Adenoviral topoisomerase II αgene transfer increases sensitivity of resistant cancer cells

Excerpt

Cellular resistance to chemotherapeutic agents is a major problem in cancer treatment. There are a number of possible mechanisms of drug resistance, one of which is changes in the level of topoisomerase IIα(topo IIα) gene expression. The topo IIα nuclear enzyme is crucial for cell survival, being involved in many essential cellular processes such as DNA replication. The enzyme is also a target for a number of key chemotherapy drugs including adriamycin and etoposide. These drugs stabilise the enzyme-DNA cleavable complex which in turn initiates cellular death processes. Therefore, alterations in the topo IIα enzyme can lead to drug resistance. One such alteration is a decrease in the level of enzyme, which leads to reduced amounts of topo II-DNA complex, thus less drug binding and less cell death. Conversely, the cytotoxicity of topo II targeting drugs increases as the level of topo IIα enzyme in the cell increases. Etoposide-resistant MDA-VP human breast cancer cells express lower amounts of enzymatically active and drug-sensitive topo II than do MDA parent cells, suggesting that the low level of topo IIα is the mechanism of resistance. …