Variables Contributing to Cancer Cachexia

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Appetite Stimulation with Megestrol Acetate in
Patients with Cancer Anorexia Cachexia
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Definitions

• Anorexia
• Uncontrolled loss of appetite for food
• Cachexia
• General physical wasting and malnutrition usually
  associated with chronic disease
• Cancer Anorexia Cachexia (CAC)
• Cancer induced breakdown of skeletal muscle,
  involving low nutritional intake and
  abnormalities in fat and carbohydrate metabolism

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Variables Contributing to Cancer Cachexia
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Treatment and Management Strategies
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Homeostatic Regulation of Body Weight
NPY, neuropeptide Y AgRP agouti-related
protein POMC pro-opiomelanocortin aMSH
alpha-melanocyte-stimulating hormone
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Leptin

• Regulates food intake, body weight and energy
  balance
• Synthesized and secreted by adipocytes into the
  blood and can enter the CNS
• Inhibits NPY/AgRP neurons, while activating POMC
  neurons

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Cytokines in Cancer

• Cytokines play a key role in activation of the
  immune response and inflammatory response
• Produced by the tumor or by the host response
  against the tumor (via macrophage, natural killer
  (NK) T cells)
• CAC patients commonly present with chronic
  expression of IL-1ß, IL-6, and TNF-a
• Cytokine concentrations correlate with tumor
  progression

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IL-1-ß, TNF-a
IKK2
MAPK
p65
NF-? B
p50
Coactivators
p65
PCAF
? B
p50
CBP
P
HAT
Acetylation
Inflammatory gene expression GM-CSF, COX-2, Other
cytokines
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Cytokine Effects on Body Weight and Energy Balance

• Gastrointestinal
• Direct inhibition of gastric motility and
  emptying
• Release of satiety hormones
• Leptin, glucagon and insulin
• Metabolic Changes
• Increase lipid, carbohydrate and protein
  metabolism

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Cytokine Regulation of Body Weight
IL-1ß, IL-6 TNF-a
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Experimental evidence Cytokines Influence
Regulation of Body Weight

• Chronic administration is capable of reducing
  food intake and producing distinct features of
  CAC (wasting, malnourishment, death)
• CAC can be relieved by administration of cytokine
  antagonists
• Cytokine receptor expression in the CNS -
  peripheral cytokines may cross blood-brain
  barrier and activate central cytokine systems

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Neuropeptide Y Dysregulation in Cancer

• Release of NPY in the hypothalamus of
  tumor-bearing rats is reduced
• NPY injected intrahypothalamically stimulates
  feeding less potently in tumor-bearing rats
  relative to controls
• Administration of IL-1ß directly into the
  cerebral ventricles antagonizes NPY-induced
  feeding in rats

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Glucocorticoid Regulation
(Cortisol)
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Urocortin

• Endogenous CRF-related peptide
• Two CRF receptor subtypes in the hypothalamus
  (CRF1 and CRF2)
• Urocortin binds with higher affinity to CRF2

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Experimental Evidence CRF2 Receptor and Appetite
Suppression

• Selective CRF2 receptor antagonist attenuates the
  effects of Urocortin and CRF on food intake and
  body weight
• Centrally administered CRF equally decreases food
  intake in both CRF1-receptor-null mice and
  wild-type mice
• Results suggest CRF2 receptor may mediate
  appetite suppression by CRF and urocortin

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Cytokines and Glucocorticoid Secretion

• Normal conditions
• Cytokines induce glucocorticoid secretion, and
  glucocorticoids limit cytokine production through
  a negative feedback loop
• Pathological conditions
• Sustained cytokine production activates
  production and secretion of CRF, leading to
  anorexia and weight loss
• Experimental Evidence
• IL-1, IL-2, IL-6 and TNFa stimulate hypothalamic
  CRF expression and release

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Megestrol Acetate (Megace )
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Background

• First used to treat hormone sensitive tumors
  (antagonizes the effects of estrogen)
• Patients experienced weight gain and appetite
  stimulation, independent of tumor response

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Megestrol Acetate Clinical Profile

• Immunosuppressive and anti-inflammatory
• Anti-gonadotropic, anti-estrogenic,
  Anti-androgenic
• Glucocorticoid-like activity
• Orexigenic capable of stimulating appetite

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Adverse Effects

• Fluid retention
• Weight gain (primarily through fat)
• Flushing
• Erectile dysfunction
• Vaginal bleeding
• Adrenal insufficiency
• Cushings syndrome

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Cushings Syndrome
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Experimental Evidence Megestrol Acetate
Influences Appetite

• Treatment with megestrol acetate decreases
  cytokine production on patients with cancer
• Central administration of megestrol acetate
  increases neuropeptide Y in the CNS of rats

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Mechanism of Action

• Mechanism of action in CAC remains to be
  clarified
• MOA possibilities
• inhibition of cytokine activity through its
  glucocorticoid- like activity
• AND/OR
• Through direct stimulation of the NYP neurons in
  the hypothalamus

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Corticosteroid
e.g., IL-1-ß, TNF-a
IKK2
MAPK
p65
NF-? B
p50
Coactivators
p65
Co-repressors
PCAF
? B
p50
CBP
P
HAT
X
Deacetylation
Acetylation
Gene repression
Inflammatory gene expression GM-CSF, COX-2, Other
cytokines
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References

• Inui A (2002) Cancer anorexia-cachexia syndrome
  current issues in research and management. CA
  Cancer J Clin 5272-91.
• MacDonald N, Easson AM, Mazurak VC, Dunn GP, and
  Baracos VE (2003) Understanding and managing
  cancer cachexia. J Am Coll Surg 197143-61.
• Mantovani G, Maccio A, Lai P, Massa E, Ghiani M,
  and Santona MC (1998) Cytokine activity in
  cancer-related anorexia/cachexia role of
  megestrol acetate and medroxyprogesterone
  acetate. Semin Oncol 2545-52.
• Mantovani G, Maccio A, Massa E, and Madeddu C
  (2001) Managing cancer-related anorexia/cachexia.
  Drugs 61499-514.
• McCarthy HD, Crowder RE, Dryden S, and Williams G
  (1994) Megestrol acetate stimulates food and
  water intake in the rat effects on regional
  hypothalamic neuropeptide Y concentrations. Eur J
  Pharmacol 26599-102.
• Plata-Salaman CR (2000) Central nervous system
  mechanisms contributing to the cachexia-anorexia
  syndrome. Nutrition 161009-12.
• Ramos EJ, Suzuki S, Marks D, Inui A, Asakawa A,
  and Meguid MM (2004) Cancer anorexia-cachexia
  syndrome cytokines and neuropeptides. Curr Opin
  Clin Nutr Metab Care 7427-34.
• Schindler AE, Campagnoli C, Druckmann R, Huber J,
  Pasqualini JR, Schweppe KW, and Thijssen JH
  (2003) Classification and pharmacology of
  progestins. Maturitas 46 Suppl 1S7-S16.

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Questions

• How would you test the assumption that megestrol
  acetate and corticosteroids inhibit cytokine
  activity through a similar pathway?
• Its not clear whether CRF induces its anorexic
  effects through the NPY neurons. How can you
  determine a possible interaction between these
  neurons?