Abasic sites in DNA of HeLa cells induced by lucanthone.
Abasic sites in HeLa cell DNA were increased in frequency by exposing the cells to lucanthone. Cell growth in the presence of lucanthone caused progressive accumulation of abasic sites and loss of cellular DNA. After 2 hr in 8 microM lucanthone, the abundance of abasic sites was 2.4 fold greater than the background of 9.9 +/- 2.0 SE abasic sites/10(6) nucleotides; 80 microM lucanthone in the growth medium increased the level 12.6 +/- 2.5 SE fold and decreased the DNA content in HeLa cells to one-half of the value obtained in untreated cells. The frequency of abasic sites in cellular DNA was determined by the aldehyde reactive probe method, with reference to abasic sites created in plasmid pBR322. The ability of lucanthone to inhibit the normal repair of abasic sites might reflect inhibition of apurinic/apyrimidinic endonuclease (HAP1) by the drug, thereby preventing an early step in the base excision repair pathway. Unrepaired abasic sites prevalent after ionizing radiation are cytotoxic lesions that promote DNA strand breaks. These results suggest a rationale for the joint lethal effects of lucanthone and ionizing radiation in cells and the accelerated tumor regression observed in cancer patients who received the combined therapy.
Mendez
Frances
F
Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210 Street, Bronx, NY 10467, USA.
Goldman
Joshua D
JD
Bases
Robert E
RE
D001665:Binding Sites; D019757:Carbon-Oxygen Lyases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006367:HeLa Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008154:Lucanthone / Q000494:pharmacology*; D010957:Plasmids / Q000187:drug effects
D004273:DNA, Neoplasm; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D008154:Lucanthone