For August 29, 2003
A FRIENDLY SKEPTIC LOOKS AT GRAVIOLA
A reader once called me a "soft-core quackbuster". Although he later retracted the charge, I have to confess that I wasn’t terribly upset at the label. As I see it, quackery exists on both sides of the medical divide: neither conventional medicine nor alternative medicine is immune from this scourge or has a monopoly on probity. A major problem with the self-proclaimed "quackbusters" is that their one-sided and tendentious attacks on alternative medicine leave the impression that conventional medicine is the only valid way of treating most forms of cancer. They come across as knee-jerk defenders of a status quo that genuinely needs to be reformed, not supported unquestioningly. On the other hand, I am wary of exaggerated claims made for any cancer treatments, whether those treatments originate in orthodox or alternative medicine, because such overblown claims are often based on (let us be generous) commercial considerations rather than solid science. A case in point is an herbal treatment called Graviola. This burst onto the Internet in early 1999 and is now incorporated into many patients' regimens. An increasing number of alternative practitioners are recommending it to their patients. What exactly is Graviola? It is a common name for Annona muricata, also known as soursop or Brazilian paw-paw. This is a small, upright evergreen tree growing 15 to 18 feet in height with large, glossy dark green leaves. (It is not to be confused with Asimina triloba, a deciduous tree of the eastern and southeast United States.) Graviola is indigenous to warm tropical areas in the Americas, including the Amazon. It produces a 6-to-9 inch, heart-shaped edible fruit, yellow-green in color, with white flesh. This is sold in tropical markets under the name guanabana or Brazilian cherimoya. It is said to be is excellent for making drinks and sherbets and, though slightly sour-acid, can be eaten out-of-hand. If you enter the term "Graviola" into Google you come up with an amazing 12,300 citations, over 2,000 of which relate to cancer. You also get a rash of sidebar advertisements such as "A great product to fight cancer," "Graviola helps to fight cancer," and "How Millions Beat Cancer," presumably with the help of this herb. The plant is also the subject of several dedicated websites. According to www.graviola.org, the plant is "an astounding cancer-fighting tree from the Amazon!" It is reputedly "10,000 times stronger in killing colon cancer than Adriamycin, a commonly used chemotherapeutic drug" and has the ability to "hunt down and destroy prostate, lung, breast, colon, and pancreatic cancers... leaving healthy cells alone!" These are formidable claims. Adriamycin (doxorubicin) is one of the most powerful (and toxic) drugs in chemotherapy. Adriamycin was discovered in Italy in the 1970s, hence the "Adria-tic" name. I well remember its introduction into oncology and how it revolutionized the treatment of several forms of cancer. But now, we are told, an herb has come to light that is not only as powerful as Adriamycin, but 10,000 times more powerful, and non-toxic to boot. The mind reels. Reading this statement, one cannot wait to find out more about this herbal product and how it could be used to help cancer patients. One pictures the evil demon Cancer, beaten and cringing in its corner, knowing that its days on earth are numbered. I don't know who first penned these effusive statements about Graviola but the claims have taken on a life of their own. I found two dozen other websites that contained the exact phrasing about Graviola being "10,000 times stronger than Adriamycin," all equally unsupported by scientific references. It seems that astounding claims concerning cancer cures spread like a virus from website to website. Since there are now hundreds of sites featuring and selling Graviola, I figured that this herb would also be well represented in PubMed, the National Library of Medicine's database of peer-reviewed articles. PubMed contains 12 million citations to nearly all medical journal articles published since the mid-1960s. But when I entered the term "Graviola" into this comprehensive search engine all I came up with was a single item. And this was not a clinical report at all but chemical arcana about screening Brazilian fruits for their aromas. There had to be something wrong. I went back to the www.graviola.org website (although exactly whose organization the '.org' refers to is not apparent) and I clicked on the "clinical references" link at the bottom of the page. All I got was a blank screen. The same thing with "data base entries" and "Graviola products." It looked as if someone had hastily removed some documentary material, but had then forgotten to remove the links. I then found a more productive tack. I read that the "active ingredients" in Graviola are a group of "annonaceous acetogenins" that are only found in the Annonaceae family, to which Graviola belongs. "These phytochemicals are being researched around the world for their active biological properties and potential uses," one website proclaimed. The phrase "annonaceous acetogenins" gave a new and promising starting point. Indeed, this term yielded 121 citations in PubMed. A lot of these were about the chemical constituents of the fruit. But taken cumulatively, one gathers that there is indeed a class of very interesting and potentially useful compounds in various branches of the Annona family. To quote scientists at Purdue University's highly regarded School of Pharmacy, "Annonaceous acetogenins are an extremely potent class of compounds, and their inhibition of cell growth can be selective for cancerous cells and also effective for drug resistant cancer cells, while exhibiting only minimal toxicity to 'normal' non-cancerous cells" (Oberlies 1995). Graviola thus joins the list of hundreds of other biologically active plants that are of potential importance to the future of medicine. Further searching in PubMed revealed that it was in fact scientists at Purdue who had first come up with the widely-circulated "more powerful than Adriamycin" claim. Here is what Dr. X.X. Liu and colleagues stated in 1999: "Annoglacins A and B were selectively 1000 and 10,000 times, respectively, more potent than Adriamycin against the human breast carcinoma (MCF-7) and pancreatic carcinoma (PACA-2) cell lines in our panel of six human solid tumor cell lines." This is very exciting in principle. However, to an inquiring, healthily skeptical mind, several questions immediately suggest themselves. One is, how much "annoglacin B" is found in a typical Graviola capsule purchased over the Internet? Quite probably it is infinitessimally small. Also lost in the promotional hoo-hah is the fact that the particular annoglacins investigated by Dr Liu and colleagues were derived not from Graviola at all but from a related, but entirely different, species, Annona glabra. This is a Polynesian tree called the pond or alligator apple. Additionally and most importantly, what do actual clinical studies show about the effectiveness of this agent against cancer? Back at the www.graviola.org website we read that "three separate research groups have isolated novel compounds in the seeds and leaves of Graviola which have demonstrated significant anti-tumorous, anti-cancerous and selective toxicity against various types of cancer cells, publishing eight clinical studies on their findings." Really? If we enter the search term Annona into PubMed, but limit our search with the modifier "clinical trials" (which includes any and all phases of clinical work), we come up with exactly...zero! My understanding of the term "clinical studies" is that they necessarily involve the treatment of human beings (or, more inclusively, pet and farm animals). Webster says that the term 'clinical' is an observation that "involves or is based on direct observation of the patient." The Cancerweb dictionary states that the word 'clinical' pertains to or is founded on "actual observation and treatment of patients, as distinguished from theoretical or basic sciences." But where are these "clinical studies" of Annona derivatives, if they are not to be found among the 12 million peer-reviewed journal articles of PubMed? The anonymous authors of the www.graviola.org website seem to have misspoken. They can't really mean clinical studies. They mean laboratory experiments that take place in test tubes with cell lines, which many knowledgeable researchers view as not directly equivalent to human cancer tissue. (See Gerald B. Dermer's book The Immortal Cell for corroboration of this point of view.) With this self-serving "slip of the tongue" the anonymous promoters of Graviola have undoubtedly convinced many cancer patients to buy their product. Have any of these patients been helped? Or have they been harmed by unknown or unmentioned side effects? Have they been deprived of precious time and thereby the opportunity to undergo other, more effective, treatments? Or have they simply been relieved of unspecified sums of money? In the vast majority of cases, we'll never know. Sadly, Graviola has now entered the netherworld of alternative cancer treatments. It promises much based on real, but very preliminary, scientific facts. Now its reputation has been tarnished by misstatements and over-promotion. Is there any way for a promising treatment to find its way back from the Purgatory of Cancer Cure-Alls? Or shall we remain forever in the dark about the merits of such treatments? Thousands of cancer patients are waiting for an answer to that riddle. --Ralph W. Moss, Ph.D. References: Augusto F, Valente AL, dos Santos Tada E, Rivellino SR. Screening of Brazilian fruit aromas using solid-phase microextraction-gas chromatography-mass spectrometry. J Chromatogr A. 2000 Mar 17;873(1):117-27. Liu XX, Alali FQ, Pilarinou E, McLaughlin JL. Two bioactive mono-tetrahydrofuran acetogenins, annoglacins A and B, from Annona glabra. Phytochemistry. 1999 Mar;50(5):815-21. Oberlies NH, Jones JL, Corbett TH, Fotopoulos SS, McLaughlin JL. Tumor cell growth inhibition by several Annonaceous acetogenins in an in vitro disk diffusion assay. Cancer Lett. 1995 Sep 4;96(1):55-62. **NOTE** To view this page in a more printable format, please CLICK HERE. IMPORTANT DISCLAIMERThe news and other items in this newsletter are intended for informational purposes only. Nothing in this newsletter is intended to be a substitute for professional medical advice.
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