Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients.
Urine from cancer patients with weight loss showed the presence of an antigen of M(r) 24,000 detected with a monoclonal antibody formed by fusion of splenocytes from mice with cancer cachexia. The antigen was not present in the urine of normal subjects, patients with weight loss from conditions other than cancer or from cancer patients who were weight stable or with low weight loss (1 kg month(-1)). The antigen was present in the urine from subjects with carcinomas of the pancreas, breast, lung and ovary. The antigen was purified from urine using a combination of affinity chromatography with the mouse monoclonal antibody and reversed-phase high-performance liquid chromotography (HPLC). This procedure gave a 200,000-fold purification of the protein over that in the original urine extract and the material isolated was homogeneous, as determined by silver staining of gels. The N-terminal amino acid sequence showed no homology with any of the recognized cytokines. Administration of this material to mice caused a significant (P<0.005) reduction in body weight when compared with a control group receiving material purified in the same way from the urine of a normal subject. Weight loss occurred without a reduction in food and water intake and was prevented by prior administration of the mouse monoclonal antibody. Body composition analysis showed a decrease in both fat and non-fat carcass mass without a change in water content. The effects on body composition were reversed in mice treated with the monoclonal antibody. There was a decrease in protein synthesis and an increase in degradation in skeletal muscle. Protein degradation was associated with an increased prostaglandin E2 (PGE2) release. Both protein degradation and PGE2 release were significantly reduced in mice pretreated with the monoclonal antibody. These results show that the material of M(r) 24,000 present in the urine of cachectic cancer patients is capable of producing a syndrome of cachexia in mice.
Cariuk
P
P
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
Lorite
M J
MJ
Todorov
P T
PT
Field
W N
WN
Wigmore
S J
SJ
Tisdale
M J
MJ
D000230:Adenocarcinoma / Q000503:physiopathology; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001823:Body Composition; D001943:Breast Neoplasms / Q000503:physiopathology; D002100:Cachexia / Q000503:physiopathology* / Q000652:urine*; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology; D018281:Cholangiocarcinoma / Q000503:physiopathology; D003110:Colonic Neoplasms / Q000503:physiopathology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000503:physiopathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D010051:Ovarian Neoplasms / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000503:physiopathology; D010446:Peptide Fragments / Q000737:chemistry; D011507:Proteinuria; D012004:Rectal Neoplasms / Q000503:physiopathology; D012016:Reference Values
D010446:Peptide Fragments; D015232:Dinoprostone