DNA topoisomerase II is an enzyme that affects nuclear structure and function and is the target of a number of anticancer drugs in clinical use, including teniposide (VM-26). We have used our polyclonal antisera that recognize both the M(r) 170,000 and 180,000 forms of topoisomerase II to examine the nuclear distribution of topoisomerase II in cytospin preparations of drug-sensitive (CEM) and V...

Doxorubicin (Adriamycin) is one of the most commonly used chemotherapeutic drugs and exhibits a wide spectrum of activity against solid tumors, lymphomas, and leukemias. Doxorubicin is classified as a topoisomerase II poison, although other mechanisms of action have been characterized. Here, we show that doxorubicin-DNA adducts (formed by the coadministration of doxorubicin with non-toxic doses...

The cytotoxicity of topoisomerase inhibitors is thought to result from the induction of enzyme-mediated DNA breaks. The fact that these breaks reverse rapidly in cells programmed to die, led us to investigate further the cytotoxic mechanisms of topoisomerase I (camptothecin) and topoisomerase II inhibitors (VP-16 and amsacrine) in Chinese Hamster lung fibroblasts (DC3F). Exposures (30 min) to c...

A subset (gamma(2)) of late herpes simplex virus 1 genes depends on viral DNA synthesis for its expression. For optimal expression, a small number of these genes, exemplified by U(S)11, also requires two viral proteins, the alpha protein infected cell protein (ICP) 22 and the protein kinase U(L)13. Earlier we showed that U(L)13 and ICP22 mediate the stabilization of cdc2 and the replacement of ...

The in vitro inhibitory effects of sitafloxacin (DU-6859a) and its three stereoisomers on bacterial DNA gyrase from Escherichia coli, topoisomerase IV from Staphylococcus aureus, and topoisomerase II from human placenta were compared. No correlation was observed between the inhibitory activities of quinolones against bacterial type II topoisomerases and those against human topoisomerase II. Sit...

Resistance to etoposide (VP-16), amsacrine (mAMSA), and doxorubicin (Adriamycin) was studied in two Chinese hamster cell lines primarily selected for resistance to the epipodophyllotoxin. Both lines demonstrated profound resistance to VP-16, and mAMSA stimulated DNA breakage. However, the resistance to mAMSA cytotoxicity in both lines was less than expected from the level of resistance to the e...

Resistance to etoposide (VP-16), amsacrine (mAMSA), and doxorubicin (Adriamycin) was studied in two Chinese hamster cell lines primarily selected for resistance to the epipodophyllotoxin. Both lines demonstrated profound resistance to VP-16, and mAMSA stimulated DNA breakage. However, the resistance to mAMSA cytotoxicity in both lines was less than expected from the level of resistance to the e...

Sequential cleavage of genomic DNA into large-scale DNA fragments of 50-300-kb, followed by formation of monoand oligonucleosomal DNA fragments, is a biochemical hallmark of programmed cell death (apoptosis). The endonuclease DFF40/CAD mediates regulated internucleosomal DNA fragmentation and chromatin condensation in cells undergoing apoptosis. DFF40 hypersensitive sites were detected in purif...

As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed hig...

The effects of topoisomerase II-reactive epipodophyllotoxins etoposide and teniposide as well as amsacrine on the viability of thymocytes in primary culture has been examined. All three drugs were shown to produce DNA cleavage detectable by resolving isolated DNA by pulsed field agarose gel electrophoresis. The DNA cleavage was found to have two components. The first was due to the interaction ...