S. Shibutani et L. Dasaradhi, MISCODING POTENTIAL OF TAMOXIFEN-DERIVED DNA-ADDUCTS - ALPHA-(N-2-DEOXYGUANOSINYL)TAMOXIFEN, Biochemistry, 36(42), 1997, pp. 13010-13017
The treatment of tamoxifen, widely used as adjuvant chemotherapy for b
reast cancer, increases significantly the risk of developing endometri
al cancer. The miscoding properties of tamoxifen-derived DNA adducts,
alpha-(N-2-deoxyguanosinyl)tamoxifens (dG-N-2-tamoxifen), have been ex
plored, using an in vitro experimental system to quantify base substit
utions and deletions. Site-specifically modified oligodeoxynucleotides
containing an epimer of trans-and cis-forms of dG-N-2-tamoxifens were
prepared postsynthetically and used as templates in primer extension
reactions catalyzed by mammalian DNA polymerases alpha, beta, and delt
a. Pol alpha catalyzed incorporation of dCMP and dAMP opposite all fou
r stereoisomers of dG-N-2-tamoxifen, accompanied by lesser amounts of
dGMP. In contrast, pol delta catalyzed preferential incorporation of d
CMP, a correct base, opposite the lesions; one of the trans-forms of d
C-N-2-tamoxifens only promoted incorporation of dTMP. Using pol beta,
preferential incorporation of dCMP, along with small amounts of incorp
oration of dAMP and dGMP, was detected. One-and two base deletions wer
e also observed with pol alpha and pol beta. The miscoding specificiti
es and frequencies of dG-N-2-tamoxifens varied depending on the DNA po
lymerase used. In addition, with pol alpha and pol beta, large amounts
of 5-base deletions were preferentially formed at the cis-forms of dG
-N-2-tamoxifen, but not at the transforms of dG-N-2-tamoxifen. We conc
lude that dG-N-2-tamoxifen adducts have high miscoding potentials.