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...

References

1 Kinoshita T, Sankawa U, Takuma T, et al. Induction of differentiation in murine erythroleukemia cells by flavonoids. Chem Pharm Bull 1985 33(9) 4109-4112. 2 Kawaii S, Tomono Y, Katase E, et al. Effect of citrus flavonoids on HL-60 cell differentiation. Anticancer Res 1999 Mar-Apr 19(2A) 1261-9. 3 Takahashi T, Kobori M, Shinmoto H, et al. Structure-activity relationships of flavonoids and the induction of granulocytic-or monocytic-differentiation in HL60 human myeloid leukemia cells. Biosci...

Mutations Gene Expression And Proliferation

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...

Supplemental Material For Chapter

Supplemental material for Chapter 3, Results of Therapy at the Cellular Level, contains Table D.1, which summarizes studies on the induction of differentiation by natural compounds, and Table D.2, which summarizes studies on the induction of apoptosis. TABLE D.1 NATURAL COMPOUNDS THAT INDUCE DIFFERENTIATION IN VITRO Induced differentiation of mouse erythroleukemia cells at a minimal concentration of 30 mM. At higher concentrations, up to 80 of cells were induced to differentiate.1 Induced...

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...

General Information

Ganoderma lucidum, also called reishi mushroom, is a common Chinese fungus mentioned in the Shen Nong Ben Cao Jing. Like a variety of other mushrooms, including the edible shiitake mushroom (Lentinus edodes), Ganoderma acts as an immunostimulant in both animals and humans. In addition to its potential to inhibit cancer through immune stimulation, Ganoderma may impede metastasis by inhibiting platelet aggregation (see Table 10.1). Intraperitoneal administration (400 mg kg every other day) of...

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...

Ginseng

Ginseng is characterized in this book as an immune stimulant, but it could also directly inhibit cancer cells. The pharmacokinetic properties of ginseng saponins have been investigated in mice.186 Since M1 appears to be the active metabolite, we focus on its properties. The plasma concentration curve for M1 in mice after an oral dose of gin-senoside Rbi is shown in Figure J.11 (based on reference 187). Using the data in this figure, the human oral clearance of M1 after ginseng saponin...

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...

Summary of Research and Conclusions

PSK (also called Krestin) and PSP (polysaccharide peptide) are semipurified polysaccharides obtained from the mushroom Coriolus versicolor. Of the two, PSK has received the most research attention, primarily in Japan, where PSK is now used clinically in cancer treatment in some situations.86,87 A relatively large number of papers have been published documenting the effects of PSK or PSP. More than 16 examined their ability to stimulate immune cells or inhibit cancer cell proliferation...

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...

Eicosanoids Prostanoids and Leukotrienes

Eicosanoids were introduced in Chapter 7. There we focused on how prostanoids and leukotrienes are produced from fatty acids, namely via the cyclooxygenase and lipoxygenase pathways, respectively. We also looked at how different fatty acids in the membrane produce different series of prostanoids and leukotrienes, then noted that eicosanoids derived from omega-6 fatty acids facilitate cancer progression and eicosanoids from omega-3 fatty acids inhibit it. We focus here on the role eicosanoids...

Nuclear Factorkappa B and Activator Protein1

Nuclear factor-kappa B (NF-kB) and activator protein-1 (AP-1) are transcription factors that control a wide range of cellular activities. Both transcription factors are particularly important to the functioning of immune cells. In general, NF-kB can be thought of as a transcription factor whose activity leads to immune activity, inflammation, and cell proliferation.30,31 Like the p53 protein, it binds to and helps regulate several different genes. NF-kB helps regulate the genes that produce...

Estimated Therapeutic and Tolerated Doses of Monoterpenes

The estimated required limonene and perillyl alcohol doses scaled from animal antitumor studies roughly agree with those calculated from pharmacokinetic and in-vitro data. The former is about 91 grams for limo-nene and 12 to 24 average 19 grams grams for perillyl alcohol doses based on pharmacokinetic data are 120 grams for limonene and 19 grams for perillyl alcohol. As discussed in Appendix J, however, the doses calculated from pharmacokinetic and in-vitro data do not provide a true...

Apigenin Luteolin Quercetin Genistein and Daidzein

A limited number of studies have investigated the oral clearance of apigenin, luteolin, quercetin, genistein, and daidzein in humans, although more studies have been conducted in rodents. Because of their complex metabolism and the analytical difficulty of measuring the vari- ous metabolites, many questions remain. Some details on the available human studies are listed in Table J.5. ous metabolites, many questions remain. Some details on the available human studies are listed in Table J.5....

Anthocyanidins and Proanthocyanidins

The pharmacokinetics of anthocyanidins and proan-thocyanidins are discussed together here because their pharmacokinetic characteristics are similar. Although the data are limited, it appears the oral clearance values for both compounds are high enough that cytotoxic concentrations would be difficult to achieve in the plasma after oral dosing. This does not preclude their use in cancer treatment, however, since both compounds may be able to inhibit cancer through noncytotoxic means. In...

Green Tea and EGCG

Phenolic compounds, of which catechins are the largest single group, account for about 35 percent of the weight of GTE green tea extract . The measured concentration of catechins and the relative levels of different catechins in green tea can vary greatly, perhaps partly from differences in growing and processing con- TABLE J.10 SUMMARY OF HUMAN PHARMACOKINETIC STUDIES ON EGCG Analysis required the estimation of one data point, which was done based on relative values from reference 5. Assumes...

Estimated Therapeutic and Loael Doses of EGCG

The estimated required dose of EGCG as scaled from animal antitumor studies is not in close agreement with that calculated from pharmacokinetic and in-vitro data. This discrepancy suggests the target human dose is still highly uncertain it can be estimated only within a large range. The required dose as scaled from antitumor experiments in animals is about 460 milligrams to 1.3 grams per day, but the dose based on pharmacokinetic calculations is much higher. Using a target in-vivo concentration...

Arctigenin and Arctium Seed

Unfortunately, the oral clearance of arctigenin has not been studied in humans or animals. However, the clearance for two different lignans silybin from milk thistle and schizandrin from Schizandra chinensis, a plant used in Chinese herbal medicine have been studied in humans. Clearance values for silybin and schizandrin can also be predicted by the FOC model. Silybin is actually a hybrid lignan that also has flavonoid aspects, but it is close enough to arctigenin to help verify the accuracy of...

Horse Chestnut

Although horse chestnut has not generally been considered an anticancer agent, one in-vitro study found that horse chestnut saponins are cytotoxic to cancer cells.78 In this book, we include horse chestnut not as a cyto-toxic compound but as one that can protect the vascula-ture and reduce edema. Through these actions, it should be able to inhibit angiogenesis, metastasis, and invasion. Even though anticancer studies on animals and humans have not yet been done, it seems likely that horse...