In a post the other day, we noted that the semi-synthetic natural product, ixabepilone, approved for advanced breast cancer was derived from a soil bacterium. Colleague PharmCanuck reminded us that the soil is not a new source for drugs: the anthracyclines, daunorubicin and doxorubicin, are derived from a strain of Streptomyces found growing on a 13th century castle along the Adriatic Sea (hence the brand name for doxorubicin, Adriamycin). Amazingly, Adriamycin remains a foundation of many breast cancer chemo regimens more than 30 years after its approval.
While we speak here quite often about plants or terrestrial microorganisms as drug sources, we tend to shortchange marine creatures and marine microorganisms. In fact, a rather old anti-leukemia drug, cytosine arabinoside (ara-C, cytarabine), was first inspired by compounds isolated from Cryptotheca crypta, a Pacific sponge - and I don't mean Kato Kaelin.
Truth be told, marine natural products research has been a booming area of our field, as evidenced by the broad coverage of topics in the program of this Gordon Research Conference in 2000 devoted solely to marine natural products. (And here is the preliminary announcement for the 2008 conference.).
The Spanish pharmaceutical company, PharmaMar, has been leading the way with several marine-derived anticancer drugs. Most advanced is ecteinascidin-743, usually just called ET-743 or its proposed brand name, Yondelis®. Originally discovered in the colonial tunicate Ecteinascidia turbinata, ET-743 is now made synthetically. ET-743 is now in Phase III clinical trials for ovarian, prostate, and breast cancers, as well as some leukemias.
The backstory on PharmaMar's webpage would make even jaded old me excited to pursue a career in marine pharmacognosy:
R&D FROM THE OCEAN
Why does PharmaMar focus on the sea? The oceans cover 70% of the Earth's surface and account for 90% of the biosphere. Over millions of years myriads of marine life forms have evolved to produce a vast diversity of uniquely sophisticated chemical entities. Among these there are molecules with potent biological activities which have developed as a form of biochemical warfare to survive in a highly competitive environment. PharmaMar has recognized the anti-tumour potential of these molecules, and is actively developing them as innovative treatments for cancer.
To tap into the marine sources PharmaMar employs expert marine biologists who search the world oceans collecting small samples of local flora and fauna from selected locations. Collected samples are identified taxonomically, shipped back frozen to our research facilities in Madrid, and incorporated in PharmaMarÂ´s unique biodiverse library already containing thousands of marine samples.
PharmaMar has other interesting preclinical candidates such as kahalalide F, a peptide derived from the sea slug, Elysia rufescens. Kahalalide F is in Phase II clinical trials for hepatocellular carcinoma.
The general public already knows of the importance of preserving rain forest ecologies because of the potential to derive drugs from uncharacterized species in these ecosystems. However, less appreciated by society is the fact that the ocean is an equally, if not more, diverse potential source of compounds that can be used as therapeutic agents.
In popularizing and communicating the need for marine conservation, I would suggest that experts in the field point to these drugs and companies like PharmaMar to provide concrete evidence in fostering public support to preserve our oceans for the good of human health.
(Full disclosure: I have no relationships with PharmaMar or any of their affiliated researchers or academic partners; I just think that their mission is unique and worthy of promotion.)
Photo credit: Ecteinascidia turbinata (Mangrove Tunicate) growing in situ, by Greg McFall, Georgia Southern University
Nice write up!
Very interesting, thank you
I don't know how I managed to miss this. Did you see my yammering about triterpene glycosides in sea cucumbers and my own experiences with marine natural products chemistry? At one point (briefly), my dream was to become a female version of Richard Evans Schultes with a scuba certification. ;^)
Natural products are coming back into vogue in Big Pharma, but they still represent a huge challenge because of synthetic difficulties and scale-up. I'm curious as to the starting materials for the clinical candidates cited in your article. Simple fragments? Related natural products in more abundance?
Hey Doc, thanks for the heads-up about your post and the nostalgic reference to the Super-Bass-O-Matic. Sea cucumber smoothies...mmm.
In answering your question, what I find amazing is that culturable bacteria and fungi can be used cost-effectively to generate precursors for even complicated molecules like ET-743. In this case, cultures of Pseudomonas fluorescens are used to generate safracin B as the precursor (see this free-access PDF of Marine Drugs 2003;1:5-17 for the structures).
Similarly, in my previous post on the recently-approved semi-synthetic epothilone, ixabepilone, optimized fermentations of the soil myxobacterium, Sorangium cellulosum, are used to generate the precursor, epothilone B.
As you point out in your comment and post, the molecular complexity of natural products makes for great candidates, but bioavailability and scale-up/semi-synthesis issues are central to making drugs out of these interesting compounds.
And yes, being a scuba Schultes might have been fun - his 1976 book on hallucinogenic plants is a fabulously detailed classic.