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Vol. 54, Issue 2, 334-341, August 1998
Istituto Dermopatico Dell'Immacolata, Rome, Italy (S.D., P.M.L.,
E.P., G.Z., E.Bo.),
Department of Experimental Medicine and
Biochemical Sciences, University of Rome "Tor Vergata," Rome, Italy
(L.T., G.G., E.Be.), and
Institute for Medical Radiobiology, University
of Zurich, Zurich, Switzerland (J.J.)
Postreplicative mismatch repair plays a major role in mediating the
cytotoxicity of agents generating
O6-methylguanine in DNA. We previously
showed that a methylating antitumor triazene compound, temozolomide,
induces apoptosis and that the persistence of
O6-methylguanine in DNA is required to
trigger the process. We wanted to test whether the latter apoptotic
signal is dependent on a functional mismatch repair system. To this
end, we used two human lymphoblastoid cell lines (i.e., the mismatch
repair-proficient TK6 line and its mismatch repair-deficient subline
MT1) that are both deficient in
O6-methylguanine repair. Temozolomide
treatment of TK6 cells brought about efficient cell growth inhibition,
G2/M arrest, and apoptosis, as indicated by the results of
cytofluorimetric analysis of 5-bromo-2'-deoxyuridine incorporation and
DNA content and evaluation of DNA fragmentation. The drug treatment
resulted also in the induction of p53 and p21/waf-1 protein expression.
In contrast, MT1 cells were highly resistant to the drug and no p53 and
p21/waf-1 induction was observed. Importantly, we could show that MT1
cells are not deficient in the p53-dependent apoptosis pathway;
treatment with etoposide, a topoisomerase II inhibitor, resulted in p53
and p21/waf-1 protein expression and apoptosis in both cell lines. In
conclusion, we demonstrate the existence of a link between a functional
mismatch repair system and the trigger of apoptosis in cells exposed to
clinically relevant concentrations of temozolomide. The results also
suggest that p53 induction in response to
O6-guanine methylation involves the mismatch
repair system.
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