Effects of anti-parathyroid hormone-related protein monoclonal antibody and osteoprotegerin on PTHrP-producing tumor-induced cachexia in nude mice.
We have previously demonstrated that parathyroid hormone-related protein (PTHrP) is a cachexia inducer, but it is still not known what PTHrP effects on target tissues induce the cachexia. Therefore, we examined the effects of anti-PTHrP antibody and osteoprotegerin (OPG) on PTHrP-producing tumor-induced cachexia. Nude mice bearing PTHrP-producing human lung cancer cells (HARA-B) exhibited cachexia with hypercalcemia 3-4 weeks after inoculation, accompanied by losses in body, adipose tissue, and muscle weight. OPG ameliorated hypercalcemia, as did neutralization of PTHrP with antibody; and it increased both body and adipose tissue weights. These increases in body and adipose tissue weight, however, were significantly less than those in mice treated with anti-PTHrP antibody. Simultaneous administration of OPG and anti-PTHrP antibody caused significant increases in body, adipose tissue, and muscle weight, along with an immediate decrease in blood ionized calcium levels. The increase in body weight was similar to that observed in mice treated with anti-PTHrP antibody alone, and the decrease in the blood ionized calcium levels was significantly greater than that in mice treated with OPG or anti-PTHrP antibody alone. These results suggest that an effect of PTHrP on target tissues other than hypercalcemia is involved in the development of cachexia. Expression of cachexia-inducing proinflammatory cytokines (interleukin-6 and leukemia inhibitory factor) is stimulated by PTHrP. This might be a mechanism by which PTHrP produces tumor-induced cachexia. It is also suggested that OPG and anti-PTHrP antibody synergistically act to ameliorate hypercalcemia, although the mechanism responsible for this is unclear.
Iguchi
Haruo
H
Division of Tumor Dynamics, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395, Japan. higuchi@nk-cc.go.jp
Aramaki
Yuko
Y
Maruta
Shigeaki
S
Takiguchi
Soichi
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy / Q000209:etiology; D008175:Lung Neoplasms / Q000150:complications; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein / Q000276:immunology* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse