Comparative binding of antitumor drugs to DNA containing the telomere repeat sequence.
Telomeres are the ends of the linear chromosomes of eukaryotes and consist of tandem GT-rich repeats in telomere sequence i.e. 500-3000 repeats of 5'-TTAGGG-3' in human somatic cells, which are shortened gradually with age. The G-rich overhang of telomere sequence can adopt different intramolecular fold-backs and tetra-stranded DNA structures, in vitro, which inhibit telomerase activity. In this report, DNA binding agents to telomere sequence were studied novel therapeutic possibility to destabilize telomeric DNA sequences. Oligonucleotides containing the guanine repeats in human telomere sequence were synthesized and used for screening potential antitumor drugs. Telomeric DNA sequence was characterized using spectral measurements and CD spectroscopy. CD spectrum indicated that the double-stranded telomeric DNA is in a right-handed conformation. Polyacrylamide gel electrophoresis was performed for binding behaviors of antitumor compounds with telomeric DNA sequence. Drugs interacted with DNA sequence caused changes in the electrophoretic mobility and band intensity of the gels. Depending on the binding mode of the anticancer drugs, telomeric DNA sequence was differently recognized and the efficiency of cleavage of DNA varies in the bleomycin-treated samples under different conditions. DNA cleavage occurred at about 1% by the increments of 1 micromM bleomycin-Fe(III). These results imply that the stability of human telomere sequence is important in conjunction with the cancer treatment and aging process.
Suh
Dongchul
D
Department of Biochemistry, Pochon CHA University, Kyungki-do, 463-836, Korea. dcsuh@hanmail.net
Oh
Yu-Kyoung
YK
Ahn
ByungChan
B
Hur
Man-Wook
MW
Kim
Hye-Ja
HJ
Lee
Mi-Hyoung
MH
Joo
Hyo-Soon
HS
Auh
Chung- Kyoon
C
D000970:Antineoplastic Agents / Q000378:metabolism*; D001761:Bleomycin / Q000378:metabolism / Q000494:pharmacology; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D003609:Dactinomycin / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D009621:Nogalamycin / Q000378:metabolism; D009690:Nucleic Acid Conformation; D012091:Repetitive Sequences, Nucleic Acid; D016615:Telomere / Q000187:drug effects / Q000235:genetics*
D000970:Antineoplastic Agents; D001761:Bleomycin; D003609:Dactinomycin; D004317:Doxorubicin; D004247:DNA; C027260:pirarubicin; D009621:Nogalamycin