Friday, February 03, 2006

Flower power & Oncology

DailyUpdates 3rd Feb, 2006: The size of the cytotoxic market in the seven major pharmaceutical markets is estimated to be approximately $9.6 billion. Datamonitor expects it to reach a peak of $12.8 billion by 2009. However, mainly due to major patent expiries, it is expected to drop to $11.3 billion by 2014 (see Commercial Insight: Cytotoxics).

According to the ATC classification system there are 5 classes of cytotoxic agent. Topoisomerase inhibitors represent a subgroup of plant alkaloids, which also encompasses the vinca alkaloids such as vincristine and vinblastine, taxanes. Topoisomerase inhibitors act by preventing the unpackaging of DNA that must occur prior to transcription and replication. The earliest drugs in this class were inhibitors of topoisomerase II, however topoisomerase I inhibitors such as topotecan started entering the market in the mid-1990’s. DNA topoisomerase II inhibitors are among the most efficacious drugs for the treatment of cancer. Despite their widespread use, the use of topoisomerase II inhibitors is limited by severe adverse effects to normal tissues, including cardiotoxicity.

In addition to problems associated with toxicity, sensitivity of cancer cells to topoisomerase II targeting agents is also, like many other cancer therapeutics susceptible to resistance. The efficacy of this class is thought to depend on the expression of the topoisomerase IIalpha isoform, and drug resistance is often associated with loss or mutation of this isoform.

Considering the success of the alkaloids as cancer therapeutics, considerable effort is still being dedicated to the identification of new drug leads including novel topoisomerase II inhibitors. The plant Euphorbia kansui, a phytotherapy long used in Chinese medicine as a cancer treatment, represents a rich source of plant alkaloids and in particular terpenes. More recently researchers have evaluated the anticancer efficacy and mechanism of action of the terpenes.

Studies have shown E kansui terpenes to markedly reduce carcinogenesis in a skin tumor model and in 2002 Wang et al reported that representatives of this chemical class reduced the proliferation of Xenopus embryonic cells, an assay that has been used as an alternative to the study of cancer cell lines in the primary screening of anticancer drugs. More recently this antiproliferative effect has been shown to be related to an inhibition of cell cycle progression and similar effects have been observed with E kansui extracts using cancer cell lines.

In an upcoming issue of Bioorganic & Medicinal Chemistry highlighted in todays DailyUpdates, Miyata and colleagues investigate the mechanism of action of the diterpenes (a sub-class of terpenes that includes the retinoids), in greater detail. In this study a variety of different diterpenes inhibited human topoisomerase II activity however the potency of this effect did not appear to correlate with cell proliferation potency. This study therefore suggests that the anticancer activity of diterpene alkaloids may involve the inhibition of topoisomerase II activity as well as other components of the cell cycle.

The diterpenes have already been the subject of a clinical investigation with, for example Triptolide derivatives being developed by Fujisawa (now Astellas following the merger of Fujisawa with Yamanouchi). The present study highlights the lack of knowledge regarding the mechanism of the diterpenes and will hopefully prompt further investigation to resolve this issue and hopefully help optimize this promising therapeutic class.


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