AUTHOR]