Cytokine activity in cancer-related anorexia/cachexia: role of megestrol acetate and medroxyprogesterone acetate.
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-I (IL-I), 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 article describes a series of experimental and clinical studies demonstrating that: (1) high serum levels of some cytokines, including IL-I, 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. In addition, it has been recently shown that "oxidative stress" resulting from reactive oxygen species, which can be induced by pro-inflammatory cytokines, is involved in tissue wasting and CACS. These results suggest promising approaches for the prevention and treatment of cytokine-induced CACS based on MA, MPA, and metabolic antioxidants.
Mantovani
G
G
Department of Medical Oncology, University of Cagliari, Italy.
Macciò
A
A
Lai
P
P
Massa
E
E
Ghiani
M
M
Santona
M C
MC
D000855:Anorexia / Q000209:etiology / Q000276:immunology; D019167:Appetite Stimulants / Q000494:pharmacology / Q000627:therapeutic use*; D002100:Cachexia / Q000209:etiology / Q000276:immunology; D016207:Cytokines / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology / Q000627:therapeutic use*; D019290:Megestrol Acetate / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D045167:Progesterone Congeners / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019282:Wasting Syndrome / Q000188:drug therapy* / Q000276:immunology*
D019167:Appetite Stimulants; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D045167:Progesterone Congeners; D014409:Tumor Necrosis Factor-alpha; D017258:Medroxyprogesterone Acetate; D019290:Megestrol Acetate