Anticachectin/tumor necrosis factor‐α antibodies attenuate development of cachexia in tumor models

Abstract

C57BL/6 mice bearing either a transplantable methylcholanthrene-induced sarcoma or Lewis lung adenocarcinoma were passively immunized every other day with a rabbit immunoglobulin fraction raised against murine cachectin/tumor necrosis factor-alpha. Mice bearing methylcholanthrene-induced sarcoma developed tumor-associated hypophagia that was attenuated by anticachectin immunoglobulin treatment. In the same tumor-bearing animals, anticachectin treatment also significantly reduced the extent of carcass protein and fat loss, and reduced tumor weight. Mice bearing Lewis lung adenocarcinoma did not develop significant anorexia or carcass lean tissue depletion as tumor growth progressed, but they lost carcass lipid. Treatment of Lewis lung adenocarcinoma bearing mice with anticachectin antibodies diminished the degree of carcass lipid depletion and prevented plasma hypertriglyceridemia. However, in both tumor models, anticachectin treatment did not affect either the development of anemia, hypoalbuminemia or the increase in serum amyloid P concentrations seen with increasing tumor burden. We conclude that an endogenous cachectin response, inhibitable by exogenously administered antibody, contributes to anorexia and to changes in body fat and protein metabolism in these tumor-bearing animals. Neutralizing endogenous cachectin production with antibodies offers the potential to reduce tissue wasting that is frequently associated with neoplastic disease, but it does not appear to affect all of the hematologic and acute phase responses in these murine tumor models.

CNTO 328, a monoclonal antibody to IL‐6, inhibits human tumor‐induced cachexia in nude mice

“…Only a few murine tumor models have been reported to induce a cachexia-like syndrome. [12][13][14][15][16] Tumor cell-and host-produced cytokines such as IL-6, TNF-␣ and IFN-␥ are thought to play an important role in the catabolism and weight loss associated with several malignant and nonmalignant conditions. 10,11,[17][18][19] However, the specific contribution of human tumor cell-secreted IL-6 to body weight loss has not been described.…”

Central Melanocortins and the Regulation of Weight During Acute and Chronic Disease

“…Cytokines such as interleukin-lbeta (IL-lb), interleukind (IL-6), and tumor necrosis factor-alpha (TNF-a) are upregulated in various animal cachexia models. Neutralization of these factors by genetic or pharmacological methods leads to attenuation of cachexia (Plata-Salaman, 1998;Plata-Salaman and Borkoski, 1994;Sherry et al, 1989;Vallieres and Rivest, 1997;Yasumoto et al, 1995). Finally, chronic infusion of IL-lp or TNF-cx causes anorexia, rapid weight loss, and catabolism of body protein stores, analogous to the state observed with chronic illness Plata-Salaman et al, 1996).…”

Cancer cachexia

“…Weight loss produced by TNF is typified by a marked anorexia, and the decrease in food and water intake is directly proportional to the decrease in body weight . However, anti-TNF antisera has been shown to delay, but not fully protect against the decrease in food intake in sarcomabearing mice (Sherry et al, 1989), suggesting that other factors in addition to TNF may be responsible for the anorexia in tumour-bearing animals. It has been suggested that TNF produces an effect on lipid metabolism through an inhibition of the enzyme lipoprotein lipase (Beutler et al, 1985b), and thus depletion of host lipids would be mediated through a different mechanism from the action of the direct catabolic factors mentioned above.…”

“…Attempts to reverse the cachexia in tumour-bearing animals with anti-TNF antibodies have produced equivocal results (Sherry et al, 1989). Unfortunately, both models used by these workers had a higher tumour burden, and measurements were made at the time of death.…”