Cytokine Involvement in Cancer Anorexia/ Cachexia: Role of Megestrol Acetate and Medroxyprogesterone Acetate on Cytokine Downregulation and Improvement of Clinical Symptoms

Abstract

The characteristic clinical picture of anorexia, tissue wasting, loss of body weight accompanied by a decrease in muscle mass and adipose tissue, and poor performance status that often precedes death has been named the cancer-related anorexia/cachexia syndrome (CACS). Chronic administration of pro-inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) either alone or in combination, is capable of reproducing the different features of CACS. High serum levels of these cytokines have been found in cancer patients, which seem to correlate with progression of the tumor. This paper describes a series of experimental and clinical studies demonstrating that: (1) high serum levels of some cytokines, including IL-1, IL-6, and TNF, are present in advanced-stage cancer patients, particularly those with CACS; (2) megestrol acetate (MA) has a beneficial therapeutic effect on CACS symptoms, such as appetite, body weight, and quality-of-life; (3) MA downregulates the synthesis and release of cytokines and relieves the symptoms of CACS; (4) cytokines play a key role in the onset of CACS; (5) medroxyprogesterone acetate (MPA) reduces the in vitro production of cytokines and serotonin (5-hydroxytryptamine, 5-HT) by peripheral blood mononuclear cells (PBMC) of cancer patients; and (6) MA and MPA reduce the cisplatin-induced 5-HT release in vitro from PBMC of cancer patients. Based on these results, a clinical study incorporating MA/MPA in combination with chemotherapy or chemoimmunotherapy may be warranted.

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

“…However, this gain had been mainly attributed to an increased fat mass, not to muscle mass and had no evidences of benefit in terms of quality of life or survival 23, 24. The mechanisms of MA responsible for contributing to increased body weight in cachectic patients are not completely clear, but some studies showed that, in addition to stimulating appetite, it also had an effect on both metabolic and inflammatory mechanisms 25, 26. Concerning skeletal muscle, previous studies performed in our laboratory in experimental animals showed a clear anabolic effect of MA in skeletal muscle.…”

Pancreatic Cancer Cachexia: Current Concepts and Clinical Management

“…Some studies suggest that the mechanisms by which MEGACE stimulates appetite and weight gain is related to decreased production and release of pro-inlammatory cytokines (IL-1, IL-6, and TNF-α) as well as the stimulation of NPY in the hypothalamus [111][112][113]. Another progestogen, medroxyprogesterone acetate, was demonstrated through in vitro experiments to decrease the production of cytokines and serotonin by PBMC of cancer patients [112,113].…”

“…Another progestogen, medroxyprogesterone acetate, was demonstrated through in vitro experiments to decrease the production of cytokines and serotonin by PBMC of cancer patients [112,113].…”

“…Since its approval, many studies have conirmed the efectiveness of MEGACE at increasing weight and thus quality of life when compared to other drugs potentially used for the management of cancer cachexia (cisapride, dronabinol, corticosteroids, and nandrolone) [108,109]. Body composition analysis has also conirmed that the weight gain observed following MEGACE intake is predominately due to increases in adipose tissue and less from increases in body luid [110].However, there were no improvements in survival found in those who were treated with MEGACE [107,109].Some studies suggest that the mechanisms by which MEGACE stimulates appetite and weight gain is related to decreased production and release of pro-inlammatory cytokines (IL-1, IL-6, and TNF-α) as well as the stimulation of NPY in the hypothalamus [111][112][113]. Another progestogen, medroxyprogesterone acetate, was demonstrated through in vitro experiments to decrease the production of cytokines and serotonin by PBMC of cancer patients [112,113].…”

Novel targets and new potential: developments in the treatment of inflammation in chronic kidney disease

“…[129][130][131][132][133] As an appetite stimulant in HD patients, megestrol acetate was found to improve appetite, increase energy and protein intake and increase dry weight and to improve quality of life. [134][135][136] The downside is that it can induce many side effects such as headaches, dizziness, confusion, diarrhea, hyperglycemia, thromboembolic phenomena, breakthrough uterine bleeding, peripheral edema, hypertension, adrenal suppression, and adrenal insufficiency.…”