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Chemosensitizing Anti-Cancer Activity of LFM-A13, a Leflunomide Metabolite Analog Targeting Polo-like Kinases

Fatih M. Uckun

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LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide) has recently been identified as an inhibitor of Polo-like kinases (Plk). LFM-A13 does not inhibit other serine/threonine kinases including CDK, CHK, RAF, DAPK, IKK, IRAK, JNK, MAPK, PKC, and SAPK. LFM-A13-treated human cancer cells develop abnormal mitotic spindles and G₂/M-arrest during cell cycle progression. LFM-A13 was not toxic to rodents or dogs at daily dose levels as high as 100 mg/kg. Notably, at a low dose level of 10 mg/kg, which does not result in delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer, LFM-A13 markedly enhanced the anti-cancer activity of the mitotic spindle poison paclitaxel. These results indicate that LFM-A13 may be useful in the treatment of cancer patients.

Authors

Fatih M. Uckun

Parker Hughes Cancer Center; St. Paul, MN

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