Carcinogenesis, Vol 18, 2191-2196, Copyright © 1997 by Oxford University Press
V Pletsa, C Valavanis, JH van Delft, MJ Steenwinkel and SA Kyrtopoulos
The DNA damaging and mutagenic activities of procarbazine, a methylating
drug employed in cancer chemotherapy and suspected of causing
therapy-related leukaemia, were investigated in the liver and bone marrow
of lambda lacZ transgenic mice (MutaMouse). The drug was administered using
two different protocols, a 'high-dose' one involving 5 daily doses of 200
mg/kg, expected to cause depletion of the repair enzyme O6-alkylguanine-DNA
alkyltransferase (AGT) and thus favour the selective accumulation of the
premutagenic lesion O6-methylguanine (O6- meG) relative to other adducts,
and a 'low-dose' one involving 10 daily doses of 20 mg/kg procarbazine.
Substantial accumulation of O6-meG was observed in both tissues examined 6
h after the end of the 'high-dose' treatment, with the liver accumulating
somewhat higher levels than the bone marrow (28.0 +/- 1.8 fmol/microg DNA
and 18.5 +/- 1.1 fmol/microg DNA respectively). However, significant
increases in mutant frequency 10 days after the end of treatment were
observed only in the bone marrow, reaching a 16-fold increase over
background following the 5 x 200 mg/kg treatment. Sequence analysis of the
mutations induced after this treatment revealed a mixed spectrum, in which
G:C-->A:T transitions (characteristic of O6-meG miscoding) were only a
secondary feature: Among 20 mutants analysed, only six such mutations were
found, including three at CpG sites, which might have arisen from
deamination of 5-methylcytosine. The other mutations observed included 1
A:T-->G:C transition, five transversions (one G:C-->T:A, one double
G:C-->C:G, two A:T-->T:A, one A:T-->C:G), five deletions and three
insertions. The mechanistic and clinical significance of these findings is
discussed.
ARTICLES
DNA damage and mutagenesis induced by procarbazine in lambda lacZ transgenic mice: evidence that bone marrow mutations do not arise primarily through miscoding by O6-methylguanine
Laboratory of Chemical Carcinogenesis, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
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