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

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