Potential antitumour mitosenes: relationship between in vitro DNA interstrand cross-link formation and DNA damage in Escherichia coli K-12 strains.
This investigation was aimed at determining the possible relationship between DNA interstrand cross-linking and the cytotoxic activity of potential antitumour mitosene compounds. Mitosenes, possessing two good leaving groups at C-1 and C-10, were found to be able to cross-link calf thymus DNA under hypoxic conditions following sodium dithionite (Na2S2O4) reduction at pH 7.0 and pH 5.5. DNA interstrand cross-linking was pH dependent for most of the mitosenes used, with a higher amount of cross-links formed at pH 5.5 compared to pH 7.0. Without reduction or under aerobic conditions no cross-link formation was detected. The importance of DNA damage for the toxic effect of these mitosenes was assayed by comparing the survival in a DNA repair deficient and a DNA repair proficient E. coli K-12 strain. A correlation between the number of cross-links formed in calf thymus DNA in vitro and the IC50 values in the DNA repair deficient E. coli strain was found. The effect of hypoxia on toxicity of mitosenes was studied in Chinese hamster V79 cells. In these cells, mitosenes appeared to be very active. Under severe hypoxic conditions toxicity of these mitosenes increased, most likely due to the increased lifetime of the activated mitosene species as compared to aerobic conditions. The results suggest that DNA cross-linking following reductive activation is important for the eventual activity of mitosenes in a bacterial system. Increased activity of mitosenes under hypoxic conditions in the V79 cells indicates that these mitosenes may be more active in hypoxic parts of tumours.
Maliepaard
M
M
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, The Netherlands.
Sitters
K A
KA
de Mol
N J
NJ
Janssen
L H
LH
Stratford
I J
IJ
Stephens
M
M
Verboom
W
W
Reinhoudt
D N
DN
D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004227:Dithionite; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D008937:Mitomycins / Q000737:chemistry* / Q000633:toxicity; D010084:Oxidation-Reduction
D003432:Cross-Linking Reagents; D008937:Mitomycins; D004227:Dithionite; C046001:mitosene