DNA sequence-specific adenine alkylation by the novel antitumor drug tallimustine (FCE 24517), a benzoyl nitrogen mustard derivative of distamycin.
FCE 24517, a novel distamycin derivative possessing potent antitumor activity, is under initial clinical investigation in Europe. In spite of the presence of a benzoyl nitrogen mustard group this compound fails to alkylate the N7 position of guanine, the major site of alkylation by conventional nitrogen mustards. Characterisation of DNA-drug adducts revealed only a very low level of adenine adduct formation. Using a modified Maxam-Gilbert sequencing method the consensus sequence for FCE 24517-adenine adduct formation was found to be 5'-TTTTGA-3'. A single base modification in the hexamer completely abolishes the alkylation of adenine. Using a Taq polymerase stop assay alkylations were confirmed at the A present in the hexamer TTTTGA and, in addition, in one out of three TTTTAA sequences present in the plasmid utilized. The sequence specificity of alkylation by FCE 24517 is therefore the most striking yet observed for an alkylating agent of small molecular weight.
Broggini
M
M
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Coley
H M
HM
Mongelli
N
N
Pesenti
E
E
Wyatt
M D
MD
Hartley
J A
JA
D'Incalci
M
M
D000225:Adenine / Q000737:chemistry; D000478:Alkylation; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D018736:DNA Adducts / Q000737:chemistry / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009588:Nitrogen Mustard Compounds / Q000737:chemistry / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000737:chemistry / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D018736:DNA Adducts; D017931:DNA Primers; D004214:Distamycins; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; D004247:DNA; D000225:Adenine