Journal Article

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.

V Pletsa, C Valavanis, J H van Delft, M J Steenwinkel and S A Kyrtopoulos

in Carcinogenesis

Volume 18, issue 11, pages 2191-2196
Published in print November 1997 | ISSN: 0143-3334
Published online November 1997 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/18.11.2191
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.

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

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.

Journal Article.  0 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.