Abasic site recognition in DNA as a new strategy to potentiate the action of anticancer alkylating drugs?
Inhibition of abasic site repair in the cell seems an attractive strategy to potentiate the action of antitumor DNA alkylating drugs. Molecules that bind specifically and strongly to the abasic site are possible candidates to achieve such inhibition. We explored this strategy by preparing molecule 4 that incorporates (1) an aminoacridine intercalator for DNA binding, (2) an adenine moiety for abasic site recognition, and (3) a linker containing two guanidinium functions to increase binding to DNA without inducing cleavage at the base-sensitive abasic site. Compound 4 was compared to analogues containing secondary amines, i.e., 1. We report on synthesis of the new heterodimer 4. We show by physicochemical studies-including determination of association constants with calf-thymus DNA, T(m) measurements, and high-field NMR examination of the complexes formed with abasic DNA duplexes-that 4 binds specifically and more strongly to the abasic site than the analogues. Compound 4 does not cleave abasic plasmid DNA. Compound 4 shows apparent synergy with the anticancer bischloroethylnitrosourea (BCNU) in L1210 and A549 cell lines in vitro. It potentiates BCNU in the in vivo tests. The results favor the pertinence of the strategy.
Belmont
P
P
INSERM U350, Institut Curie Recherche, Laboratoire Raymond Latarjet, Centre Universitaire, 91405 Orsay Cedex, France.
Jourdan
M
M
Demeunynck
M
M
Constant
J F
JF
Garcia
J
J
Lhomme
J
J
Carez
D
D
Croisy
A
A
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm