Andrew M. Creighton

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The enzyme DNA topoisomerase II, which removes the catenations formed between the DNA molecules of sister chromatids during replication and is a structural component of chromosome cores, is needed for chromosome condensation in yeast and in Xenopus extracts. Inhibitors of topoisomerase II arrest mammalian cells before mitosis in the G2 phase of the cell(More)
Formation constants for the calcium(II), copper(II), iron(II), magnesium(II), manganese(II) and zinc(II) complexes ofdl-NN'-dicarboxamidomethyl-NN'-dicarboxymethyl-1,2-diaminopropane (ICRF 198) and the 1,2-diamino-butane homologue (ICRF 226) have been measured potentiometrically at 37°C andI=150 mmol dm−3 [NaCl]. The constants are used in computer(More)
Anticancer drugs targeted to the nuclear enzyme DNA topoisomerase II are classified as poisons that lead to DNA breaks or catalytic inhibitors that appear to completely block enzyme activity. To examine the effects of the bisdioxopiperazine class of catalytic inhibitors to topoisomerase II, we investigated a Chinese hamster ovary (CHO) subline selected for(More)
A series of twelve structurally related bisdioxopiperazines that included ICRF-187 (dexrazoxane), ICRF-159 (razoxane), ICRF-193, and ICRF-154 were examined both for their ability to inhibit the growth of Chinese hamster ovary (CHO) cells and their ability to inhibit the catalytic activity of mammalian DNA topoisomerase II. The bisdioxopiperazines exhibited(More)
Topoisomerase II is an ATP-operated protein clamp that captures a DNA helix and transports it through another DNA duplex, allowing chromosome segregation at mitosis. A number of cytotoxic bisdioxopiperazines such as ICRF-193 target topoisomerase II by binding and trapping the closed enzyme clamp. To investigate this unusual mode of action, we have used(More)
A Chinese hamster ovary (CHO) cell line highly resistant to the non-cleavable complex-forming topoisomerase II inhibitor dexrazoxane (ICRF-187, Zinecard) was selected. The resistant cell line (DZR) was 1500-fold resistant (IC50 = 2800 vs 1.8 microM) to continuous dexrazoxane exposure. DZR cells were also cross-resistant (8- to 500-fold) to other(More)
In recent years, radiolabelled monoclonal antibodies have been evaluated for their use in the diagnosis and treatment of neoplastic disease. One isotope which has not been assessed for antibody targeting is 32P, even though it has many favourable radiobiological characteristics and has been used clinically for the treatment of certain neoplastic disorders(More)
The antitumor drug mitindomide (NSC 284356) was shown to inhibit the decatenation activity of human and Chinese hamster ovary (CHO) topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.1]. Mitindomide did not induce the formation of topoisomerase II-DNA covalent cleavable complexes in CHO cells. These results taken together indicate that(More)