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• W2725275720 abstract "3552 Tumor metastasis is a most severe aspect of tumor development in patients, largely because tumors are detected too late when metastasis already has occurred. Established tumor therapies mostly include cytotoxic drugs with rather narrow therapeutic windows. Hence, for the treatment in earlier tumor stages, where the suppression of metastasis spread might still be possible, the need is high for new therapies with good tolerability and safety. The activation of the immune system, and in particular, the activation of toll-like receptor (TLR) signaling offers new promising approaches. Several immune-stimulatory TLR9 agonistic oligonucleotides containing a phosphorothioate backbone and CpG subsequences (CpG-ODN) are in advanced clinical trials. A clear clinical proof of concept (POC), though, was achieved so far solely with the imidazoquinoline imiquimod, which activates TLR7. Imiquimod is approved for topical application, where it has remarkable efficacy on superficial basal cell carcinomas. The POC for systemic application of TLR agonists in oncology is still pending, though. CpG-ODN such as H1826 or H2006 (Hartmann et al, 2000) can strongly suppress growth of established human xenograft tumors in nude mice (devoid of T-cells), upon repeated i.v. administration (Gekeler et al, 2006). Here we show remarkable efficacy of CpG-ODN (qdx4 i.v.) with doses as low as 1 mg/kg in suppression of metastasis of murine Renca kidney cancer cells to the lungs of immune competent Balb/c mice without any sign of intolerance. Classical cytotoxics such as 5-fluor-uracil (20 mg/kg, qdx4 i.v.) showed only moderate efficacy in this setting. Furthermore, CpG-ODN-5mC having C-5 methylated cytosine throughout the molecule were totally inactive in this model, providing evidence that the tumor suppressing activity is dependent on TLR9. Since expression of TLR7 on immune cells is similar to TLR9 expression we asked whether similar metastasis suppressing activity might be seen with TLR7 agonists of different chemical structures. The guanosine derivative isatoribine (7-thia-8-oxoguanosine) and an imiquimod derivative were tested in the same setting (qdx4 i.v.) with doses of up to 30 mg/kg. Remarkably, a virtually full suppression of development of lung metastases was observed with both molecules with good tolerability. In vitro assays using hPBMC (human peripheral blood mononuclear cell) fractions approved a specific cytokine response (e.g. IL6, IP10) which was induced by these molecules. Our work provides a convincing rational for clinical development of TLR9 or TLR7 agonists for suppression of cancer metastasis and points to the possibility of systemic application of such drugs." @default.
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• W2725275720 date "2007-05-01" @default.
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• W2725275720 title "Metastasis of murine Renca kidney cancer cells to the lungs of Balb/c mice is strongly suppressed by TLR9 or TLR7 agonists" @default.
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