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Part I of this book discusses cancer at the cellular level, and Part II discusses cancer at the level of the organism. The latter refers to interactions between groups of cancer cells (tumors) and the body. As we will see, a conglomeration of interrelated events occur within an individual cancer cell, as well as between tumors and the body, which allows a cancer to proliferate and spread. For convenience, I refer to these as procancer events. For example, one procancer event is the production of enzymes by tumors that allows them to invade local tissues. The mechanism-based approach to cancer treatment used throughout this book views each of these procancer events as a potential target for cancer inhibition. Although a very large number of procancer events occur during a tumor's life, to simplify and focus this approach, I group them into seven primary clusters of events. The inhibition of these seven event clusters thus becomes the goal of the mechanism-based approach outlined here.

This chapter defines the seven event clusters and identifies each with a strategy for cancer inhibition. In addition, we look more closely at why combinations of compounds will be most effective at inhibiting these seven clusters and why the synergism that occurs within combinations is needed for natural compounds to be effective. We will also look at how combinations of compounds might be designed, then introduce the natural compounds to be discussed. Finally, some practical information is provided to help the reader understand the concentrations reported and the relationship between animal doses and their human equivalents.

It seems useful to start with the basics of what occurs in cancer; thus we begin with a look at how normal cells behave and how a normal cell becomes a cancer cell during carcinogenesis.

DEVELOPMENT OF CANCER AND CHARACTERISTICS OF CANCER CELLS

Imagine a healthy tissue containing thousands of cells. Each cell serves the greater good, which is the continuation of a person's life. Each cell is programmed so that when the cell is old or no longer needed, it dies a peaceful and timely death. This death is called apoptosis. All cells are in communication, which allows for the smooth repair and replacement of tissues and other aspects of cell behavior. Communication takes place either indi rectly, via exchange of messenger compounds such as hormones and growth factors, or directly, via cell-to-cell contact. Contact allows cells to respond to the "feel" of neighboring cells, via cell adhesion molecules, and to exchange messenger molecules through cell-to-cell portals called gap junctions. With the help of proper communication, appropriate cells proliferate when new cells are needed, and when enough new cells have been produced, cell division stops.

Cancer cells are the descendants of a normal cell in which something has gone wrong. In this normal cell, some kind of internal or external stress causes a mix-up in its genetic code (its DNA). This event is said to "initiate" the cell to a precancerous state. After its DNA has been damaged, the cell withdraws from close communication with its neighboring cells. Interrupted cell-to-cell communication is a common result of DNA damage or other forms of cellular damage. Separated from the regulatory controls of its community, it is now at the mercy of its environment. Let us say that the environment around this cell contains a promoting agent, which is a compound that stimulates cell proliferation. In response to the promoting agent, this precancerous cell divides to produce daughter cells, and these daughter cells divide to produce more daughter cells, and so on. All are proliferating only in response to the promoting agent. The promoting agent may be a chemical foreign to the body, or it could come from a natural process such as inflammation. One day, the worst occurs. The genetic instabilities passed down through the generations finally result in one cell that becomes capable of self-stimulation, and on this day an autonomous cancer cell is born. This cell no longer requires the promoting agent to stimulate its proliferation. The role of the promoting agent is made obsolete by the cell's ability to make proteins such as growth factors that stimulate proliferation.

This original cancer cell divides to produce daughter cells, these cells also divide, and soon there is a population of cancer cells. As they divide, they develop malignant characteristics, such as the ability to invade and metastasize. They also develop other characteristics that help assure survival, for example, the ability to evade the immune system, to mutate when faced with adverse conditions, and to induce the growth of new blood vessels through the process called angiogenesis. The development of these characteristics marks the third stage in carcinogenesis, the first two stages being initiation and promotion, respectively. In this book, I use the term progression to refer to both the third stage of carcino-genesis proper and to the entire postpromotion period of the cancer's life. This correctly implies that progression is an ongoing, evolving process.

Compared to normal cells, cancer cells have lost touch with their neighboring cells, their community purpose, and even largely with one another. They are a race of self-serving, easily adaptable cells, whose proliferation continues with the slightest provocation. They use more than their fair share of resources, live longer than their fair share of time, and produce more than their share of offspring. In short, they exhibit the two deadly characteristics of cancer: uncontrolled proliferation and uncontrolled spread.

SEVEN STRATEGIES FOR CANCER INHIBITION

To be clear, not all cancers develop exactly as in the scenario above. This scenario is common, however, and within it lies the foundation for all our discussions on cancer inhibition. From it, we can identify seven clusters of procancer events:

1. Induction of genetic instability. Each cancer cell carries within itself genetic instability, and this instability increases the chances the cell will be able to mutate as needed to adapt to its environment.

2. Abnormal expression of genes. In essence, the function of genes is to make proteins—a process called gene expression. When they are expressed, some genes produce proteins that inhibit cancer progression, and others produce proteins that facilitate it. In cancer cells, abnormal expression of genes occurs, resulting in too few proteins that inhibit cancer and too many that facilitate it.

3. Abnormal signal transduction. Signal transduction is the movement of a signal from outside the cell toward the cell's nucleus, where it can stimulate proliferation or other activities. One important source of external signals comes from growth factors. Growth factors are soluble molecules that bind to specific receptors on the cell's surface and stimulate the cell's activities. A second source of external signals comes from cell adhesion molecules (CAMs). Cells interact with their environment through CAMs located on their surface. Cell adhesion molecules are proteins that act like fingers to regulate the degree of contact with other cells and tissues and inform cells of their surroundings. Other factors are also involved in signal generation and signal transduction. For example, cancer cells can produce their own growth factors, thereby allowing self-stimulation; they can produce extra receptors for growth factors; and they can produce free radicals, which can make growth factor receptors more responsive to stimulation.

4. Abnormal cell-to-cell communication. By decreasing their contact with normal cells, cancer cells are freed to act independently. As mentioned previously, cell-to-cell communication occurs via portals between adjacent cells (gap junctions) and through cell adhesion molecules. Normal cell-to-cell communication through gap junctions maintains homeo-stasis and discourages cancerlike behavior. Normal CAM activity keeps cells in place and prevents signal transduction that may be initiated by abnormal CAM activity.

5. Induction of angiogenesis. Angiogenesis is the growth of new blood vessels toward and within tumors (or other tissues). Solid tumors require angiogenesis in order to grow. Tumors need blood vessels to supply oxygen and nutrients, and the blood vessels created by angiogenesis provide the channel by which tumor cells metastasize to distant locations.

6. Invasion and metastasis. Tumors can spread both locally, via invasion of adjacent tissues, and distantly, via metastasis through the blood and lymph circulation. The spread of cancer, along with uncontrolled proliferation, is a central hallmark of malignancy.

7. Immune evasion. Cancer cells shield themselves from immune attack, thereby evading destruction; they can hide from immune cells by employing various camouflaging techniques or can produce immu-nosuppressive compounds that impair the ability of immune cells to function.

These seven event clusters provide the targets for the anticancer strategies laid out in this book. Each of the seven clusters of procancer events is illustrated in Figure 1.1.

Since each of these seven clusters is a target for therapy, we can identify seven strategies for cancer inhibition. Keep in mind that natural compounds can be used to carry out each of these seven strategies and that the best results will be seen when all seven are used together. The seven strategies are as follows:

1. Reduce genetic instability. Genetic instability is aggravated by oxidative stress (stress caused by free radicals). Cancer cells exist in an oxidative environment, and although such an environment kills some cells, many continue to survive. As oxidative stress increases, the declining population of surviving cells exhibits greater instability and higher mutation rates, in theory eventually producing more

Figure 1.1

Seven Clusters of Procancer Events

Figure 1.1

Seven Clusters of Procancer Events

aggressive and successful cancers. Thus one way of reducing genetic instability is by reducing oxidative stress. Other possible means of reducing genetic instability are discussed in Chapter 2.

2. Inhibit abnormal expression of genes. One way that gene expression can be normalized is through modifying the activity of transcription factors. Transcription factors are proteins that act as switches in the nucleus to turn on gene expression. Genes that inhibit cancer progression are commonly underexpressed in cancer cells, and genes that facilitate cancer are commonly overexpressed. Therefore, cancer can be inhibited by normalizing the activity of those transcription factors that control the expression of these genes. The use of natural compounds to affect transcription factors is discussed in Chapter 5.

3. Inhibit abnormal signal transduction. The movement of a signal from outside the cell toward the nucleus relies on several proteins (including kinase enzymes and ras proteins, discussed later), and so signal transduction can be inhibited by blocking the actions of these proteins; using natural compounds for this purpose is discussed in Chapter 4. Signal transduction is a normal process needed by healthy cells, but in cancer cells the volume of signal transduction is excessive, and the signals that flow favor proliferation and spread. Thus the intent is not to eliminate signal transduction but to bring it down to normal levels.

4. Encourage normal cell-to-cell communication. Normal cell-to-cell communication can be fostered by improving gap junction communication and by normalizing CAM activity. Natural compounds that encourage normal cell-to-cell communication are discussed in Chapter 6.

5. Inhibit tumor angiogenesis. Like signal transduc-tion, angiogenesis is a normal process; it is needed during wound healing and in other situations. An-giogenesis in tumors, however, unlike that in normal conditions, is uncontrolled and ongoing. Our intent then is not to eliminate angiogenesis but to normalize its occurrence by normalizing the factors that control it. Angiogenesis is most successful if certain chemicals called angiogenic factors are present, as well as certain environmental conditions, such as hypoxic (low-oxygen) ones. Cancer can be inhibited by blocking the release or action of angiogenic factors or by otherwise altering the local environment to inhibit tumor angiogenesis. Natural compounds that inhibit tumor angiogenesis are discussed in Chapters 7 and 8.

6. Inhibit invasion and metastasis. Invasion requires enzymatic digestion of the healthy tissue surrounding the tumor. It also requires the migration of tumor cells. Invasion can be reduced by inhibiting enzymes that digest local tissues, by protecting normal tissues from the enzymes, and by reducing the ability of tumor cells to migrate. Natural compounds that inhibit invasion are discussed in Chapter 9. Metastasis requires that cells detach from the primary tumor, en-zymatically digest blood vessel walls to gain access to and exit from the blood circulation, and evade the immune system while in the circulation. Thus metastasis can be checked by inhibiting any one of these processes. Natural compounds that do so are discussed in Chapter 10.

7. Increase the immune response. The immune response against cancer cells can be increased by stimulating the immune system and by reducing the ability of cancer cells to evade immune attack. Both actions are best taken in tandem, since without prevention of immune evasion, immune stimulation will have little benefit; healthy, vital immune cells can destroy cancer cells, but only if the cancer cells can be recognized as foreign to the body. Chapters 11 and 12 discuss the use of natural compounds to stimulate the immune system and inhibit immune evasion.

When natural compounds are used in these strategies, some will directly inhibit cancer cells, causing them to die, revert to normalcy (a process called differentiation), or just stop proliferating. Others will inhibit cancer progression indirectly by inducing changes in the local environment that are unfavorable to angiogenesis, invasion, or metastasis. This might include, for example, inhibiting the enzymes produced by cancer cells that allow invasion. Thus we can group natural compounds into two broad categories of action: those that act directly on cancer cells to inhibit proliferation (called direct-acting compounds) and those that inhibit cancer progression by affecting tissues or compounds outside the cancer cell (called indirect-acting compounds). In addition, we can add a third category: compounds that inhibit cancer through stimulating the immune system. Although immune attack produces a direct cytotoxic effect against cancer cells, immune stimulants themselves generally do not.a

USING NATURAL COMPOUNDS IN COMBINATION

From the above discussions we begin to see why using combinations of natural compounds is so important. A well-designed combination of compounds will target all seven clusters of procancer events, a task a single compound could not perform. In addition, since most natural compounds inhibit several procancer events, a large combination of natural compounds will redundantly target all seven clusters of events. Redundant targeting is useful in that if one compound fails to perform its task, another is available to back it up. Redundancy is in fact common in stable systems. In nature, for example, biologic diversity provides redundant controls of insect pest populations.

a By convention, we say that a cytotoxic effect occurs if cells are killed and a cytostatic effect occurs if cells are kept from proliferating. Cytotoxic and cytostatic effects can be readily studied in vitro. However, many in-vitro tests do not actually differentiate between the two, and in this book, I use the term cytotoxic to refer to both cytotoxic and cytostatic effects unless stated otherwise.

Synergism in Combinations

The use of combinations provides one other important advantage: the possibility of additive or synergistic interactions. (For convenience, unless stated otherwise, the term synergism is used loosely to refer to either additive or synergistic interactions.) Synergism is important because it allows lower and safer doses of each compound to be used; in fact, it is more than important, it is required for our purposes. As discussed in Chapter 13, most direct-acting natural compounds, if used alone, would require excessive and unsafe doses to inhibit cancer. My colleagues and I have conducted preliminary research on large combinations of natural compounds, and other groups have conducted research on small combinations of natural compounds. The research as a whole strongly suggests that when used in combination, natural compounds can produce synergistic effects in vitro.b If synergistic effects are also produced in vivo, and there is reason to believe they would be, such interactions would make essentially all direct-acting natural compounds discussed in this book potentially effective when used at safe doses. This is true even if the interactions are additive rather than truly synergistic.

That most direct-acting natural compounds discussed here require synergism to be effective at safe doses is, ironically, related to the reason they are included in this book—they are milder than most chemotherapy drugs and less apt to produce adverse effects. Most of these compounds are on the average (geometric average) about 21-fold less toxic than most chemotherapy drugs.1'c Furthermore, the most toxic natural compound is about 270-fold less toxic than the most toxic chemotherapy drug.d However, they are also less toxic to can-

b In vitro, literally, "in glass, " refers to studies conducted in the test tube, and in vivo, literally, "in life, " refers to studies conducted in animals.

c The geometric average is used at a few places in this book. It is the average of a group of n numbers as calculated by (x1 -x2 • xj1/n and is near the arithmetic average when the numbers are evenly dispersed. It is used instead of the arithmetic average primarily when the arithmetic average is heavily influenced by a relatively small number of extreme outlying points. In these cases, the geometric average can be a more meaningful descriptor.

d The geometric average of the oral lethal dose (LD50) in rats predicted for 20 of the natural compounds discussed is 1.5 g/kg (see Table 1.4 in Appendix I). This is in contrast to the 21 -fold lower LD50 geometric average of 72 mg/kg for a representative sample of 17 chemotherapy drugs (NCI data obtained from the reference given). Furthermore, the lowest LD50 for the natural compounds is 270 mg/kg, whereas the lowest LD50 for the chemotherapy drugs is 1 mg/kg. The equivalent human doses are about 4.4 grams and 16 milligrams, respectively. Sixteen milligrams is a very small amount of material!

cer cells than most chemotherapy drugs. Most of the natural compounds discussed are active in vitro at concentrations of about 1 to 50 mM. A target concentration of 15 mM is used in most of the dose calculations in later chapters. In contrast, standard chemotherapy drugs tend to be active at much lower concentrations. Based on a simple analysis of data from the National Cancer Institute, the average effective concentration (IC50) for nine common chemotherapy drugs was 0.48 mM.2'a This is roughly 30-fold lower than the active concentrations of the natural compounds considered here.

Therefore, high concentrations are required to inhibit cancer, and this requires large doses. For roughly 65 percent of the direct-acting natural compounds, such high doses are likely to cause adverse effects. As previously stated, however, synergistic interactions will make essentially all of these direct-acting natural compounds potentially effective when used at safe doses.

Designing Combinations

Chapter 13, the introductory chapter to Part III, discusses how natural compounds might be chosen for use in combinations, but an overview of the process can provide some context for how the compounds discussed in Parts I and II might be used. Although compounds could be chosen for the particular procancer events they inhibit, it is more practical and probably just as useful to consider the design of combinations as a process of elimination; one that can be based on five constraints:

• Using a large number of compounds to assure redundancy, facilitate synergism, and target all seven clusters of procancer events. An ideal number of compounds might be 15 to 18, which means only about half the compounds discussed in this book would be used.

• Choosing compounds so that all three categories (direct acting, indirect acting, and immune stimulants) are represented. Since each compound tends to inhibit multiple procancer events, by using a large combination and compounds from all three categories, it is likely that all seven clusters of procancer events will be inhibited.

• To assure diversity, if a pair or group of compounds appear to act very similarly, using only one of the pair or a few of the group.

• Eliminating compounds that are not practical for whatever reason. For example, some compounds a These are actually GI50 values rather than IC50 values. The GI50 is an adaptation of the IC50 by the National Cancer Institute to correct for cell count at time zero. The average value quoted here is based on data from sensitive cell lines.

discussed may not be commercially available at present.

• Eliminating compounds that do not appear to have strong anticancer effects relative to the other natural compounds.

The above process of elimination can be used to guide the initial design of a combination; after which it could be refined to meet the needs of a particular patient.

INTRODUCTION TO THE COMPOUNDS

Of the hundreds of natural compounds known to be active against cancer (at least in vitro), this book focuses primarily on only 38. This is clearly a very small percentage. Narrowing the focus was necessary for several reasons. For one thing, few data are available for most of those known to be active. For another, many would not be safe for human consumption. For these and other reasons, a set of criteria was used to narrow the focus; compounds were included that met most, if not all, of the following:

• They are not already approved as prescription drugs by the U.S. Food and Drug Administration. Furthermore, they are not patented or trade secret products, so their composition is known and they are not licensed to one manufacturer. Although such products can be useful, I will leave it to the manufacturers to argue their benefits.

• The compounds or their plant sources have a history of safe human use as food or in herbal medicine traditions.

• They are active at concentrations that are achievable in humans after oral administration. In many cases, this requires them to be used in synergistic combinations.

• They are expected to be nontoxic to the patient at the required dose. Again, this may require low doses and synergistic combinations.

• They are not excessively expensive.

• They are readily available commercially or could be readily available within the next few years.

• Sound theoretical reasoning exists to support the hypothesis that they may be useful in cancer treatment. For example, the means by which they may inhibit cancer cells is understood.

• They are suitable for long-term therapy because they are safe and can be administered orally.

Preference was also given to compounds that inhibit multiple procancer events. By affecting multiple events, these compounds are more likely to inhibit a wider range of cancers under a greater variety of circumstances. The ability to inhibit multiple events also increases the chances that synergistic interactions will occur between compounds. In addition, preference was given to compounds with other desirable characteristics, such as dissimilarity to the other compounds, being of interest to the public, and being useful for instructive reasons. Although the compounds selected do include many of those already being used by cancer patients, not all in common use were included; it was not possible to discuss all compounds that may be of interest.

Some of the 38 compounds do not look as promising at this time as others. In particular, flaxseed, EGCG (from green tea), and hypericin (from St. John's wort) are all associated either with some uncertainties in safe or effective doses, or they are not likely to produce a strong anticancer effect relative to the other compounds. However, they are still discussed because of public interest in them, because it is instructive to see the problems associated with them, and because new research may remove the uncertainties and place them in a more promising light.

The primary compounds of interest are listed in Table 1.1. (Additional natural compounds are mentioned from time to time, but only in passing.) A detailed description of each is provided in Part III, and chemical information for most, including structural diagrams, is given in Appendix A. Note that thousands if not millions of natural compounds exist; but most of these do not inhibit cancer, and some are not safe for human ingestion. To avoid confusion, the term natural compound in this book refers only to those compounds listed in Table 1.1, unless specifically stated otherwise.

Most of the compounds in the table are available through supplement or herbal suppliers. They are formulated as pills, powders, liquids, or whole plant parts. Some formulations contain crude plant material and some contain extracts of various potencies. A small number are not yet commercially available, while a larger number are not yet available in the preferred form of high-potency standardized extracts. Such concentrated extracts are standardized to contain a specific amount of the active ingredient(s). It is likely that most will be available as standardized extracts in the future.3

As discussed earlier, natural compounds can be divided into three groups: those that inhibit cancer cell proliferation directly, those that act by indirect means to inhibit cancer progression, and those that stimulate the a To learn about the latest availabilities, or to inform us of availability, please visit our web page at www.ompress.com.

immune system. Table 1.2 lists them according to category. Of course, many compounds have multiple actions, and they could be placed in more than one category. Placing these in a single category is a judgment call. For example, melatonin has a beneficial effect on the immune system and can directly inhibit some types of cancer cells. The same could be said of ginseng. Here melatonin and ginseng are both characterized as immune stimulants. Judgment calls aside, the arrangement of natural compounds in this table is still a useful starting point for conceptualizing their behavior.

The natural compounds listed in Table 1.1 have received different amounts of in-vitro, animal, or human study. For some compounds, only a few studies involving cancer cells have been completed, whereas for others, there have been many dozens. Because a compound has received few studies does not mean it is ineffective. By the same token, because a compound has received many studies does not indicate it is highly effective. In fact, some studies could have reported negative results. Still, the number and type of studies roughly indicate how well the anticancer effect has been characterized. In this regard, human studies are, of course, the most useful in predicting effects in humans. Animal studies are less useful than human studies, and in-vitro studies are less useful still. On the other hand, in-vitro and animal studies can be the most useful in determining mechanisms of action. Thus all three types are useful and necessary.

To provide a rough estimate of how well the anticancer effects of different compounds have been characterized, compounds are ranked in Table 1.3 according to a scoring system that gives one point for each in-vitro study, three points for each animal study, and nine points for each human study. Although somewhat arbitrary, this system is useful in providing a very general ranking of how well different compounds have been characterized. The number of in-vitro, animal, and human studies listed is an estimate based on searches of the MEDLINE database of the National Library of Medicine. These searches covered the period between the mid-1960s and, depending on the compound, September-December of 2000. Other studies may exist that are not indexed in MEDLINE, and of course, new studies are being indexed on a regular basis. Also note that the studies listed do not include those that did not use cancer cells. For example, general studies on the inhibition of invasion enzymes are not listed unless the study specifically measured the ability of a compound to inhibit the invasion of cancer cells. Neither do they include cancer prevention studies or studies in which compounds were used in combination with chemotherapy drugs or radiotherapy (except for glutamine and

TABLE 1.1 NATURAL COMPOUNDS OF INTEREST

COMPOUND

BRIEF DESCRIPTION

Anthocyanidins

Red-blue flavonoid pigments found in berries and other plants.

Apigenin

A flavonoid found in many plants.

Arctigenin

An active compound in burdock seeds (Arctium lappa).

Astragalus membranaceus

An herb used as an immunostimulant in Chinese herbal medicine.

Boswellic acid

An active compound in frankincense (Boswellia carteri or B. serrata).

Butcher's broom (Ruscus aculeatus)

An herb used to treat venous insufficiency.

Bromelain

A proteolytic enzyme obtained from pineapples.

Caffeic acid phenethyl ester (CAPE)

An active compound in bee propolis.

Centella asiatica

A tropical herb used to treat skin conditions. Also known as gotu kola.

Curcumin

An active compound in the spice turmeric (Curcuma longa).

EGCG (epigallocatechin gallate)

An active compound in green tea (Camellia sinensis).

Eleutherococcus senticosus

An herb with immunostimulant properties. Also known as Siberian ginseng and Acanthopanax senticosus.

Emodin

An active compound in the herb Polygonum cuspidatum and in other herbs.

EPA and DHA (eicosapentaenoic and docosahexaenoic acids)

Omega-3 fatty acids that are found together in fish oil. Of the two, EPA is of primary interest here.

Flaxseed (Linum usitatissimum)

A seed used as food and as a fiber agent.

Garlic (Allium sativum)

A medicinal herb and common flavoring agent. We are interested here mostly in its primarily metabolite, DADS (diallyl disulfide).

Ganoderma lucidum

A mushroom used in Chinese herbal medicine that has immunostimulating properties.

Genistein and daidzein

Isoflavonoids found in legumes such as soy.

Ginseng (Panax ginseng)

An herb with immunostimulant properties.

Glutamine

An amino acid that acts as a fuel for intestinal cells.

Horse chestnut (Aesculus hippocastanum)

An herb used to treat venous insufficiency.

Hypericin

An active compound in the herb St. John's wort (Hypericum perforatum).

Luteolin

A flavonoid found in many plants.

Melatonin

A hormone that is used clinically to induce sleep.

Monoterpenes

Fragrant essential oils. Monoterpenes include limonene, perillyl alcohol, and geraniol.

Parthenolide

An active compound in the herb feverfew (Tanacetum parthenium).

Proanthocyanidins

Flavonoids that are used to treat venous problems and other conditions.

PSP and PSK

Mushroom extracts (obtained from Coriolus versicolor) that have immunostimulant properties.

Quercetin

A flavonoid found in many plants.

Resveratrol

A compound found in wine and grapes, in the herb Polygonum cuspidatum, and in other herbs.

Selenium

A trace element that plays a role in the body's antioxidant system.

Shiitake (Lentinus edodes)

A mushroom that has immunostimulant properties.

Vitamin A (retinyl esters, retinol, and ATRA)

A vitamin important in vision, cell proliferation, and immune function. Retinol (as retinyl esters) is the dietary and supplement form of vitamin A, and ATRA (all-trans retinoic acid) is a primary active metabolite.

Vitamin C

An antioxidant vitamin that prevents scurvy and assists immune cells.

Vitamin D3 (1,25-D3)

A vitamin important in calcium uptake that has antitumor properties. 1,25-D3 is its primary active metabolite.

Vitamin E (alpha-tocopherol)

An antioxidant vitamin that protects lipid membranes. Alpha-tocopherol is the form of vitamin E most used as a supplement.

PSP/PSK, which have primarily been studied in combi- Table 1.3 shows some interesting trends. First, there nation with chemotherapy). are a few compounds with very low scores, some having received only one study. Many of these low scores are

TABLE 1.2 THERAPEUTIC CATEGORIES OF NATURAL COMPOUNDS

CATEGORY

COMPOUNDS

Immune stimulants

Astragalus, bromelain, Eleutherococcus, Ganoderma, ginseng, glutamine, melatonin, PSP/PSK, shiitake

Indirect-acting compounds

anthocyanidins, butcher's broom, horse chestnut, proanthocyanidins, vitamin C

Direct-acting compounds

apigenin, arctigenin, boswellic acid, CAPE, Centella, curcumin, EGCG, emodin, EPA/DHA, flaxseed, genistein and daidzein, garlic, hypericin, luteolin, monoterpenes, parthenolide, quercetin, resveratrol, selenium, vitamin A, vitamin D3 (1,25-D3), vitamin E

not surprising. For example, the three lowest-ranked compounds are indirect-acting ones. Most of the indirect-acting compounds listed in Table 1.2 have not generally been thought of as potential cancer treatment agents because they do not inhibit cancer cells in vitro at reasonable concentrations or they do not occur in the plasma at high concentrations after oral administration. A prime example would be horse chestnut. This book is among the first to argue that such compounds may still be useful in cancer treatment through their ability to protect the vasculature and reduce edema. Centella is another compound low on the list, having received only one in-vitro study and one animal study. Compounds quite similar to Centella have received more study, however, and it is reasonable to suppose it will produce comparable results. Clearly, all compounds in the list are still experimental, but those at the bottom of the list with a score of less than about 10, should be considered extremely so, relative to the others.

At the top of the list, a few compounds have received much study, including study in humans. For example, about 54 human studies have been conducted on PSK, and a relatively high number have also been conducted on melatonin. At least some of the human studies referenced in this list were randomized, placebo-controlled, double-blind studies. Thus it would be incorrect to say that natural compounds have not been studied in humans. Some clearly have been, but in all cases, additional study is still necessary, especially on their use in combinations.

PRACTICAL CONSIDERATIONS ON EFFECTIVE CONCENTRATIONS AND SCALING OF DOSES

We now turn to two practical considerations: identifying effective concentrations and scaling doses from animal studies. Both are mentioned here to give some context for understanding the concentrations and doses reported later in Parts I and II.

Effective Concentrations

Concentrations in this book are most commonly reported in micromolar ((M) units, the number of micromoles per liter of solution.3 The text may indicate, for example, that a compound inhibits the proliferation of cancer cells at 30 (M. Commonly, this will be specified in the text by saying that the IC50 of a compound is 30 mM. The IC50 is the in-vitro concentration that inhibits the noted activity (such as cell proliferation) by 50 percent. Scientists use the IC50 as a convenient indicator of the concentration at which the compound is considered active.

To make sense of the reported concentrations, the reader should keep a few points in mind. First, most direct-acting natural compounds are active against cancer cells in vitro within the concentration range of about 1 to 50 mM. Second, for most of these compounds it is difficult to achieve in-vivo plasma concentrations much greater than 1 to 15 mM. Therefore, assuming that the concentration that is effective in vitro will also be effective in vivo, the required concentrations in vivo are often higher than the achievable concentrations. In other words, when used alone, the required dose for many compounds is higher than the safe dose. Although this is a problem if natural compounds are used singularly, it is reasonable to expect it will not be a problem if they are used in synergistic combinations. As stated above, synergistic interactions would make essentially all direct-acting natural compounds discussed potentially effective when used at safe doses. We can state as a general rule of thumb that compounds active in vitro at concentrations of 50 mM or less have good potential to be useful in vivo when they are used in synergistic combinations.

a A 1 micromolar (M) concentration is equal to 1x10-6 moles per liter, a 1 millimolar (mM) concentration is equal to 1x10-3 moles per liter, and a 1 nanomolar (nM) concentration is equal to 1x10-9 moles per liter. Research papers sometimes use the unit of micrograms/milliliter ((g/ml). To convert (g/ml to (M, multiply by 1,000 and divide by the molecular weight. Molecular weights for most natural compounds are provided in Appendix A.

A few direct-acting compounds, specifically the monoterpenes, vitamin E, and diallyl disulfide (an active garlic compound), are effective at concentrations of 100 mM or greater. These compounds are still useful due to their favorable pharmacokinetic profiles, however. High plasma concentrations can be safely achieved after oral dosing. At the other extreme, only very low plasma concentrations can be achieved in vivo for a few other compounds, but this is also not a problem, since these compounds are also active at relatively low concentrations. An example is 1,25-D3, the active metabolite of vitamin D3.

Scaling Doses from Animal Studies

It is important to note that a dose (per kilogram body weight) that is effective in animals is not the same as the dose that would be effective in humans. Animals metabolize drugs at a different rate and sometimes in a different way than humans. In general, the rate of drug metabolism is related to body mass. A small animal will metabolize and excrete drugs much more quickly than a human. For this reason, the effective dose (per kilogram body weight) in an animal will be greater than that for a human. Stated another way, the dose required to produce a given plasma concentration in a small animal will be larger than the dose needed to produce the same plasma concentration in a human.

The scaling of doses between animals and humans is an uncertain science, and this is especially true of scaling oral (as opposed to intravenous) doses. In addition, note that a compound found effective in animals would not necessarily be so in humans. Nonetheless, animal studies are still useful to suggest compounds that may be effective in humans, and despite the uncertainties, scaling of animal doses to humans is commonly done.

Several generic methods have been devised to scale doses from animals to

TABLE 1.3 RANKING BASED ON THE NUMBER OF STUDIES CONDUCTED

COMPOUND

IN VITRO

ANIMAL

HUMAN

SCORE

PSP and PSK

16

39

54

619

EPA and DHA

57

66

12

363

Melatonin

14

13

28

305

Vitamin D3 (1,25-D3)

133

27

4

250

Glutamine

7

21

17

223

Vitamin C

37

17

7

151

Genistein and daidzein

85

21

0

148

Vitamin A^

23

12

7

122

Ginseng

33

15

4

114

Bromelain

14

11

6

101

Astragalus

13

13

5

97

Selenium

35

20

0

95

Quercetin

73

4

0

85

Vitamin E*

44

5

0

59

Eleutherococcus

4

8

3

55

Monoterpenes

15

7

2

54

EGCG and green tea

29

6

0

47

Boswellic acid

8

3

2

35

Apigenin and luteolin

26

2

0

32

Ganoderma and shiitake

2

9

0

29

Curcumin

19

3

0

28

Garlic

7

7

0

28

Emodin

14

3

0

23

Resveratrol

18

1

0

21

Flaxseed

7

3

0

16

Propolis and CAPE

11

1

0

14

Anthocyanidins

6

2

0

12

Hypericin^

9

0

0

9

Parthenolide

4

1

0

7

Arctigenin

7

0

0

7

Proanthocyanidins

5

0

0

5

Centella

1

1

0

4

Butcher's broom

1

0

0

1

Horse chestnut

1

0

0

1

Includes studies in conjunction with chemotherapy. ^ Retinol or retinyl esters, but not A TRA. * Alpha-tocopherol and vitamin E succinate. § Does not include studies on photoactivated hypericin.

Includes studies in conjunction with chemotherapy. ^ Retinol or retinyl esters, but not A TRA. * Alpha-tocopherol and vitamin E succinate. § Does not include studies on photoactivated hypericin.

human dose (grams)

Equation 1.1

Figure 1.2a Interspecies Scaling Based on Acute Toxicity Data

16

)s

m

14

2

3

e

12

s

o

D

10

n

ra

m

8

X

t

n m

6

ra

>

4

¡X

LU

2

0

Figure 1.2a Interspecies Scaling Based on Acute Toxicity Data

- rat

1

y

----------

Rodent Dose (mg/kg)

200 400 600

Rodent Dose (mg/kg)

1000

Figure 1.2b Interspecies Scaling Based on Acute Toxicity Data

Figure 1.2b Interspecies Scaling Based on Acute Toxicity Data

Rodent Dose (mg/kg)

Rodent Dose (mg/kg)

humans. This book uses one common method based on data from acute toxicity studies, a method described in Appendix B. The result of this method is illustrated in Figures 1.2a and 1.2b (the latter is a blowup of the zero to 200-mg/kg dose range). A quick formula for the method is given in Equation 1.1.

This equation, like most equations and calculations used in this book, is based on a 70-kilogram (154 pound) human, a 0.2-kilogram rat, and a 0.025-kilogram mouse. Again, keep in mind that this and other scaling methods provide only a rough approximation of the human dose. To be certain of that dose, we must do human studies.

Many of the animal doses in this book are reported both as the actual animal dose and as the estimated human equivalent, and therefore the reader need not keep referring to Equation 1.1 or the figures. In some cases, only the estimated equivalent human dose is reported. For example, a 100-mg/kg dose in rats might be reported as a "1.6-gram dose, as scaled to humans." Regardless of the reporting format, every conversion made in this book is based on Equation 1.1, with modifications for route of administration as discussed below.

Since we are interested in orally administered natural compounds, animal studies using the oral route most closely mimic the intended human use and are most valuable. Although many of the animal studies reported here did use the oral route, a good number used either the intraperitoneal route (injection into the intestinal cavity) or the subcutaneous route (injection below the skin). These routes of administration are not only physically different from the oral route but usually produce different results in terms of plasma concentrations and metabolism of the compound. It is useful to convert these doses to their oral equivalents but unfortunately, this sort of conversion is also an inexact science and has little precedent in the literature. Although it can be done, the results of such conversions provide only very rough approximations of an oral dose. The methods used to make these conversions and the reasoning behind them are explained in Appendix I.

REFERENCES

1 Based on data from the U.S. National Toxicology Program online database 1999. http://ntp-server.niehs.nih.gov/

2 Based on data from the Developmental Therapeutics Program online database, U.S. National Cancer Institute. http://dtp.nci.nih.gov/

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