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Why we don’t prescribe bark for cancer

My valued colleague, Dr. Antonio Baines, recently invited me to speak for his graduate course in Toxicology.  Dr. Baines’ course is one of the most highly-regarded graduate classes at North Carolina Central University for M.S. students in Biology and Pharmaceutical Sciences.  Antonio asked that I discuss the pharmacology and toxicology of herbal and non-botanical dietary supplements but pretty much gave me free reign as to the mechanism by which I would do so.

In the past, I have often introduced herbal supplements to students who already know a bit about drug and toxicant action by taking the example of the anticancer drug, taxol (Note: Little “t” taxol was the name originally given to this chemical by its co-discovers but the corporate sponsor used it as a registered trademark for the brand name, big “t” Taxol, and the USAN proposed the use of the cumbersome paclitaxel as the generic name.).  As I noted in my previous post, taxol is an anticancer drug isolated from the bark of the Pacific yew tree, Taxus brevifolia, and was the first compound shown to kill cancer cells by promoting microtubule polymerization (and preventing depolymerization).

As a teaching tool in demonstrating how far we’ve come since Sertürner first isolated codeine and morphine from the opium poppy, I ask students to answer a rather simple, seemingly flippant, but highly informative question:

If taxol is an anticancer drug with known clinical activity against ovarian, lung, and breast cancer, why don’t we prescribe Taxus bark for cancer?

Similarly, why doesn’t the dietary supplement industry promote ground Taxus bark as an oral dosage form, herbal remedy to promote well-being for cancer patients?

These questions get to the heart of why we have come over 200 years from  Sertürner’s day: to purify and concentrate pharmacologically-active constituents from natural products:

1. Drug metabolism and lack of oral bioavailability: Orally adminstered drugs are subject to first-pass metabolism when absorbed in the gut.  The mesenteric blood supply collects into the hepatic portal vein and must get through the liver before being distributed to the rest of the body.  The primary Phase I drug oxidizing enzymes and Phase II drug conjugating enzymes are in their highest concentrations in the liver and many compounds are metabolized to inactive compounds before they even reach the systemic circulation. (N.B., The intestinal mucosa also contains some cytochrome P450 isozymes, so metabolism starts even earlier than that.)  As a result, many drugs, like taxol, must be given intravenously to preclude first-pass metabolism.

2. Influence of bark composition: Lignans and cellulosic compounds might interfere with the absorption of taxol by preventing its dissolution.  In fact, any change in the amount or composition of inactive excipients in a prescription drug can dramatically influence dissolution and drug absorption. Other components of the bark might as as competitive inhibitors of taxol’s binding to tubulin or, in a broader sense, have some other adverse influence on drug pharmacodynamics.  In addition, other components of the bark might enhance the metabolism of taxol.  This leads us into:

3. What is the appropriate dose of bark?:  This is a major stumbling point with herbal medicines.  Indeed, botanical products may contain physiologically-active compounds, but these may be at concentrations too low to achieve relevant plasma concentrations.  Taxus bark contains 0.05 to 0.005% taxol. Even if taxol were orally-active, the amount of bark one would have to ingest would be so large as to present a patient compliance issue (or at least severe gastrointestinal discomfort).

4. Reproducibility: If a tumor response was observed, how would one know how much bark to give the patient for the next dose? The environment (weather, soil composition, water, sun) in which the trees are grown can all influence the abundance of secondary metabolites present in crude plant material.  Hence, there are significant lot-to-lot variations in the chemical composition of botanical products. Even if all of the above issues were circumvented, the reproducibility of subsequent doses might have unpredictable biological effects.

5. Toxicological issues: Again related to growth environment, many plants are bioaccumulators of heavy metals from the soil, especially cadmium.  With many recent reports of heavy metal contamination of herbal remedies, companies are only now beginning to test their raw materials for heavy metals.  Plant materials could also be contaminated with pesticides, insecticides, or harmful microorganisms that would also be removed if the active principle were purified.  Moreover, there have been several cases of botanical products intentionally or accidentally adulterated with other prescription drugs (called ‘undeclared drugs’ by the US FDA) in the attempt to produce a biological effect that the plant medicine is incapable of having itself.

There are certainly more issues that readers are welcome to add in the comments.  The point of this exercise was to demonstrate to students the distinctions between the safety and efficacy of crude plant products relative to pure drugs isolated from such natural sources.  This discussion and list was compiled in a fraction of the time it took me to type it.

I wish to acknowledge the students of Dr. Antonio Baines’ BIOG 5140 – Toxicology class at North Carolina Central University for their individual contributions to this post:

Onize (Ony) Aiyede, Lavita Anderson, Chantal Bodkin-Clarke, Jamila Broadway, Shailendra Devota, Chang Hun Lee, and Roketa Sloan.

Posted in: Herbs & Supplements, Science and Medicine

Leave a Comment (11) ↓

11 thoughts on “Why we don’t prescribe bark for cancer

  1. Great post, Dr. Kroll! Simple, informative, educational! Just what I needed this morning.

  2. Calli Arcale says:

    Another issue is cost. I understand that the drug is manufactured by a genetically engineered bacterium now, which is a lot cheaper than wholescale logging of Pacific Yew in order to obtain enough bark. So sometimes transgenic bacteria and/or synthetic processes can save a lot of money. (There’s an environmental subtext to that too, since harvesting yew bark involves logging, and the yield is apparently not very good.)

  3. Prometheus says:

    To echo Calli, when taxol (small “t”) was discovered to be a useful cancer chemotherapeutic, it was soon determined that the demand for taxol would rapidly lead to the extinction of the Pacific Yew. At the time, this was felt by some cancer sufferers to be a reasonable exchange.

    Fortunately, a semi-synthetic process was developed using 10-deacetylbaccatin from the needles of cultivated Taxus baccata (European Yew), which has spared the Pacific Yew. As I understand it, all taxol is currently made using plant cell fermentation without harming a single standing tree.

    So, to add to Dr. Kroll’s excellent clinical reasons to use paclitaxel/taxol/Taxol instead of Pacific Yew bark, there is also an ecological reason, as well. The hard work of several researchers to come up with various semi-synthetic and completely synthetic (not currently used commercially) ways to make this drug prevented the extinction of the Pacific Yew.

    Prometheus

  4. Joe says:

    Interesting post.

    As I recall (I expect you do too), taxol was named in the 1960s, and there was/is extensive, chemical literature on it. When Bristol-Myers (B-M) developed it as a drug (1980s) they had first right to suggest a name to USAN. B-M found a (totally unrelated) registered, trade-named product (Taxol) in France; so they recommended paclitaxel as a generic name. USAN accepted that, and then asked what B-M wanted for a trade name; B-M replied they had bought the trade name Taxol, and they had a well-known name for their drug.

    Afterwards, B-M started complaining about the use of “taxol” in chemical literature. The response was “rave on”- we don’t care.

    David- I thought poor (aqueous) solubility prevented taxol’s oral use; the first-pass effect notwithstanding.

  5. anjou says:

    Thank you David–there needs to be more of this type of information on the internet to counter the millions of herbal hype sites on the web.

    Just last week, a patient of mine,told me about a friend of hers who was diagnosed with breast cancer and was told she needed a lumpectomy, and perhaps radiation. Well, the woman refused even a simple lumpectomy and is using some sort of herbal medicine instead….. it is so unfortunate when folks like this, who have a real hope of cure with conventional medicine, believe the hype and refuse the treatments offered by their doctors.

    My partner is a cancer researcher, I am in remission from cancer. The amount of misinformation regarding herbs and cancer on patient support boards is astounding.

    Several years back my partner wrote something similar to help patients on a lymphoma support board understand some things about herbs and cancer– he used hypothetical numbers etc, but here’s what he said:

    “To address the hypothetical question as to how much of a natural source containing the above mentioned drug must be consumed in order to receive an equivalent quantity of pure drug, one needs to know the yield of the active ingredient within the natural source. (this simplified approach ignores the potential confounding problems of having to co-ingest other compounds which may either antagonize the activity of the useful anticancer drug, and/or which may contribute their own unique toxicities, and assuming the drug was absorbed and distributed as well when taken orally as when given by injection).

    To illustrate by way of example, if one were to chew a tree bark containing a useful anticancer drug (ie yew), and the yield of that drug within the tree bark were 0.1%, then eating 100 gm (about 3 oz) of bark would be equivalent to having ingested 0.1gm of active drug. If a patient required 0.1 gm of active drug for each kg of body weight (typical adult male weighs 70kg), as determined by from the clinical studies conducted, this would amount to 7 gm of active drug per injection (*assuming the drug must be injected to be optimally effective) One would have to consume 210 oz of tree bark, or 13 pounds, to ingest the needed amount of drug.

    For the anticancer drug taxol, it has been estimated that each patient received, in the course of their therapy, and amount of pure drug obtained from the bark of 1 1/2 yew trees.”

    anjou

  6. Jules says:

    Um, how about also: the Pacific yew is an endangered species, harvesting the bark kills the tree, and you’d need a lot of bark to get a therapeutic amount of taxol out of it? (Oddly, this was all covered in organic chemistry–I think it was during the lesson on enantiomeric compounds and chiral reactions)

    Taxol (with a capital T) is still partially a natural drug. They found that part A of Taxol is synthesized naturally in the needles of the Pacific yew, and these could be taken with (near) impunity. Part B of Taxol is, from what I understand, pretty difficult to make, but it’s doable, and getting parts A and B together is relatively simple.

  7. Indeed, anjou, this little exercise was influenced in part by discussions with my senior colleague.

    Jules, Prometheus noted above the ecological/environmental issues as well. Not only is the yew an extremely slow growing tree but it is also the habitat for the northern spotted owl, an endangered species.

    An excellent historical overview of this story can be found in Goodman and Walsh’s, “The Story of Taxol: Nature and Politics in Pursuit of an Anti-Cancer Drug.”

    French chemist, Pierre Potier, devised a scheme to produce taxol from 10-DAB, the intermediate Prometheus notes is derived from the needles of the European yew, Taxus baccata. However, it was the 5-step synthesis developed by Florida State’s Bob Holton and colleagues that B-MS licensed for production of Taxol. The use of plant cell culture cited by Prometheus is news to me so I’ll have to look into that.

    Nevertheless, Potier’s work led to the synthesis of docetaxel (Taxotere). This semi-synthetic taxane has some advantages of taxol in terms of potency and it being a poor substrate for the Pgp/MDR1 drug efflux pump.

    Many thanks to you all (yew all?) for your comments and especially to Dr. Baines and our excellent NCCU graduate students for these discussions.

  8. Wallace Sampson says:

    Some personal and not necessarily scientific observations.

    I was honored to spend 2 days with Scientific American (TV) with host Alan Alda a few years ago. One of our tours was to a traditional Chinese medicine pharmacy in San Francisco Chinatown. Alda asked what I thought of the pharmacy techniques. The pharmacist on listening to a patient’s complaints, reached into several (of about 100) drawers of dried plant materials, withdrew a small handfull of each, weighed an undisclosed amount of each on a hand held balance, and combined them into a white envelope for the “patient.” It was pretty gross.
    I had seen the same thing in our CSICOP tour of mainland China’s medicine in 1995. I replied simply, that it looked pretty gross to me. (I do not recall if that comment was included or clipped.)
    Our guide, an officer of the Chinatown Chamber of Commerce whispered to me outside that he knew the pharmacist did not know what he was doing. Nevertheless, a couple of non-Chinese customers dropped praises of the pharmacist’s knowledge and effectiveness for reducing their arthritic symptoms. Who knows what was in the plant materials, or what was responsible for perceived improvements? Contents? Suggestion?
    David Kroll’s explanation of hidden factors is mandatory for thinking about the problem

  9. Apreche says:

    I read this article when it was first posted, but I recently put two and two together and have changed my stance on medical marijuana.

    If you don’t prescribe tree bark, why prescribe burnt plants? Clearly the correct answer is to prescribe purified and concentrated THC to be delivered in some other form. This exists in pill form as marinol, but supposedly it causes stomach pain and has other side effects.

    I can’t imagine it would be that hard to prescribe a THC inhaler instead of prescribing the combustion of plant matter. At the very least, you could inhale the pure THC with a bong, using steam as opposed to smoke from burnt leaves.

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