Mutations induced by some DNA minor groove binding alkylators in AS52 Chinese hamster cells.
Nitrogen mustards are commonly used in cancer chemotherapy. They interact with DNA at electronegative sites, primarily forming N7 guanine mono-adducts and interstrand cross-links. Targeting nitrogen mustards to DNA by attachment of a DNA minor groove binding carrier such as the bisbenzimidazoles Hoechst 33258 (pibenzimol) or Hoechst 33342 (HOE) makes it possible to direct DNA alkylation to more specific stretches of DNA. We have performed a detailed molecular analysis of 6-thioguanine resistant clones arising in Chinese hamster AS52 cells after treatment with HOE, in comparison with a mono- and bifunctional pair of bisbenzimidazole-targeted nitrogen mustards (MGBs). HOE showed no significant ability to induce 6-thioguanine resistant mutants, possibly because drug-treated cells are highly susceptible to apoptosis within very short times. Neither of the MGBs caused the rapid cell death seen with the bisbenzimidazole. However, both MGBs were weaker mutagens than previously found for undirected mustards in the same system, an effect that we suggest could relate to greater structure-directed binding to less mutable DNA sites in the minor groove. Additionally, the nature of some of the mutants suggested there may be a small component of topo I and/or II-mediated events in the mutagenicity of the MGBs. Both MGBs showed high activity in causing deletion mutations, which may be due to errors in attempted repair of the complex lesions formed by minor groove targeted alkylators.
Wu
X C
XC
Auckland Cancer Society Research Center, Faculty of Medicine and Health Science, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Marcinkowski
K
K
Turner
P M
PM
Ferguson
L R
LR
D000477:Alkylating Agents / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001426:Bacterial Proteins / Q000187:drug effects / Q000235:genetics; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D006690:Bisbenzimidazole / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells / Q000187:drug effects; D002699:Chlorambucil / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D029968:Escherichia coli Proteins; D008466:Mechlorethamine / Q000378:metabolism / Q000494:pharmacology; D015162:Micronucleus Tests / Q000379:methods; D009154:Mutation; D009588:Nitrogen Mustard Compounds / Q000378:metabolism / Q000494:pharmacology*; D010430:Pentosyltransferases; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011506:Proteins; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D013866:Thioguanine / Q000494:pharmacology
D000477:Alkylating Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D029968:Escherichia coli Proteins; C407098:MGB1 compound; D009588:Nitrogen Mustard Compounds; D011506:Proteins; C407097:MGB2 compound; D002699:Chlorambucil; C113412:chlorambucil half mustard; D008466:Mechlorethamine; D004247:DNA; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; D013866:Thioguanine; D006690:Bisbenzimidazole; C017807:bisbenzimide ethoxide trihydrochloride