Differential killing of mismatch repair-deficient and -proficient cells: towards the therapy of tumors with microsatellite instability.
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.
Cejka
Petr
P
Institute of Molecular Cancer Research, University of Zürich, Zurich, Switzerland.
Marra
Giancarlo
G
Hemmerle
Christine
C
Cannavó
Elda
E
Storchova
Zuzana
Z
Jiricny
Josef
J
D048868:Adaptor Proteins, Signal Transducing; D000619:Aminohydrolases / Q000235:genetics; D001230:Aspergillus / Q000201:enzymology / Q000235:genetics; D020137:Base Pair Mismatch / Q000502:physiology*; D002352:Carrier Proteins; D002460:Cell Line; D004260:DNA Repair / Q000502:physiology*; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006561:Herpes Simplex / Q000201:enzymology / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D016296:Mutagenesis; D009363:Neoplasm Proteins / Q000172:deficiency*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D009687:Nuclear Proteins; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D013937:Thymidine Kinase; D000619:Aminohydrolases; C019795:blasticidin S deaminase; D000070957:MutL Protein Homolog 1; D015774:Ganciclovir