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Eur J Pharmacol. 2007 Jun 1;563(1-3):1-17. Epub 2007 Feb 17.

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

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EA2381, Université Paris 7, Paris, France.


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.

[Indexed for MEDLINE]

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