A carbamate analogue of amsacrine with activity against non-cycling cells stimulates topoisomerase II cleavage at DNA sites distinct from those of amsacrine.
AMCA (methyl N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), an amsacrine analogue containing a methylcarbamate rather than a methylsulphonamide side chain, contrasts with amsacrine, doxorubicin and etoposide in its relatively high cytotoxicity against non-cycling tumour cells. AMCA bound DNA more tightly than amsacrine, but the DNA base selectivity of binding, as measured by ethidium displacement from poly[dA-dT].[dA-dT] and poly[dG-dC].[dG-dC], was unchanged. AMCA-induced topoisomerase cleavage sites on pBR322, C-MYC and SV40 DNA were investigated using agarose or sequencing gels. DNA fragments were end-labelled, incubated with purified topoisomerase II from different mammalian sources and analysed after treatment with sodium dodecylsulphate/proteinase K. AMCA stimulated the cleavage activity of topoisomerase II, but the DNA sequence selectivity of cleavage was different from that of amsacrine and other topoisomerase inhibitors. It was similar to that of the methoxy derivative of AMCA, indicating that the changed specificity resulted from the carbamate group rather than from the methoxy group. The pattern of DNA cleavage induced by AMCA was similar for topoisomerase II alpha and II beta.
Baguley
B C
BC
Cancer Research Laboratory, University of Auckland, School of Medicine, New Zealand.
Leteurtre
F
F
Riou
J F
JF
Finlay
G J
GJ
Pommier
Y
Y
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects* / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000502:physiology; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D016259:Genes, myc; D051379:Mice; D014148:Tranexamic Acid; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C105581:methyl-N-(4-(9-acridinylamino)-2-methoxyphenyl)carbamate; D000677:Amsacrine; D014148:Tranexamic Acid; D004250:DNA Topoisomerases, Type II