Microsatellite instability (MSI) induced by Yondelis and protection with aspirin
Atsuko Kanzaki, Kentaro Nakayama, Manabu Fukumoto, Yves Pommier, Yuji Takebayashi, Dept of Pathology, IDAC, Tohoku University, Sendai, Japan; LMP, CCR, NCI, NIH, Bethesda, MD.
Yondelis is a DNA minor groove alkylating agent in phase II/III trials. Recently, we demonstrated that the cytotoxicity of Yondelis is dependent on transcription-coupled-nucleotide excision repair (TC-NER). We reported an Yondelis-resistant cell line derived from colon carcinoma SW480 with acquired defect for XPG (3? endonuclease in the NER system). In the present study, we characterized MSI induced by Yondelis using the SW480 cell lines, which has no preexisting microsatellite instability (MSI) phenotype. We observed MSI at BAT25 after exposure to subtoxic concentration of Yondelis for 3 weeks without deletion and mutation of hMLH1. Further one year exposure to Yondelis gradually increased the frequency of MSI and induced lack of hMLH1. Sequence analysis at BAT25 showed stepwise deletion of poly A in each sample. However, alteration of MSI-related molecules (hMSH2, hMSH6, hPMS2) besides hMLH1 was not observed in the Yondelis-resistant SW480 cells. These findings suggest that Yondelis induces initial MSI independently of hMLH1, which may induce secondary mutations upon continuous exposure of Yondelis. We also report that aspirin, a cancer preventive agent, completely inhibited MSI induced by Yondelis and produced synergistic cytotoxicity in association with Yondelis in several cell lines. Taken these data together, the combination-therapy of Yondelis with aspirin may be useful in clinic, to prevent secondary genetic alternations in cancer.