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Vol. 56, Issue 6, 1309-1316, December 1999
Are
Resistant to Acridines and Mitoxantrone: Analysis of Cytotoxicity and
Cleavable Complex Formation
School of Biochemistry and Genetics (F.E., E.W., C.A.A.) and Cancer
Research Unit and Department of Child Health (M.J.T.), The Medical
School, The Cookson Building, University of Newcastle upon Tyne, United
Kingdom; Department of Medical Physics and Radiation Oncology, Memorial
Sloan-Kettering Cancer Center, New York, New York (L.L., G.L.);
Department of Molecular and Cellular Biology, Harvard University,
Cambridge, Massachusetts (W.L.); and Auckland Cancer Society Research
Centre, University of Auckland School of Medicine, Auckland, New
Zealand (B.C.B.)
Murine transgenic cell lines lacking DNA topoisomerase II (topo II)
have been used to assess the importance of topo II as a drug target.
Western blot analysis confirmed that the topo II 
/ cell lines
did not contain topo II protein. In addition, both the topo II
+/+ and topo II / cell lines contained similar levels of topo
II
protein. The trapped in agarose DNA immunostaining assay (TARDIS)
was used to detect topo II and cleavable complexes in topo II
/ and topo II +/+ cells. These results show that both topo II
and are in vivo targets for etoposide, mitoxantrone, and amsacrine
(mAMSA) in topo II +/+ cells. As expected, only the -isoform was
targeted in topo II / cells. Clonogenic assays comparing the
survival of topo II / and topo II +/+ cells were carried out
to establish whether the absence of topo II caused drug resistance.
Increased survival of topo II / cells compared with topo II
+/+ cells was observed after treatment with amsacrine (mAMSA),
methyl
N-(4'-[9-acridinylamino]-2-methoxyphenyl) carbamate
hydrochloride (AMCA), methyl
N-(4'-[9-acridinylamino]-2-methoxyphenyl)carbamate hydrochloride (mAMCA), mitoxantrone, and etoposide. These studies showed that topo II / cells were significantly more resistant to
mAMSA, AMCA, mAMCA, and mitoxantrone, than topo II +/+ cells, indicating that topo II is an important target for the cytotoxic effects of these compounds.
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