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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.

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Related in: MedlinePlus

The effects of C26 tumor on development of cachexia (defined as loss of more than 5% of body weight (BW) after inoculation of tumor cells) in mice.(A) Left panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207707 30 mg/kg (grey line) group (n = 9 each). (B) Right panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207858 30 mg/kg (grey line) group (n = 9 each). Note: Statistical comparison between Vehicle+Tumor and treatment groups was significant.
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pone-0004774-g004: The effects of C26 tumor on development of cachexia (defined as loss of more than 5% of body weight (BW) after inoculation of tumor cells) in mice.(A) Left panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207707 30 mg/kg (grey line) group (n = 9 each). (B) Right panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207858 30 mg/kg (grey line) group (n = 9 each). Note: Statistical comparison between Vehicle+Tumor and treatment groups was significant.

Mentions: Although both compounds did greatly ameliorate symptoms of cachexia, tumor growth in both compound groups was not altered compared to Vehicle+Tumor group. Tumor weights in mice treated with SNT207707 (1.03±0.07 g) and SNT207858 (1.11±0.09 g) were not different from those in the corresponding control groups (1.17±0.06 g and 1.19±0.05 g, respectively). It has to be noted that even though all inoculated animals developed a tumor, not all tumor bearing mice became cachectic, i.e. lost more than 5% of body weight in the course of the experiment. According to this definition, cachexia was not observed in 2 of 9 and 3 of 9 animals of the Vehicle+Tumor control groups whereas 8 out of 9 in the SNT207707 and 6 out of 9 mice in the SNT207858 treated group, respectively, did not show cachexia. Kaplan-Meier analysis of the onset of cachexia revealed a statistical difference between the SNT207707+Tumor (p<0.05) and SNT207858+Tumor (p<0.01) groups each compared to respective Vehicle+Tumor controls (Figure 4).


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 C26 tumor on development of cachexia (defined as loss of more than 5% of body weight (BW) after inoculation of tumor cells) in mice.(A) Left panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207707 30 mg/kg (grey line) group (n = 9 each). (B) Right panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207858 30 mg/kg (grey line) group (n = 9 each). Note: Statistical comparison between Vehicle+Tumor and treatment groups was significant.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0004774-g004: The effects of C26 tumor on development of cachexia (defined as loss of more than 5% of body weight (BW) after inoculation of tumor cells) in mice.(A) Left panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207707 30 mg/kg (grey line) group (n = 9 each). (B) Right panel: Kaplan-Meyer plot for Vehicle control (dashed black line), Vehicle+Tumor control (black line), and SNT207858 30 mg/kg (grey line) group (n = 9 each). Note: Statistical comparison between Vehicle+Tumor and treatment groups was significant.
Mentions: Although both compounds did greatly ameliorate symptoms of cachexia, tumor growth in both compound groups was not altered compared to Vehicle+Tumor group. Tumor weights in mice treated with SNT207707 (1.03±0.07 g) and SNT207858 (1.11±0.09 g) were not different from those in the corresponding control groups (1.17±0.06 g and 1.19±0.05 g, respectively). It has to be noted that even though all inoculated animals developed a tumor, not all tumor bearing mice became cachectic, i.e. lost more than 5% of body weight in the course of the experiment. According to this definition, cachexia was not observed in 2 of 9 and 3 of 9 animals of the Vehicle+Tumor control groups whereas 8 out of 9 in the SNT207707 and 6 out of 9 mice in the SNT207858 treated group, respectively, did not show cachexia. Kaplan-Meier analysis of the onset of cachexia revealed a statistical difference between the SNT207707+Tumor (p<0.05) and SNT207858+Tumor (p<0.01) groups each compared to respective Vehicle+Tumor controls (Figure 4).

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