Extensive interference of DNA packaging processes affected by chemotherapeutic drugs.
The therapeutic and cytotoxic effects exerted by DNA-binding drugs used for chemotherapy originate from a rather large variety of modifications sustained by the nucleic acids upon interaction with the chemical agents. Notably, these modifications are generally considered as involving the following localized chemical or structural processes: base alkylations, frameshift mutations or strand breakages at specific sites, interstrand cross-links, and local structural transitions within the secondary configurations. We find that antitumor agents hinder or prevent altogether the long range packaging of DNA molecules into compact, ordered states. This effect, observed even at low drug to base pair ratios, is general: it is induced by DNA groove binders as well as by intercalators. Nucleoprotein complexes are found to be efficiently protected against the decondensing effect of the drugs. These observations point toward a generic mechanism for the effectiveness of DNA-binding drugs against tumor cells and viruses as well as for the severe effects of chemotherapy on male fertility: actively dividing systems, such as tumor cells, are characterized by regions of chromatin which are decondensed for the purpose of replication and transcription, and therefore accessible to the drugs. Similarly, both viral infection and spermatogenesis, where histones are replaced by protamines, involve transient formation of relatively uncondensed DNA species and subsequent packaging into extremely tight structures.
Department of Organic, Weizmann Institute of Science, Rehovot, Israel.
Z
Z
Reich
R
R
Ghirlando
T
T
Arad
S
S
Weinberger
A
A
Minsky
D002865:Chromomycins / Q000494:pharmacology*; D002942:Circular Dichroism; D004247:DNA / Q000187:drug effects / Q000648:ultrastructure*; D003609:Dactinomycin / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology*; D004214:Distamycins / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008854:Microscopy, Electron; D009690:Nucleic Acid Conformation; D011758:Pyrroles / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence
D002865:Chromomycins; D004214:Distamycins; D011758:Pyrroles; D003609:Dactinomycin; D004247:DNA; D008274:Magnesium; D003630:Daunorubicin