Natural Compounds and the Future of Cancer Chemotherapy

Townsend Letter for Doctors and Patients,  August, 2001  by John Boik

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An evolution in thinking in the field of cancer chemotherapy is bringing conventional medicine and alternative medicine closer together than anyone previously had imagined possible. For fifty years cancer chemotherapy has been dominated by potent drugs that either interrupt the synthesis of DNA or destroy its structure once it has formed. Unfortunately, their toxicity is not limited to cancer cells and normal cells are also harmed. The severe adverse effects induced by these drugs are now well-known. Efforts to develop less toxic drugs that affect only malignant cells have been hampered by our limited understanding of cancer cell biology -- cancer treatment has turned out to be more problematic than anyone expected.

Cancer cells are difficult to target exclusively because they are so similar to normal cells. Both proliferate using the same cellular machinery, and destroying that machinery in one destroys it in the other. This is why cancer chemotherapy has failed, in general, to provide high response rates. It rather blindly goes about its business of destroying DNA and the damage it causes to normal cells limits the amount of drug that can be taken. Rapidly dividing cells are particularly affected because their high proliferation rate makes them dependent on frequent DNA synthesis. Thus chemotherapy has been highly successful on fast-growing cancers such as testicular cancer and some forms of leukemia. The majority of adult solid tumors, being relatively slow growing, do not respond nearly so well, however. Rapidly dividing normal cells, including those in the hair follicles, bone marrow, and gastrointestinal lining, are also affected -- damage to these account for most of the adverse effects seen.

The excessive adverse effects of chemotherapy have motivated researchers to consider new treatment options. During the last 20 years, efforts to identify the mechanisms that drive cancer cell proliferation have started to uncover the subtleties that make cancer cells unique. This information has led to what can be called a mechanism-based approach to treatment in which each mechanism -- each link in the chain of cancer cell proliferation -- is a target for therapy. [1] A whole new generation of mechanism-based drugs is being developed that specifically target cancer cells; such drugs promise to be more effective and have fewer adverse effects than current chemotherapy regimes.

The broadened range of targets within the mechanism-based approach has spurred thousands of laboratories around the world to hope they may discover the magic drug that cures cancer. Such an approach, however, contains a fatal flaw that greatly reduces the likelihood of finding broad cures. Pharmaceutical firms and research institutes are searching for the "silver bullet," but solutions based on a silver-bullet scheme rarely work as intended in medicine, ecology agriculture, or any other natural science. Even penicillin, the king of silver bullets, is now of diminishing usefulness because of widespread development of bacterial strains resistant to it. [2] Like microorganisms, cancer cells are quick to develop resistance to monodrug therapies. To find long-lasting solutions to the cancer dilemma, we must shift our thinking to a more organic approach, as, for example, has been done in organic farming where primary emphasis is placed on creating an environment in which insect pests cannot easily survive. This app roach builds the health of the soil and attacks the pest from several different angles, which is, of course, the exact opposite of a silver-bullet approach.

A holistic approach is sure to prevail in the long term. Numerous mechanisms active in a cancer cell allow it to behave the way it does, and just as important, there is intelligence in a cancer cell that enables it to compensate when one of these mechanisms is thwarted. At best, a single drug can target only one or a few mechanisms, and therefore the affected cell retains the ability to adapt. As all researchers and physicians know, cancer cells are excellent adapters. The most effective treatments then are likely to be ones that simultaneously target multiple mechanisms; furthermore, they will redundantly target them. The power of redundancy in population control is a central theme of basic ecology. Mice populations, for example, are far more stable if several natural predators control them. What one predator misses, another picks up.

The Role of Natural Compounds

The mechanism-based approach is perfectly suited to the use of natural compounds. In fact, several natural compounds were used as probes in the initial research that discovered the mechanisms. The term natural compound refers here to a small subset of the hundreds of thousands of compounds that occur in nature (see Table 1). The examples listed all derive from herbs or other natural sources with a history of use as a food or medicine, all are relatively nontoxic, and sound theoretical reasoning exists to support the hypothesis that they may be useful in cancer treatment. These compounds are not only well suited for the mechanism-based approach but also for use in combinations that target multiple mechanisms; each compound tends to affect multiple targets, and combinations redundantly do so. An example of this can be seen in Figure 1. [3] Here, the five compounds on the left are seen to redundantly affect the seven mechanisms on the right. It is beyond the scope of this article to explain these mechanisms, oth er than to say that PTK, PKC, NF-kB, and [PGE.sub.2] refer to enzymes, proteins, or lipid-soluble compounds that play a role in cell proliferation. The overall effect is clear: natural compounds can be used to provide a multifaceted attack on cancer cells.