Use of Natural Compounds to Reduce Adverse Effects of Chemotherapy

Many chemotherapy drugs induce necrosis or apop-tosis in cancer cells by generating free radicals, but at the same time, these prooxidant mechanisms are responsible for adverse effects on normal cells. For example, doxorubicin, one of the most widely used chemotherapy drugs, induces DNA damage in cancer cells through a prooxidant mechanism. One of its primary side effects is heart damage that is also caused by its prooxidant ac-tion.9'10'11 Because doxorubicin treatment can reduce total...

Functions of Glutathione

Glutathione plays an essential role in both normal and cancer cells, and on that basis, it is worth reviewing in detail. In addition, since glutathione is commercially available and has been recommended as an antioxidant by some authors, it seems important to explain why this book does not support its use. Adequate glutathione concentrations are crucial to cells because glutathione is the most abundant low-molecular-weight thiol antioxidant they contain. In this regard, glutathione's role is...

Estimating Allowable Dose Reductions Due to Synergism

A primary reason we are so interested in synergistic interactions is that they will allow lower doses of each compound to be used. As stated, the calculations in Part III suggest that dose reductions due to synergistic interactions are required for most direct-acting compounds, if they are to be useful. A method for estimating allowable dose reductions follows but keep in mind that it is based on results from our research, which was conducted in vitro. Translation of in-vitro data to in-vivo...

Invivo Redox Effects of Antioxidants

As with in-vitro studies, the effects an antioxidant produces in vivo are likely to be dependent on its concentration, the presence of metal ions, and the amount of other antioxidants and ROS present. In addition, the metabolism of the compound can greatly affect its redox reactivity. For example, quercetin, which shows both antioxidant and prooxidant effects in vitro, occurs in the plasma mainly in its conjugate forms (i.e., quercetin combined with glucuronic acid, a derivative of glucose)....

Immune System In Cancer Treatment

The immune system's postulated role in preventing cancer by destroying cancer cells, along with other evidence, tells us it can also help destroy cells of established cancers. Its ability to do so, referred to as antitumor immunity, involves both the innate and adaptive immune systems. For example, recent evidence suggests the immune system may be capable of detecting the protein products of oncogenes on the cell surface immune responses to the HER-2 neu protein and mutated ras and p53 gene...

Estimating Effective Doses

There are three available data types on which to base estimates for an effective dose human anticancer data animal antitumor data and a combination of pharma-cokinetic and in-vitro data. Each type has advantages and disadvantages, but all can provide helpful information. In Part III, we estimate a target dose by using as many of these types as available data allow, then we compare the doses estimated with each to corroborate their values. For most compounds, human data are not available and...

Summary of Research and Conclusions

Although Astragalus is one of the most commonly used Chinese herbs and is used extensively in Chinese hospitals for treating cancer patients (in combination with chemotherapy), relatively few studies on Astragalus are indexed in the MEDLINE database. Presumably, many more are available in Chinese journals. Because of the custom of using combinations in Chinese herbal medicine, most of the indexed studies of Astragalus are ones on herbal combinations. Some 13 in-vitro studies relate to cancer or...

Second Stage of Wound Healing

After dilation of blood vessels and formation of edema, the second stage in wound healing is immune cell migration, in particular migration of neutrophils and macrophages. Within an hour after the inflammatory response begins, neutrophils migrate toward the injury site. They are attracted partly by the previous release of prostanoids and leukotrienes. Neutrophils predominate in early stages of inflammation but tend to die off early. They are replaced by macrophages, which are large enough to...

General Information

Eleutherococcus senticosus is a shrubby member of the ginseng family. Like Astragalus, it is a common Chinese herb and is mentioned in the Shen Nong Ben Cao Jing. A complex taxonomic controversy exists regarding similarities between the Eleutherococcus and Acanthopanax species, however, and it is not certain that the Shen Nong Ben Cao Jing was actually referring to Eleutherococcus senticosus. Some scholars have combined Eleutherococcus and Acanthopanax into the same (Eleutherococcus) genus,...

Invitro and Animal Studies

Most of the in-vitro and animal studies conducted on bromelain and polyenzyme therapies focused on their effects on immune function and or inflammation these were discussed in Chapter 12. The evidence indicates that immune modulation and anti-inflammatory effects may account for a large part of any anticancer effects seen in animals or humans. Only three in-vitro studies have investigated the direct effects of bromelain on cancer cells. One study reported that bromelain (at 5 to 8 pM) inhibited...

Vitamin C And Antioxidants

We now look at compounds that derive from saccha-rides, or sugars. Saccharides are the closest relatives to glucose, the starting material for all botanical compounds in fact, glucose itself is a saccharide. The term saccharide refers to any carbohydrate, but is especially applied to the simple sugars monosaccharides, disac-charides, oligosaccharides, and polysaccharides.3 This chapter discusses vitamin C, which is a monosac-charide derivative structurally similar to glucose (compare Figures...

Nasopharyngeal Cancer

In a study of 272 patients with nasopharyngeal cancer, half were treated with radiation therapy and half with radiation combined with the formula Yi Qi Yang Yin Tang. The five-year relapse rate was 68 percent lower for patients who received the combined therapy (12 percent versus 38 percent). Three- and five-year survival rates also significantly improved in the group that had the combined treatment (87 percent versus 66 percent at three years, and 67 percent versus 48 percent at five years).70...

Adhesion Proteins And Cancer Cell Migration

From the above, it should be clear that production of hyaluronidase or collagenase by tumor cells or other adjacent cells can lead to matrix digestion, which subsequently allows tumor cell invasion. One more aspect of this process is the mechanism by which tumor cells walk during invasion. It is useful to consider the close analogy between the migration of immune cells toward an infection site and the movement of cancer cells away from the central tumor. In both cases, the cells rely on the...

Using Combinations Of Polysaccharides

The dose required for a variety of polysaccharides may range from 2 to 9 grams per day. To achieve this without using excessive amounts of any single herb, combinations of herbs can be used. For example, a decoction comprised of 30 grams of Astragalus and 15 grams of Eleutherococcus contains a polysaccharide dose of roughly 3 grams, assuming that each herb contains about 7 percent polysaccharides. Herbs can also be combined with semi-purified polysaccharides like PSK to achieve the desired...

P53 Protein as a Transcription Factor

The p53 gene acts as the guardian of DNA, and in the event of DNA damage it performs three crucial functions. First, it halts the cell cycle, for example, by in- a Peptides consist of a few amino acids joined together and proteins consist of manyjoined together. creasing the expression of the p21 gene. Second, it initiates DNA repair. Third, if the DNA cannot be repaired, it initiates apoptosis, for example, by increasing the expression of the Bax gene. To perform these diverse functions, the...

Macrophages and Cancer

Like NK cells, macrophages do not recognize foreign antigens. In addition, they do not recognize self-proteins. Their activation mechanisms are poorly understood but may involve receptors for certain carbohydrates, complement, and other proteins. Although bacterial products are among the most potent activators, macrophages can also be activated by contact with tumor cells. Macrophages destroy foreign substances by phagocytosis (ingestion) by secretion of proteases, hydrogen peroxide, or other...

Triterpenoids

Although many triterpenoids inhibit cancer cell proliferation in vitro, they are not generally thought of as anticancer compounds. Rather, triterpenoid-rich plants have been used in herbal medicine traditions more for their anti-inflammatory effects and their protective effects on the vascular system. We included them here partly for these characteristics, which may inhibit angiogenesis (see Chapters 7 and 8) as well as invasion and metastasis (see Chapters 9 and 10). In addition, some...

Inhibition Of Cancer By Omega3 Fatty Acids

We have seen that intake of saturated and omega-6 fatty acids may promote tumor progression through a variety of mechanisms. Now we turn to the potential of omega-3 fatty acids, primarily EPA and DHA as found in fish oil, to inhibit tumor development and metastasis. Many of the successful animal studies used high doses of EPA or fish oil, which produced anticancer effects through a prooxidant mechanism. Although these results are not very relevant to our interests the doses are excessive and we...

Animal Studies

In animal studies, subnormal melatonin concentrations TABLE 22.10 POTENTIAL ANTICANCER ACTIONS OF Chapter 2 Mutations, Gene Expression, and Proliferation Chapter 3 Results of Therapy at the Cellular Level Chapter 5 Transcription Factors and Redox Signaling Chapter 6 Cell-to-Cell Communication Chapters 9 and 10 Invasion and Metastasis have facilitated the growth of various cancers. example, removing the pineal gland in hamsters increased the progression rate of melanoma.228 In others, oral...

First Stage of Wound Healing

During the first stage of inflammation, blood vessels dilate and vascular permeability increases. That is, cap illaries become leaky and allow certain blood components to escape into the extracellular space. This creates localized swelling, or edema. Increased vascular permeability is a very important requirement for angiogenesis and in fact may be its rate-limiting step. Increased vascular permeability is initially induced by the release of histamine from circulating immune cells (basophils)...

Migration Through The Circulation

Once cells detach from the tumor and enter the blood, the second step in metastasis is the migration of tumor cells through the circulation. A significant percentage of migrating tumor cells die in this step due to forces present in the circulation. The most important of these forces may be the immune system. Although there is considerable evidence that the immune system plays a prominent role in inhibiting metastasis, the issue is complex, and no simple correlation between immune status and...

Stimulation Of Cancer Progression By Saturated And Omega6 Fatty Acids

In 1982, the National Research Council identified fats (referring to saturated and omega-6 fatty acids) as the single dietary component most strongly related to cancer risk. One of their recommendations was that fat intake be reduced to no more than 30 percent of total dietary calories.2 The average American now consumes approximately 33 percent of dietary calories as fat.3,4 This is down slightly from 36 to 40 percent in the late 1970s. The Council report was based on early studies that...

Background For Parts I And Ii

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...

Cell Adhesion Molecules

Cell adhesion molecules are specialized proteins located on the outside of the plasma membrane. Due to recent advances in laboratory techniques, research on CAMs has flourished and the pivotal role they play is understood more completely. Through interactions with the ECM and other cells, CAMs regulate proliferation, architecture, cell migration, differentiation, apoptosis, angiogenesis, and invasion.1-5 We can think of CAMs as the fingers of a cell, but instead of 10 fingers, cells have many...

Innate And Adaptive Immunity

Without an immune system we would quickly fall prey to the plethora of viruses, bacteria, and parasites that live within and around us. The immune system is a multi-layered defense system. In its broadest sense, it includes physical barriers, such as the skin and the lining of the gastrointestinal tract chemical barriers, such as stomach acid microbial barriers, such as beneficial intestinal microflora and the immune system proper (immune cells, antibodies, and so forth). This chapter focuses...

Conclusion

Lipid-soluble vitamins represent a unique class of potential anticancer compounds. Two vitamins, A and D3, in the form of their active metabolites, have the ability to enter the nucleus and directly affect gene transcription. Since few other natural compounds discussed here can do this, when used in combinations they offer valuable diversity. The effects of vitamin E are limited primarily to the plasma membrane. Since the membrane's characteristics govern antigen presentation, the uptake and...

Flavonoids and Immune Function

The effects of flavonoids on the immune system are complex and poorly understood. Depending on the conditions, flavonoids may inhibit, assist, or have no effect on immune function. Their effects on immune function are due to their ability to inhibit eicosanoid-mediated inflammation, histamine-induced inflammation, PTK or PKC activity, cell motility, or several of these. Many flavonoids can impede leukocyte proliferation and function in vitro. For example, genistein can inhibit T-cell and...

Immunoglobulin Superfamily of Adhesion Molecules

The immunoglobulin superfamily of cell adhesion molecules contains the evolutionary precursors of the immune system. The most studied groups of immu-noglobulin adhesion molecules are N-CAMs (found in nervous tissue), intercellular cell adhesion molecules (ICAMs), vascular cell adhesion molecules (VCAMs), and platelet endothelial cell adhesion molecules (PE-CAMs). All of these play a role in assisting immune cells and cancer cells to arrest at a target location on the vascular wall. The...

Use of Immunotherapy in Conventional Cancer Medicine

We now look at how immunotherapy has been used in conventional cancer medicine. From this discussion, we obtain ideas on how natural compounds might be used to produce some of the same effects on the immune system, and we also see how the use of natural compounds differs from that of most conventional immunotherapy agents. The primary distinction between conventional immunotherapy agents and natural immunostimulant compounds is that the former tend to be cells or cyto-kines activated or...

Use of Natural Compounds to Increase Drug Accumulation or Reduce Drug Resistance

Cancer cells are better able to adapt to stress than normal cells. In cancer treatment, this adaptation results in tumor cells that develop resistance to chemotherapy drugs, which is a primary obstacle to treatment success. Cancer cells often develop resistance not only to the drug to which they have been exposed but also to other drugs and noxious agents they have not encountered. Development of this nonspecific or multidrug resistance might be likened to a battleship crew placed on battle...

Oral Clearance Values in Dose Estimates

One of the most important pharmacokinetic parameters of a drug is its clearance (CL) because it can be used to estimate a required dose. Clearance values are not directly measured in pharmacokinetic studies they are calculated based on other values that are measured. Clearance refers to the theoretical volume of body fluid that is cleared of a drug per unit time, and so it represents the rate at which a drug is removed from the body. Additional information on clearance is in Appendix B, along...

Transcription Factors And Redox Signaling

Transcription factors bind to the regulatory portion of a gene and directly serve to initiate gene transcription (see Figure 2.4). In this way, they have final control over production of all proteins within a cell, and therefore they control much of a cell's behavior. In order to do their job, they must be present in sufficient quantity and must be activated to bind to their target gene. Their quantity is dependent on gene expression, since transcription factors are themselves protein products...

Estimated Therapeutic and Tolerated Doses of Vitamin D3

We do not calculate a dose estimate for 1,25-D3 using a combination of pharma-cokinetic and in-vitro data because the range of active concentrations in vitro is so large (0.01 to 1 jM). Any specific target concentration that might be chosen would be somewhat arbitrary. Consequently, we calculate dose estimates based only on animal and human studies. The estimated required dose of 1,25-D3 scaled from animal antitumor studies is not in close agreement with doses used in human studies, suggesting...

Immune Evasion by Tumors

The immune system must recognize a cancer cell as foreign before it can be destroyed. If the immune system is able to recognize a substance as foreign, that substance is referred to as being antigenic. One might expect the immune system to have trouble recognizing tumors as foreign, but in fact most tumor cells appear to be strongly antigenic. Unfortunately, recognition of a foreign substance does not necessarily ensure that an immune reaction will take place. Although most human tumor cells...

Role Of The Immune System In Cancer Prevention

Some researchers believe the immune system plays a critical role in preventing tumor development by searching out and destroying newly transformed cells. This process, known as immune surveillance, was first proposed by Ehrlich in 1909, and is supported by the following observations that associate immune depression with increased cancer risk 11'12 Children with immunodeficiency diseases have increased rates of lymphoma, leukemia, and Hodgkin's disease. Approximately 40 percent of patients with...

Supplemental Material For Chapter

This appendix contains three tables that provide supplemental material for Chapter 8, Natural Inhibitors of An-giogenesis. Table F.1 summarizes studies on the prevention of increased vascular permeability. Table F.2 summarizes studies on the ability of natural compounds to beneficially affect prostanoid and leukotriene synthesis such compounds increase production of 3-series prostanoids and 5-series leukotrienes, derived from omega-3 fatty acids, or inhibit production of 2-series prostanoids...

Sesquiterpenes

TABLE 21.12 POTENTIAL ANTICANCER ACTIONS Chapter 3 Results of Therapy at the Cellular Level Chapter 4 Growth Factors and Signal Transduction Chapter 5 Transcription Factors and Redox Signaling Chapter 6 Cell-to-Cell Communication Chapters 9 and 10 Invasion and Metastasis Inhibit hyaluronidase, beta-glucuronidase, or elastase Sesquiterpenes are compounds composed of three isoprene units. Like monoterpenes, some sesquiterpenes are found in the essential oils of plants, and like stilbenes, some...

Growth Factors And Signal Transduction

Growth factors and signal transduction play crucial roles in stimulating cell proliferation and in maintaining a cell's life. Briefly, growth factors are soluble extracellular proteins that bind to receptors on the outside of the cell. This binding elicits a chemical signal that is transferred to the cell's nucleus through a series of steps called signal transduction. The result is the activation of transcription factors and the initiation of gene expression. In addition to growth factors,...

Beta Carotene and Cancer

Even though beta-carotene is not fully covered in this book, it is of interest for several reasons it can be converted to vitamin A in vivo, it may have an effect on cancer risk, and it is widely used as a supplement. However, the results of human trials using beta-carotene are conflicting. Although high plasma levels of beta-carotene from dietary intake tend to be associated with reduced cancer risk, studies also indicated that beta-carotene supplements may actually increase cancer risk, at...

References

1 Ghoneum M, Mermel O, Williams L, et al. Susceptibility of propolis-treated tumor cells to human natural killer cell activity in vitro. Cancer Detect Prevent 1995 19(1) 106. 2 Guarini L, Su ZZ, Zucker S, et al. Growth inhibition and modulation of antigenic phenotype in human melanoma and glioblastoma multiforme cells by caffeic acid phenethyl ester (CAPE). Cellular and Molecular Biology 1992 38(5) 513-527. 3 Cheshier JE, Ardestani-Kaboudanian S, Liang B, et al. Immunomodulation by pycnogenol...

Garlic

Few animal studies have investigated the ability of garlic or its primary constituent, DADS, to alter the efficacy or safety of chemotherapy drugs. In one study, intraperitoneal administration of garlic extract (equivalent to 2 g kg of garlic) reduced the toxicity of cyclophosphamide in mice but not its antitumor effects. The effect might have been from an antioxidant mechanism, since lipid peroxidation in the liver was reduced.92 The equivalent human dose is about 19 grams of garlic by...

Overview Of Angiogenesis

Angiogenesis, the growth of new blood vessels, is needed anywhere new tissue is growing. Thus it not only occurs in benign and malignant tumors but also in wound healing, ovulation, menstruation, and pregnancy. Abnormal angiogenesis also takes place in other diseases, including rheumatoid arthritis, psoriasis, and atherosclerosis. Researchers believe that if angiogenesis can be inhibited in cancer patients, tumor growth will be inhibited or even reversed. Although inhibition of tumor...

EPADHA and Immune Function

Numerous in-vitro, animal, and human studies have reported that omega-3 fatty acids, in particular EPA and DHA, can suppress immune cell activity.110-122 Omega-3 fatty acids are therefore potent anti-inflammatory agents, and for this reason EPA and fish oil (which contains EPA) have been reported useful in reducing the symptoms of autoimmune-related diseases such as lupus, rheumatoid arthritis, psoriasis, and colitis.114,123-125 Although the exact mechanism of immune suppression is not well...

Clinical Studies With Chinese Herbal Formulas

No discussion on using natural immunostimulant compounds in cancer therapy would be complete without some consideration of the many clinical studies that have been done in China. Studies have been conducted on the combined use of chemotherapy and Chinese herbal medicine, as well as on the anticancer use of Chinese herbal medicine alone. The majority of herbal formulas used in the Chinese studies were composed primarily of immunostimulant herbs such as those in Table 12.1 (for example, most...

Safety of Synergistic Combinations

If synergistic combinations are potent in damaging cancer cells, it might seem they could also damage normal cells. The potential for such cannot be fully known until toxicity studies are done however, there is reason to think that combinations like those proposed here would be safe. For one thing, a sizable percentage of the compounds discussed show some selectivity to cancer cells in vitro, harming cancer cells more than normal ones. One can reasonably suppose this same selectivity would...

Polysaccharides

Herbal medicine, plants containing these compounds are often classified as vital energy (qi) tonics for example, Astragalus membranaceus contains high-molecular-weight polysaccharides and Panax ginseng contains saponins. Both are considered qi tonics. Actually, many herbs that stimulate the immune system include compounds from both chemical families. Eleutherococ-cus senticosus is an example. Ginseng also contains both saponins and polysaccharides, although the former are more prominent. In...

Ginseng

Some 33 in-vitro studies have been conducted on the effects of ginseng extracts or isolated saponins on cancer cells.89-93 As a whole, these suggest that ginseng or its isolated saponins can inhibit cancer cell proliferation and invasion, usually at 10 to 180 pM (for the saponins). Fifteen animal studies have been conducted on the antitumor effects of ginseng extracts or its isolated saponins.94-98 These studies suggest that the extracts and saponins can decrease tumor growth and metastasis and...

Types Of Dietary Fat And Their Sources

Fatty acids are long, straight-chain molecules of 4 to 24 carbon atoms that can be categorized as saturated, monounsaturated, or polyunsaturated. The differences between these are based on the chemistry of the molecule. Saturated fats contain only single bonds between all carbon atoms single bonds leave the maximum number of bonding sites open, which are then filled by hydrogen atoms. As a result, these compounds are said to be fully saturated with hydrogen. In contrast, mono-unsaturated fatty...

Increased Calorie Intake

Calorie intake by itself may stimulate cancer progression, and dietary fat is a major source of calories. In a study of 149 women treated for breast cancer, higher levels of total fat intake were associated with increased risks of recurrence and death. A large part of this risk increase appeared to be due to increased calorie intake.59 In rats, a 30 percent reduction of calorie intake reduced growth of transplanted human prostate cancer cells, vascular endothelial growth factor (VEGF)...

Effects of Phytoestrogens on Proliferation of Cancer Cells In Vitro

Ultimately, we are interested in the estrogenic effects of genistein on cancer cells. A number of in-vitro studies with estrogen-dependent cancer cells have been conducted, and indeed it appears that genistein and some other flavonoids can stimulate cell proliferation. Their ability to do so, however, seems to depend on the fla-vonoid concentration and the presence or absence of estrogen. In-vitro studies have shown that low concentrations of genistein (1 nM to 1 mM) can stimulate proliferation...

Topkat Model

Oxford Molecular Group (see Appendix L) has contributed predictions of rat oral toxicity for many compounds discussed in this book. These predictions were generated using their TOPKAT toxicity assessment software program, which predicts toxicity based on the two-dimensional chemical structure. This program calculates structural and electronic descriptors for each compound, compares this information against information calculated for compounds with experimentally derived toxicity values, and...

Platelet Aggregation and Fibrin Production

Platelet aggregation and fibrin production can play an important role in metastasis. Three mechanisms by which they can promote metastasis are 2,3 Activated platelets are sticky and can act as a glue to enhance adhesion of tumor cells to the blood vessel lining. Platelet-secreted growth factors like platelet-derived growth factor (PDGF) can stimulate the proliferation of tumor cells and contribute to their survival within the blood circulation. The excessive fibrin production surrounding tumor...

Estimated Therapeutic and Loael Doses of Hypericin

The estimated required dose of hypericin scaled from animal antitumor studies is not in close agreement with that calculated from pharmacokinetic and in-vitro data. This discrepancy implies the target human dose can be estimated only within a large range. The required dose scaled from animal antitumor experiments (on photoac-tivated hypericin) is about 520 milligrams per day (range of 120 to 920 milligrams), whereas the anticancer dose based on pharmacokinetic calculations is much lower. Using...

Summary of Research and Conclusions3

At least 35 in-vitro studies have reported that selenium produces cytotoxic effects on a variety of cancer cell lines.1-5, b At least 20 studies have reported that selenium produced antitumor effects in animals.6-11, c Hu- a s in all sections of Part III with this heading, the information summarized was obtained primarily from the MEDLINE database papers not indexed in MEDLINE are generally not included. The summaries are only for studies conducted with cancer cells mechanistic studies not...

Estimated Therapeutic and Loael Doses of Garlic

The estimated required dose as scaled from animal antitumor studies is in reasonable agreement with the required dose as calculated from pharmacokinetic and in- a One may wonder why relatively high doses of DADS are required when oral garlic can reduce cholesterol production in humans at moderate doses. The difference is probably because allicin concentrations in the liver are high after oral administration of garlic, and the liver is the major producer of cholesterol in the body. Allicin is...

Estimated Therapeutic and Loael Doses of Flaxseed Lignans

The estimated required dose of flaxseed scaled from animal antitumor studies does not agree with the estimated dose calculated from pharmacokinetic and in-vitro data therefore, the target human dose can be estimated only within a large range. The anticancer dose based on pharmacokinetic calculations is much higher than the one from animal studies. Using a target in-vivo concentration of 15 mM of mammalian lignans (30 mM after adjustment for conjugates), the required flaxseed dose is about 3,500...

Centella asiatica

The single study conducted on Centella reported that its extracts inhibited cancer cell growth in vitro and in animals.36 Other in-vitro and animal studies on related compounds corroborate these results. The compounds include ursolic, oleanolic, and boswellic acids, all triter-penes related to asiatic acid, a primary triterpene in Centella. Moreover, additional mechanistic studies suggest that Centella triterpenoids have the capacity to fight cancer (for example, they counteract collagenase...

Cell Detachment And Movement Into A Vessel

The initial step in metastasis is detachment of cells from the primary tumor. Once detached, cancer cells contact a blood vessel (usually within the tumor) and secrete or induce the secretion of proteolytic enzymes, which digest the basement membrane. Tumor cells then slip between the cells of the vascular lining to enter the circulation. This process of intravasation is facilitated by the poorly developed basement membranes and fragile capillaries produced within the tumor during...

Quercetin Apigenin and Genistein

Quercetin, apigenin, and genistein have all been reported to affect production or activity of multidrug resistance protein (MRP) and P-glycoprotein in vitro. In some studies, MRP and or P-glycoprotein were inhibited and in others, they were stimulated or there was a bi-phasic effect, where one or both proteins were inhibited at high concentrations and stimulated at low concentrations. Thus, based on the in-vitro studies, the effects of these flavonoids on multidrug resistance is somewhat...

Mutations Gene Expression And Proliferation

Cancer Since 1913

Mutations inheritable changes in the DNA are central to the transformation of a normal cell into a cancer cell, to the development of malignant properties of cancer cells, and to cancer cells adaptation to their environment. The rate of genetic change is especially great when a cancer cell is faced with obstacles to its survival. Since mutations, along with proliferation, are so important to the survival of a cancer, this chapter discusses these events in some detail, starting with the basics...

Mathcad And Axum

Mathcad is a robust advanced calculation software package for the technical community. This application tool is designed to solve complex mathematical problems (i.e., linear, nonlinear, quadratic, and mixed-integer programming), create graphs and sketches, and share results via the Internet. Axum is a technical publication-quality graphing and data analysis package used for exploring, customizing, and presenting data. Several of the figures shown in this book were created in Axum, and it was...

Melatonin

The pharmacokinetic properties of melatonin after oral administration have been studied in humans. Figure J.14 illustrates the plasma concentration curve after oral administration of 100 milligrams (based on reference 234). The oral clearance based on this study is 560 L hr, which is very similar to the values of 530 and 500 L hr calculated from two other human studies after a single dose of 3 milligrams and multiple administrations of 50 milligrams every four hours, respectively.235,236 We use...

Terpenes Monoterpenes

We first discuss the pharmacokinetics of limonene and perillyl alcohol, then calculate required doses. From these, we estimate the required dose for geraniol. Based on a phase I trial in which an 18-gram limonene dose was given to humans, the oral clearance for production of perillic acid, the active metabolite of limo-nene, was 110 L hr.168 Plasma concentrations of perillic acid after repeated limonene administrations were about half as high, however, which suggests that treatment induces...

CAPE and Propolis

Although CAPE and bee propolis hold promise, as evidenced by their in-vitro effects against cancer cells and in-vivo effects against inflammation, the pharmacokinetic properties of CAPE remain uncertain they have not been studied in animals or humans. Still, we can estimate a value for the total clearance of CAPE by using the TOC model, which predicted a value of 58 L hr (see Table I.3). Of all compounds listed in that table, the predictions for CAPE and the related compound caffeic acid are...

Structural Diagrams For Selected Natural Compounds

Figure A.2 Guanine Figure A.3 Thymine Figure A.4 Cytosine Figure A.5 Uracil Figure A.6 Adenosine Diphosphate Figure A.7 Deoxyadenosine Diphosphate Figure A.8 Methylated Cytosine (Adenosine is used here as a sample nucleotide and is shown in its oxygenated and deoxy form. The diphosphate is shown, but nucleotides also exist in mono- and triphosphate forms.) Figure A.9 S-adenosylmethionine (SAM) NH Figure A.11 Figure A.12 Cysteine Sodium Selenite Figure A.9 S-adenosylmethionine (SAM) NH Figure...

Free Oral Clearance Foc Model

The FOC model estimates oral clearance based on chemical structure and related descriptors. It appears to be unique, since no other such linear regression model seems to have been published in pharmacology journals. It is not the first time, however, that linear regression or other mathematical techniques have been used to model other pharmacokinetic parameters related to oral clearance. For example, linear regression models have been used to predict intestinal absorption and total body...

Glycosidases Proteases And Cancer

As discussed previously, the strength and structure of the ECM is provided by collagen fibers linked together by GAG chains. To break free of the ECM, cancer cells (or cancer-stimulated immune cells) produce enzymes that degrade these ECM components. These enzymes include glycosidases, which break apart GAG chains, and proteases, which break apart protein structures. Many different types of proteases and glycosidases may be involved in cancer invasion, but only two primary ones are discussed...

Iron Withholding Strategies in Therapy

Because iron withholding assists in the treatment of cancer and infection, several strategies have been investigated that facilitate it The simplest method to lower iron stores is bloodlet It is interesting to note that bloodletting has been used since antiquity by a variety of cultures to treat infections and other diseases.87 Modern research also indicates that bloodletting can have beneficial effects. For example, therapeutic bloodletting has been reported to reduce oxidation of serum...

The Ecm And Cancer

The ECM not only provides a barrier to tumor invasion, it also governs the behavior of the cells it surrounds. The makeup of the ECM varies in gross or a Proteoglycans are a subset of glycoproteins. Glycoproteins are proteins bound to glucose residues. b Fibronectin is an adhesive glycoprotein found on the surface of cells and in the ECM. It binds to cell surfaces, collagen, fibrin, and other components, and it is involved in cell adhesion, cell motility, and other processes. subtle ways in...

Intraperitoneal Orin Model

A number of studies mentioned in this book administered a natural compound by the intraperitoneal (i.p.) route. In these studies, the dose is injected into the intraperitoneal cavity surrounding the intestines. Compared with oral administration, intraperitoneal administration bypasses the degrading effects of stomach acids and intestinal bacteria metabolism of the drug a In this study, the LOAEL dose was called the two-year minimum effect dose. by intestinal bacteria and intestinal enzymes and...

Invitro and lnvivo Anticancer Studies

A small number of in-vitro studies have investigated the cytotoxic effects of enterodiol and enterodiol on cancer cells. In one study, enterolactone inhibited proliferation of human breast cancer cells by about 75 percent at 33 mM.77 In another, enterolactone decreased proliferation of four human colon cancer cells lines at 50 to 100 mM, and it was more than twice as effective as enterodiol.72 One other study reported that enterodiol was not effective against two human leukemia cell lines.66...

Histamine The Role of Mast Cells

Histamine is generated by mast cells in response to tissue injury and other factors.3 Mast cells migrate toward tumors in response to growth factor production, and once at the site, the histamine they release increases vascular permeability and stimulates angiogenesis.122123 Numerous natural compounds inhibit the release of histamine from mast cells. This release is referred to as mast cell granulation, since histamine is stored in intracellular pouches called granules. Natural compounds that...

Preface

This book discusses numerous natural compounds that show promise in the treatment of cancer. It examines fully what research has told us about them, and it proposes ways of using them that could significantly increase their value in cancer treatment beyond what has previously been demonstrated. To understand the meaning of this new approach, one needs to see it in the context of the big picture of cancer research. We stand at a turning point in the field of cancer chemotherapy. The last 50...

Estimated Therapeutic and Tolerated Doses of EPADHA

EPA has been studied as a treatment agent for a number of noncancerous conditions, including autoimmune disorders and heart disease. Although effective dosages of fish oil are still uncertain, common doses range from 2 to 20 grams per day.176 177 The various effects become apparent within four weeks of administration. The optimal dose of EPA DHA and its efficacy in treating human cancer are still uncertain. The antitumor dose of EPA, DHA, or fish oil scaled from rodent experiments is 12 to 48...

Collagenases and Their Inhibitors

Collagenases are a family of enzymes that digest collagen, the fibrous protein found in connective tissue. Collagen is derived from the Greek words kolla (glue), and gennan (to produce), reflecting its role in gluing cells together. Collagen accounts for approximately 30 percent of the body's total protein store. Each type of collagenase degrades a specific type of collagen. For example, the basement membrane around capillaries contains type IV collagen, and therefore type IV collagenase is a...

Boswellic Acid

Seven in-vitro studies have reported that boswellic acid inhibited proliferation and or induced differentiation in leukemia or central nervous system cancer cell lines.54-60 In addition, cyto-toxic effects against two cancer cell lines have been observed by our research group.61 At least three animal antitumor studies have been published, which found that boswellic acids inhibited the growth of transplanted brain cancer cells and leukemia cells in rodents.62 63 64 Two human studies have also...

Garlic CompoundsDADS

Propranolol Plasma Concentration

As discussed in Chapter 18, the principal garlic constituent of interest is DADS. Unfortunately, the phar-macokinetic parameters of DADS have not been well characterized. One study has been conducted on radio- labeled allicin in rats, however, and this information can be used to make rough estimates, since DADS and allicin probably display somewhat similar pharmacokinetics. The blood concentration curve of radiolabeled allicin in rats is shown in Figure J.3 (adapted from reference 22).a The...

Herbal Immunostimulant Compounds

The (probable) active ingredients of the herbal compounds in Table 12.1 tend to fall into a limited number of chemical families one of these is high-molecular-weight polysaccharides, which are large sugar molecules. Natural compounds containing them include Astragalus, Ganoderma, Eleutherococcus, and PSK. A second family of immunostimulating compounds is the saponins. Natural compounds with these are Eleuthero-coccus and ginseng. It is tempting to speculate that the most effective combinations...

Estimated Therapeutic and Loael Doses of Arctigenin and Arctium Seed

Since animal antitumor data are lacking, the doses of arctigenin or Arctium seed needed to produce an anticancer effect can be estimated only by making calculations based on pharmacokinetic and in-vitro data. Therefore, the resulting estimates cannot be confirmed with an independent source of data. Using a target in-vivo concentration of 15 pM (30 pM after adjustment for conjugates), the required arctigenin dose is about 1.4 grams per day. The corresponding Arctium seed dose is about 27 grams...

Anthocyanidins

Anthocyanidins are red-blue pigments in plants, and they are especially high in fruits such as blueberries, bilberries, and other berries. Like many other flavon-oids, anthocyanidins exist in nature almost exclusively in their glycoside (anthocyanin) forms. Although the glycosides are found in many plants, the primary commercial source of anthocyanins is Vaccinium myrtillus (bilberry), in which they occur at about 3 percent.185 Bilberries are eaten as food and have also been used medicinally to...

Metabolism and Absorption of Phenolic Compounds

Before calculating doses for fla-vonoids, we first discuss their metabolism and absorption. The important point to remember is that flavonoids are extensively metabolized in vivo, and they occur in the plasma primarily in their glucuronide conjugate forms. These characteristics were first mentioned in Chapter 13 and are examined in more detail here. As discussed in that chapter, the production of conjugates is not limited to flavonoids but is shared by many other phenolic compounds. Therefore,...

Estimated Therapeutic and Loael Doses of Melatonin

Melatonin is characterized in this book as an immune stimulant (see Table 1.2), but in addition to immune effects it may also have direct cytotoxic effects against TABLE 22.11 ESTIMATED THERAPEUTIC AND LOAEL DOSES FOR MELATONIN* Required dose as scaled from animal antitumor studies Doses used in human anticancer studies Required cytotoxic dose as determined from pharmacokinetic calculations Target dose based on human studies and pharmacokinetic calculations Minimum required antitumor dose...

Lignans

Lignans are widely distributed in the plant kingdom, with several hundred lignan compounds isolated in about 70 different families.64 Lignans may produce a number of medicinal effects. For example, many appear to have liver-protective properties, including silybin from milk thistle (Silybum marianum) and schizandrin from Schizandra chinensis, both of which are used in herbal medicine. Some lignans have caused cytotoxic effects in cancer cells, an example being podophyllo-toxin, obtained from...

Introduction

Flaxseed, the seed of Linum usitatissimum, is widely used as food and as a bulking agent in treating constipation. It is also a rich source of dietary plant lignans. After ingestion, flaxseed lignans are metabolized by colonic bacteria to produce the two major mammalian lignans, enterodiol and enterolactone. In one human study, oral administration of 10 grams per day of flax-seed increased urinary excretion of enterodiol and enter-olactone in women by about 18-fold and 9-fold, respectively.82...

Feverfew

At least three in-vitro studies have reported that parthenolide inhibited the proliferation of multiple cancer cell lines.131'132'133 In these studies, parthenolide was active at concentrations between 3 and 9 mM. In addition, cytotoxic effects against two cancer cell lines have been observed by our research group.61 At least one animal antitumor study has been conducted in it, TABLE 21.13 ESTIMATED THERAPEUTIC AND LOAEL DOSES FOR PARTHENOLIDE* Required dose as scaled from animal antitumor...

Lactic Acid Insulin and Angiogenesis

We end this chapter with a brief discussion of the relationship between lactic acid, insulin, and angiogenesis in wound healing and cancer. As mentioned earlier, vascular cells proliferate and migrate toward an angiogenic stimulus, usually toward a low-oxygen (hypoxic) environment. In wound healing, hypoxia occurs from a lack of blood circulation in the traumatized area. In tumors, hypoxic conditions occur both through inflammation, which reduces blood flow, and the chaotic development of blood...

Anticopper Strategies

Although copper-chelating compounds could be useful in lowering copper availability, the safest and most effective natural compounds known to do so are molybdenum and its relatives. Diets deficient in copper may also be of some use. In the human study mentioned in Chapter 8, administration of the molybdenum compound tetrathiomoly-bdate appeared to stop the growth of advanced cancers in five of six patients, apparently by inhibiting angio-genesis. Tumor growth inhibition occurred when plasma...

Lactic Acid and Insulin

As mentioned, under hypoxic conditions lactic acid may stimulate production of angiogenic factors by macrophages. Unfortunately, few natural compounds have been tested for their effects on lactic acid generation in cancer cells. In one study, apigenin and luteolin inhibited both proliferation and lactic acid release from a human adenocarcinoma cell line in vitro.127 In other studies, the flavonoid quercetin reduced the production of lactic acid in healthy rat cells, probably by blocking the...

Alphalipoic acid

Alpha-lipoic acid is a potent water- and fat-soluble thiol antioxidant mentioned briefly in previous chapters. It is discussed here in more detail as an example of an antioxidant that can reduce the side effects of chemotherapy without reducing its antitumor effects. Alpha-lipoic acid effectively increases glutathione concentrations in vitro and in vivo. For example, intraperitoneal administration (at 4 to 16 mg kg) increased the glutathione content in liver and kidney cells in mice, while this...

Natural Compounds That Stimulate Andor Support The Immune System

A large number of natural compounds can stimulate or support the immune system or do both. A selected list of some of the major compounds is provided in Table 12.1. Note that many other natural compounds discussed in this book (and many not included) could act as immunostimulants or supportive agents. For example, CAPE has been reported to increase the susceptibility of tumor cells to NK cell attack and induce expression of tumor-associated antigens on human melanoma and brain cancer cells...

Human Studies

Human studies on enzymes have been published in journal articles and books, as well as in literature from manufacturers. We start with the six human studies published in journals. Unfortunately, five of these were only available in abstract form (three articles were not in English and two were published only as abstracts) all five were uncontrolled. Briefly, one study reported that Wobenzym, a polyenzyme product, in combination with hyperthermia, immunostimulants, and hormone therapy, improved...

Emodin

Few studies exist on the pharmacokinetics of emodin after oral administration. One investigated emodin pharmacokinetics in rabbits, but unfortunately, the actual dose given was not clearly specified.157 The plasma concentration-time curve from this study is shown in Figure J.8. The dose needed to produce this peak concentration can be estimated by using data from three different studies emodin studies in rabbits and mice and an aloe-emodin one in rats.158,159160 These suggest that a dose of...

Antioxidant Effects of Isoflavones Flavones Flavonols and other Phenols

Phenolic compounds, including isoflavones, flavones, and flavonols, can act as antioxidants due to the hydrogen-donating capacity of their phenolic groups and, in some cases, their metal-chelating potential. The latter may block the generation of copper- and iron-induced free radicals. Table 19.1 ranks various phenolics and other antioxidants in comparison to vitamin C in their ability to scavenge aqueous free radicals in vitro. As seen, most flavonoids are more active than vitamins C and E....

Curcumin

Pharmacokinetics studies of curcumin have been performed in mice, rats, dogs, and humans. These reported that after oral administration, only a small concentration of free curcumin exists in the plasma, with the bulk of curcumin being conjugates of it and its primary metabolites. Unfortunately, almost all pharmacokinetic studies have investigated plasma concentrations of the free form, and little is known about pharmacokinetics of the conjugate forms. In two rat studies, oral administration of...

Evidence for Synergism Against Cancer Cells

Research already provides evidence that synergistic interactions can occur within combinations of direct-acting natural compounds. Such interactions have been clearly documented by in-vitro studies. In addition, a small number of animal studies have also reported syn-ergistic effects. For example, in three studies in mice, combinations of ATRA and 1,25-D3 synergistically inhibited proliferation of transplanted human breast cancer cells or inhibited angiogenesis induced by cancer cells.3 45...

Estimated Therapeutic and Loael Doses of Propolis

The estimated required dose of propolis scaled from animal antitumor studies is not in close agreement with that calculated from pharmacokinetic and in-vitro data. This discrepancy suggests an uncertain target human dose that can be estimated only within a large range. The required dose scaled from an animal antitumor ex periment is about 1.3 grams daily, similar to the 0.96 to 11 grams scaled from animal anti-inflammatory experiments. The dose based on pharmacokinetic calculations is much...

Vitamin E

Numerous in-vitro studies have observed that vitamin E (alpha-tocopherol) or VES (vitamin E succinate) increased the effectiveness of chemotherapy against cancer cells or protected normal cells or both VES (at concentrations greater than about 9.2 mM) produced a synergistic effect with doxorubicin against human prostate cancer cells. At lower concentrations, it had an additive effect.161 VES (at 50 mM), with or without beta-carotene (at 50 mM), increased the cytotoxicity of melphalan toward...

Vitamin A

Transport and Metabolism of Vitamin A Because the metabolism, transport, and mode of action of vitamin A differ from most other natural compounds discussed in this book, it is worthwhile to discuss these aspects in more detail. Most natural compounds affect cancer cells by altering events at the plasma membrane or in the cytoplasm. In contrast, ATRA travels directly to the nucleus and affects gene transcription. The effects of ATRA are mediated through its ability to bind to retinoid receptors...

Estimated Therapeutic and Loael Doses of Enzymes

Since they are such large molecules, the intestinal absorption of enzymes has been questioned, but ample evidence now demonstrates that enzymes are indeed absorbed in their active forms in humans and animals. This has been reported for bromelain, trypsin, papain, and chymotrypsin in a number of studies, including animal studies using radiolabeled enzymes and antibody studies in humans.236,237 Approximately 6 percent of papain and 38 percent of orally administered bromelain are found in plasma...

Estimated Therapeutic and Loael Doses of Isoflavones Flavones and Flavonols

The estimated required doses as scaled from animal antitumor studies (and anti-inflammatory studies) reasonably agree with estimated doses calculated from pharmacokinetic and in-vitro data. The required dose scaled from animal antitumor studies ranges from 250 milligrams to 9.9 grams, and that based on pharmacoki-netic calculations is similar. Using a target in-vivo concentration of 15 mM for each compound (30 pM after adjustment for conjugates see Appendix J), the required dose ranges from 720...