Photosensitization of human leukemic cells by anthracenedione antitumor agents.
1,4-Diamino-substituted anthraquinone antitumor agents (mitoxantrone and ametantrone) and structurally related 1,5- and 1,8-diamino-substituted compounds (AM1 and AM2) were tested for their ability to photosensitize human leukemic cells in culture. Viability was measured using the 3,4,5-dimethylthiazol-2,5-diphenyl tetrazolium bromide assay, and DNA and membrane damage were assessed. Following a 1-h exposure to AM2, a dose of drug required to give 50% loss of cell viability (53 microM) was obtained in the dark, which was reduced to approximately 2.4 microM following illumination for 2 min (lambda greater than 475 nm), a dose of light that was completely nontoxic to the cells in the absence of drug. A shift in the cell viability curve was also observed for AM1 but, under identical conditions, the dose modification was only 8.9. In contrast, neither ametantrone nor mitoxantrone gave a decreased viability upon illumination. DNA single-strand breaks as measured by alkaline elution correlated with cell viability. Frank DNA single-strand breaks were produced by AM2 and light, suggesting the production of free radicals. The strand breaks produced by AM2 in the dark and by mitoxantrone (with or without illumination) were protein concealed. No evidence of photo-induced membrane damage, as determined by transport of the model amino acid cycloleucine, could be observed even at supralethal doses.
Hartley
J A
JA
Department of Oncology, University College and Middlesex School of Medicine, London, United Kingdom.
Forrow
S M
SM
Souhami
R L
RL
Reszka
K
K
Lown
J W
JW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008027:Light; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D008942:Mitoxantrone; C020182:ametantrone