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Eicosapentaenoic Acid As a Targeted Therapy for Cancer Cachexia

Cathedra of Oncology and Palliative Medicine, Medical Oncology Division, Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain

To the Editor: In their elegant double-blind, placebo-controlled study, published in the Journal of Clinical Oncology, Bruera et al¹ concluded that fish oil—with high-doses of eicosapentaenoic acid (EPA)—did not significantly influence nutritional status after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite. We totally agree with this indisputable conclusion, but several considerations about the underlying efficacy of EPA in cancer cachectic patients immediately arise.

In animal and in vitro models of cancer cachexia, EPA activity on cachectic signs is related to its ability to abrogate the enhancer effect modulated by 15-hydroxyeicosatetraenoic acid on the promoter region of the proteasome C3 subunit gene. 15-hydroxyeicosatetraenoic is a second messenger induced by a proteolysis inducing factor (PIF) in skeletal muscle.² Thus, PIF enhances proteasome activity and induces an unrestrained destruction of skeletal muscle,³ an inherent and differential feature of cancer cachexia.⁴ Actually, PIF is believed to play a central role in human cancer cachexia.³ Furthermore, in several cell lines, EPA induces cell cycle arrest and apoptosis, suggesting additional mechanisms for future analysis in vivo.^5,6 Regarding this molecular background, different studies analyzed EPA activity on cachectic patients previously diagnosed with advanced pancreatic cancer, and more than 80% of patients had PIF presence in their urine samples. In these studies, a clear-cut benefit regarding lean body mass and survival was reported.^7,8 Paradoxically, we believe that these clinical^7,8 and molecular observations^2,3 concur with the negative data about EPA supplements provided by Bruera et al¹ in patients with no PIF measurement, suggesting that EPA treatment must be considered as a targeted therapy against PIF activity. So, the results by Bruera et al could be partly attributed to the absence of the EPA target. Consequently, we have to keep in mind that excellent targeted-drugs may be missing in clinical studies⁹ when the target is not previously detected. We recommend that future studies with EPA in cancer cachectic patients include a PIF determination or a proteasome activity assay to avoid confounding target-related factors.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

1. Bruera E, Strasser F, Palmer JL, et al: Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double blind, placebo-controlled study. J Clin Oncol 21:129–134, 2003[Abstract/Free Full Text]

2. Smith HJ, Lorite MJ, Tisdale MJ: Effect of cancer cachectic factor on protein synthesis/degradation in murine C2C12 myoblasts: modulation by eicosapentaenoic acid. Cancer Res 59:5507–5513, 1999[Abstract/Free Full Text]

3. Tracey KJ: Lethal weight loss: the focus shifts to signal transduction. Science’s STKE: http//www.stke.org/cgi/content/full/OC_sigtrans;2002/130/pe21

4. Williams A, Sun X, Fischer JE, et al: The expression of genes of ubiquitin-proteasom proteolytic pathway is increased in skeletal muscle from patients with cancer. Surgery 126:744–750, 1999[Medline]

5. Heimli H, Finstad HS, Drevon CA: Necrosis and apoptosis in lymphoma cell lines exposed to eicosapentaenoic acid and antioxidants. Lipids 36:613–621, 2001[Medline]

6. Chiu LC, Ooi VE, Wan JM: Eicosapentaenoic acid modulates cyclin expression and arrests cell cycle progression in human leukemic K-562 cells. Int J Oncol 19:845–849, 2001[Medline]

7. Barber MD, Ross JA, Voss AC, et al: The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer 81:80–86, 1999[CrossRef][Medline]

8. Wigmore SJ, Barber MD, Ross JA, et al: Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 36:177–184, 2000[CrossRef][Medline]

9. Burton A: What went wrong with Iressa? Lancet Oncol 3:708, 2002[CrossRef][Medline]

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  Eduardo D. Bruera
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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Belda-Iniesta, C. Articles by Baron, M. G. Search for Related Content PubMed PubMed Citation Articles by Belda-Iniesta, C. Articles by Baron, M. G. Related Articles Related Article Social Bookmarking                            What's this?