Williams J R, Casero R A, Dillehay L E
Johns Hopkins Oncology Center, Baltimore, Maryland 21287-5001.
Biochem Biophys Res Commun. 1994 May 30;201(1):1-7. doi: 10.1006/bbrc.1994.1661.
Difluoromethylornithine (DFMO) depletes cells of polyamines, sensitizing cells against the action of antineoplastic drugs and altering ability to repair radiation-induced DNA strand breaks. Others have hypothesized that the mechanism by which polyamine depletion sensitizes cells is through inhibition of DNA strand break repair or through altering the spectrum of initial DNA damage. We have compared the effect of polyamine depletion on cytotoxic effects in V79 cells for three agents that damage DNA: PUVA (8-methoxypsoralen and ultraviolet light, 365 nm), gamma-rays and UVC (ultraviolet light, 254 nm) in polyamine depleted V79 cells. DFMO pretreatment sensitizes cells to PUVA and gamma-ray toxicity but not to UVC. Unlike UVC photoinduction of DNA lesions, PUVA- and gamma-ray-induced DNA damage is modulated by chromatin structure. Our results suggest that polyamine depletion sensitizes cells to the action of PUVA and gamma-rays by mechanisms disparate from those for UVC, suggesting that the level or type of initial damage, rather than DNA repair, per se, may be the more important determinant of enhanced cytotoxicity.
