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Differential Killing of Mismatch Repair-Deficient and -Proficient Cells

Towards the Therapy of Tumors with Microsatellite Instability

Institute of Molecular Cancer Research, University of Zürich, Zurich, Switzerland

DNA mismatch repair (MMR) defects bring about a strong mutator phenotype and microsatellite instability (MSI). In an attempt to exploit MSI in cancer therapy, we constructed expression vectors carrying a thymidine kinase/blasticidin deaminase fusion gene downstream from a (C)₁₂ or an (A)₂₆ microsatellite and stably transfected these constructs into human cells in which the MMR status could be regulated by doxycycline. We now show that ganciclovir-resistant clones arising through frameshifts in the (C)₁₂ microsatellite were 20 times more frequent in cells in which MMR was inactivated. This difference may be exploited in gene therapy of tumors with MSI, which represent a substantial proportion of cancers of many different tissues.