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Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice.

Weyermann P, Dallmann R, Magyar J, Anklin C, Hufschmid M, Dubach-Powell J, Courdier-Fruh I, Henneböhle M, Nordhoff S, Mondadori C - PLoS ONE (2009)

Bottom Line: This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure.Both compounds were found to distinctly increase food intake in healthy mice.In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route.

View Article: PubMed Central - PubMed

Affiliation: Santhera Pharmaceuticals (Switzerland) Ltd, Liestal, Switzerland.

ABSTRACT

Background: Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide alpha-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC)-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure.

Methodology/principal findings: SNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctly increase food intake in healthy mice. Moreover, in mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration (starting the day after tumor implantation) of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass.

Conclusions/significance: In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantage for the treatment of cachexia patients.

Show MeSH

Related in: MedlinePlus

The effects of (A) SNT207707 and (B) SNT207858 in C26 tumor bearing mice.Left panels: Mean body weight development of Vehicle control (open squares), Vehicle+Tumor control (closed squares), and 30 mg/kg (A) SNT207707 and (B) SNT207858 (grey triangles) group (n = 9 each). Middle and right panels: Difference in lean body mass and fat mass between day of tumor inoculation (day 0) and end of experiment (day 15). Each value represents mean±SEM. Statistical difference vs. Vehicle+Tumor * p<0.05, *** p<0.001.
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pone-0004774-g003: The effects of (A) SNT207707 and (B) SNT207858 in C26 tumor bearing mice.Left panels: Mean body weight development of Vehicle control (open squares), Vehicle+Tumor control (closed squares), and 30 mg/kg (A) SNT207707 and (B) SNT207858 (grey triangles) group (n = 9 each). Middle and right panels: Difference in lean body mass and fat mass between day of tumor inoculation (day 0) and end of experiment (day 15). Each value represents mean±SEM. Statistical difference vs. Vehicle+Tumor * p<0.05, *** p<0.001.

Mentions: Once daily oral administration of both compounds SNT207858 and SNT207707 starting the day after tumor implantation significantly reduced the tumor induced weight loss. The outcomes of the two experiments were quite comparable: In both experiments, the tumor was palpable around day 4 after inoculation. Similarly, in both experiments the vehicle-treated tumor controls stopped gaining weight around day 11 and began to show weight loss on day 13. In both experimental series, the compounds almost completely prevented weight loss, and the average body weight of the tumor bearing compound treated groups was significantly higher than that of the Vehicle+Tumor group. Figure 3 (left panel) depicts the results graphically.


Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice.

Weyermann P, Dallmann R, Magyar J, Anklin C, Hufschmid M, Dubach-Powell J, Courdier-Fruh I, Henneböhle M, Nordhoff S, Mondadori C - PLoS ONE (2009)

The effects of (A) SNT207707 and (B) SNT207858 in C26 tumor bearing mice.Left panels: Mean body weight development of Vehicle control (open squares), Vehicle+Tumor control (closed squares), and 30 mg/kg (A) SNT207707 and (B) SNT207858 (grey triangles) group (n = 9 each). Middle and right panels: Difference in lean body mass and fat mass between day of tumor inoculation (day 0) and end of experiment (day 15). Each value represents mean±SEM. Statistical difference vs. Vehicle+Tumor * p<0.05, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654097&req=5

pone-0004774-g003: The effects of (A) SNT207707 and (B) SNT207858 in C26 tumor bearing mice.Left panels: Mean body weight development of Vehicle control (open squares), Vehicle+Tumor control (closed squares), and 30 mg/kg (A) SNT207707 and (B) SNT207858 (grey triangles) group (n = 9 each). Middle and right panels: Difference in lean body mass and fat mass between day of tumor inoculation (day 0) and end of experiment (day 15). Each value represents mean±SEM. Statistical difference vs. Vehicle+Tumor * p<0.05, *** p<0.001.
Mentions: Once daily oral administration of both compounds SNT207858 and SNT207707 starting the day after tumor implantation significantly reduced the tumor induced weight loss. The outcomes of the two experiments were quite comparable: In both experiments, the tumor was palpable around day 4 after inoculation. Similarly, in both experiments the vehicle-treated tumor controls stopped gaining weight around day 11 and began to show weight loss on day 13. In both experimental series, the compounds almost completely prevented weight loss, and the average body weight of the tumor bearing compound treated groups was significantly higher than that of the Vehicle+Tumor group. Figure 3 (left panel) depicts the results graphically.

Bottom Line: This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure.Both compounds were found to distinctly increase food intake in healthy mice.In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route.

View Article: PubMed Central - PubMed

Affiliation: Santhera Pharmaceuticals (Switzerland) Ltd, Liestal, Switzerland.

ABSTRACT

Background: Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide alpha-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC)-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure.

Methodology/principal findings: SNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctly increase food intake in healthy mice. Moreover, in mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration (starting the day after tumor implantation) of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass.

Conclusions/significance: In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantage for the treatment of cachexia patients.

Show MeSH
Related in: MedlinePlus