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Cytotoxicity of TRAIL/anticancer drug combinations in human normal cells

Olivier Meurette1, Anne Fontaine, Amelie Rebillard

  • 1INSERM U620, IFR140, Faculté de Pharmacie, Université de Rennes 1, 2 avenue Prof. Léon Bernard, 35043 Rennes cedex, and Département d'Hématologie, Hôpital Pontchaillou, France.

Annals of the New York Academy of Sciences
|March 27, 2007
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with chemotherapy shows varied toxicity. TRAIL/cisplatin is toxic to normal human cells, unlike TRAIL/5-fluorouracil, while neutrophils remain resistant.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • TRAIL (TNF-alpha-Related Apoptosis-Inducing Ligand) induces cancer cell apoptosis but faces resistance issues.
  • Combination therapy with chemotherapy aims to overcome TRAIL resistance in cancer treatment.
  • The impact of TRAIL-chemotherapy combinations on normal human cells is not well understood.

Purpose of the Study:

  • To evaluate the toxicity of TRAIL combined with cisplatin or 5-fluorouracil on various human normal cells.
  • To determine the differential sensitivity of normal cell types to these combination therapies.

Main Methods:

  • Treatment of human primary hepatocytes, resting lymphocytes, PHA-IL2-activated lymphocytes, and neutrophils with TRAIL/cisplatin and TRAIL/5-fluorouracil.
  • Assessment of cell viability and apoptosis induction.

Main Results:

  • TRAIL/cisplatin demonstrated toxicity towards primary hepatocytes and resting lymphocytes.
  • Both TRAIL/cisplatin and TRAIL/5-fluorouracil were toxic to PHA-IL2-activated lymphocytes.
  • Freshly isolated neutrophils exhibited resistance to TRAIL alone and in combination with either chemotherapeutic agent.

Conclusions:

  • TRAIL/cisplatin combination therapy poses a risk to certain normal human cells, including hepatocytes and lymphocytes.
  • TRAIL/5-fluorouracil combination shows a potentially safer profile for some normal cell types compared to TRAIL/cisplatin.
  • Neutrophils appear to be a resistant cell population to TRAIL-based combination therapies, suggesting differential immune cell responses.

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