The Pharmaceutical Journal Vol 267 No 7169 p510-525
13 October 2001

BPC 2001 summary

Natural products and the treatment of cancer

To abandon natural products as a source of leads for new compounds would be doing mankind a disservice, according to Professor Roger Waigh, school of pharmaceutical sciences, University of Strathclyde. There are worrying signs that some pharmaceutical companies have reined back natural product research. In his view, this is a fundamental mistake. For 300 million years, plants have been producing compounds to defend themselves, and this was something mankind could benefit from.

Professor Waigh spoke about a series of compounds, the benzylisoquinolines, which are transformed in some Rutaceous plants into benzo[c]phenanthridines. Work with these compounds has led to the synthesis of ethoxidine, structurally similar to the natural product fagaronine. Fagaronine has a clear feature — it has four conjugated aromatic rings and the molecule is twisted — allowing it to bind well to DNA. Fagaronine is a topoisomerase I poison. By contrast, there are differences between the way that fagaronine and ethoxidine bind to DNA and there is evidence that ethoxidine is a topoisomerase I suppressor, not a poison. According to Professor Waigh, ethoxidine inhibits the growth of glioblastoma in mice. He said that colleagues in France are testing the compound against a melanoma cell line, with positive results.

Compounds from marine invertebrates

Dr Marcel Jaspars, marine natural products laboratory, University of Aberdeen, said that marine organisms are an important source of natural products. About 70 per cent of the world is covered in water. Data from the United States National Cancer Institute indicate that anticancer activity has been documented for 1.8 per cent of extracts from marine animals, compared with less than 0.4 per cent from terrestrial plants. This could be because marine organisms are under intense evolutionary threat and need good chemical defence systems.

Dr Jaspar’s work is focused on invertebrates, such as sponges, sea squirts and soft corals, from Fiji and Indonesia. His group has isolated aaptamines, such as demethyloxyaaptamine, from the Indonesian sponge Aaptos aaptos. This compound has shown activity in vitro against ovarian tumour cells. They have also isolated sarcophine from the Indonesian soft coral Sarcophyton species. Some of the most promising compounds to date have been isolated from the Fijian sponge Geodia globostellifera. A related compound, stelliferin riboside, has been shown to have solid tumour selectivity greater than that of its parent stelletin. Stelliferin riboside is now entering first-stage pharmacology studies. Three proline-rich cyclic peptides (axinellin, wainunuamide and phakellistatin 2) have been isolated from another Fijian sponge, Stylotella aurantium.

RAID programme

Dr Gordon Cragg, chief of the natural products branch, developmental therapeutics programme, US National Cancer Institute, described anticancer compounds in development at the NCI. Around 60 per cent of anticancer drugs in commercial use or currently in clinical development are of natural origin. The NCI has several agents in preclinical development through its RAID (rapid access to intervention development) programme, a collaborative agreement with academic partners, to support new drug applications and clinical trials. Examples of compounds in development through this route are a thapsigargin prodrug, which undergoes activation to thapsigargin by prostate specific antigen and induces apoptosis in human prostate cancer cells. Other examples are betulinic acid, cephalostatin, spongistatin and the microbial-derived 12,13-desoxyepothilone B and wortmannin (a protein kinase B inhibitor).

Another route for developing novel anticancer agents is through the NCI’s drug development group (DDG). The difference between the DDG and the RAID programme is that for projects managed by the DDG the NCI, and not the investigator partner, sponsors clinical trials. Examples of compounds in development through the DDG programme include 2-methoxyoestradiol, adaphostin and 2-methoxyantimycin. A synthetic halichondrin B analogue (a tubulin inhibitor) will enter clinical trials before the end of the year. Further information can be obtained from the NCI website (dtp.nci.nih.gov).

Dr Cragg ended by describing some of the directions that NCI is considering in its continuing search for novel anticancer compounds. One direction is the exploration of extreme environments for extremophilic microbes. These include deep sea vents, thermal hotsprings and deep core drillings and mines, inhabited by thermophiles, and Arctic and Antarctic areas, where psychrophiles might be found. For example, tube worms packed with bacteria had been found in deep sea environments.

Microbial genomics is another possible route to novel agents. More than 99 per cent of microbes available had yet to be cultured; this was a vast untapped resource of novel chemistry and drugs.

Another approach is to extract genomic DNA from environmental samples, such as soil. The insect world is another untapped resource, he said.

Concluding, Dr Cragg said: “I think the way to go is to combine all the various techniques ... natural products will still play a key role”. However, there is a need to combine this approach with combinatorial chemistry and synthesis to optimise results.

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