Clinical Oncology UpdateEtoposide: four decades of development of a topoisomerase II inhibitor
Introduction
DNAtopoisomerases are nuclear enzymes which make transient DNA strand breaks allowing the cell to manipulate the topology of its DNA1, 2. DNA topoisomerases are essential for DNA replication, transcription, chromosomal segregation and DNA recombination. Two major topoisomerase forms are present in all cells: the type I enzyme which makes single-strand cuts in DNA and type II enzymes which cut and pass double-stranded DNA. DNA topoisomerase I was first described in 1971[3]and DNA topoisomerase II in 1976[4]. Several commercially available antineoplastic drugs are now known to be inhibitors of topoisomerase I (irinotecan, topotecan) or topoisomerase II (etoposide, teniposide, doxorubicin, daunorubicin, idarubicin, mitoxantrone). This review will concentrate primarily on the development of etoposide as an antineoplastic agent. Etoposide was the first agent recognised as a topoisomerase II inhibiting anticancer drug. Research on etoposide has helped the understanding of mechanisms by which drugs poison topoisomerase II. Recognition of the relationship of topoisomerase II inhibition and a resulting antineoplastic effect has stimulated development of other agents. Currently available topoisomerase II inhibitors are briefly described.
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Historical development
Podophyllotoxins have been used as medications by various cultures for over 1,000 years (Table 1)[5]. In the 19th century, podophyllin was found to be topically effective for skin cancers. In 1946, the antimitotic properties of podophyllin were established[6]. Clinical evaluation of podophyllotoxin and selected derivatives demonstrated modest antineoplastic activity. However, toxicity of podophyllin was prohibitive7, 8. In the 1950s, investigators at Sandoz Pharmaceuticals began synthesising a
Other topoisomerase II targeting antineoplastic agents
In addition to etoposide, five other topoisomerase II targeting antineoplastic agents (teniposide, doxorubicin, daunorubicin, idarubicin and mitoxantrone) have been approved for clinical use in the US by the Food and Drug Administration (Table 8). Other topoisomerase II inhibitors (Table 9) which have demonstrated antitumour activity in animal or clinical studies have not been approved for general clinical use in the US.
Conclusion
Four decades of research have led to the recognition that certain antineoplastic drugs poison topoisomerase II, thereby killing cancer cells. These studies have provided a new target site for drug development. Etoposide, the lead drug in this class, continues to be a widely used agent with activity against a wide range of cancers. It is a standard component of therapy for small cell lung cancer, testicular cancers and lymphomas. Optimal and convenient schedules have been devised over the past
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