Genetic changes and bioassays in bleomycin- and phleomycin-treated cells, and their relationship to chromosomal breaks.
The recombinogenicity of damaged chromosomes in diploid Saccharomyces cerevisiae cells treated with bleomycin and structurally related phleomycin was measured, along with aneuploidy and mutation events. Phleomycin was substantially (up to 26-fold) more effective than bleomycin in producing genetic changes at all concentrations, even when colony-forming abilities of cells growing in the presence of bleomycin or phleomycin were similar. These results suggest that the DNA lesions produced by the two structurally related analogs could differ in their nature or frequency, or could be processed differently by the cells. Bioassays were developed and used to compare the cytotoxicities of freshly dissolved bleomycin and phleomycin with the cytotoxicities of lysates prepared from bleomycin- and phleomycin-treated cells. Unexpectedly, lysates prepared from bleomycin-treated cells were 1.5-3.5 times more cytotoxic than freshly dissolved bleomycin after 45-min treatments (3-33 x 10(-6) M). In contrast, lysates prepared from phleomycin-treated cells were 3-38 times less cytotoxic than freshly dissolved phleomycin (0.5-6.4 x 10(-6) M). Cytotoxicities of all lysates were higher after 36-h treatments than after 45-min treatments. At 3.3 x 10(-6) M, this increase was eightfold for bleomycin and 15-fold for phleomycin. Nevertheless, lysates from phleomycin-treated cells were considerably more cytotoxic than lysates from bleomycin-treated cells or freshly prepared bleomycin, consistent with the higher effectiveness of phleomycin than bleomycin in producing chromosomal breaks, genetic changes, and cell killing.
Koy
J F
JF
Department of Microbiology, City University of New York Medical School, NY.
Pleninger
P
P
Wall
L
L
Pramanik
A
A
Martinez
M
M
Moore
C W
CW
D000782:Aneuploidy; D001761:Bleomycin / Q000633:toxicity*; D002474:Cell-Free System; D015825:Chromosomes, Fungal / Q000187:drug effects*; D004249:DNA Damage; D004271:DNA, Fungal / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D009154:Mutation; D010692:Phleomycins / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013997:Time Factors
D004271:DNA, Fungal; D010692:Phleomycins; D001761:Bleomycin