Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help.

Abstract

Liver or lung metastases usually relapse under chemotherapy. Such life-threatening condition urgently needs new, systemic anticancer compounds, with original and efficient mechanisms of action. In B16 melanoma mice treated with cyclophosphamide, D'Agostini et al. [D'Agostini, C., Pica, F., Febbraro, G., Grelli, S., Chiavaroli, C., Garaci, E., 2005. Antitumour effect of OM-174 and Cyclophosphamide on murine B16 melanoma in different experimental conditions. Int. Immunopharmacol. 5, 1205-1212.] recently found that OM-174, a chemically defined Toll-like receptor(TLR)2/4 agonist, reduces tumor progression and prolongs survival. Here we review 149 articles concerning molecular mechanisms of TLR2/4 agonists, alone or in combination with chemotherapy. It appears that TLR2/4 agonists induce a well controlled tumor necrosis factor-alpha (TNF-alpha) secretion, at plasma levels known to permeabilize neoangiogenic tumor vessels to the passage of cytotoxic drugs. Moreover, TLR2/4 agonists induce inducible nitric oxide synthase (iNOS) expression, and nitric oxide is able to induce apoptosis of chemotherapy-resistant tumor cell clones. Finally, TLR2/4-stimulation activates dendritic cell traffic and its associated tumor-specific, cytotoxic T-cell responses. Therefore, parenteral TLR2/4 agonists seem promising molecules to prolong survival in cancer patients who relapse under chemotherapy.

• Authors: Ricardo P Garay, Patrice Viens, Jacques Bauer, Gérard Normier, Marc Bardou, Jean-François Jeannin, Carlo Chiavaroli
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 563 Issue 1-3 Pg. 1-17 (Jun 01 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17383632 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• BCG Connaught
• BCG Vaccine
• Lipid A
• Lipopolysaccharides
• ONO 4007
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Nitric Oxide Synthase Type II
• defoslimod

Topics

• Animals
• Antineoplastic Agents (immunology, metabolism, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• BCG Vaccine (immunology)
• Chemotherapy, Adjuvant
• Dendritic Cells (drug effects, metabolism)
• Drug Resistance, Neoplasm
• Enzyme Induction (drug effects)
• Humans
• Immunotherapy (methods)
• Interleukin-10 (metabolism)
• Lipid A (analogs & derivatives, pharmacology)
• Lipopolysaccharides (pharmacology)
• Neoadjuvant Therapy
• Neoplasms (drug therapy, immunology, metabolism, pathology, therapy)
• Nitric Oxide Synthase Type II (biosynthesis)
• Recurrence
• Signal Transduction (drug effects)
• T-Lymphocytes, Cytotoxic (drug effects, metabolism)
• Toll-Like Receptor 2 (agonists, immunology, metabolism)
• Toll-Like Receptor 4 (agonists, immunology, metabolism)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)