ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
PLANTS AS A SOURCE OF ANTI-CANCER AGENTS

G. M. Cragg and D. J. Newman
Natural Products Branch, Developmental Therapeutics Program, Division of Cancer
Treatment and Diagnosis, National Cancer Institute, , Maryland, U S A.

Keywords: camptothecins, combretastatins, flavopiridol, podophyllotoxins, taxanes,
vinca alkaloids, cell cycle target inhibitors.

Contents

1. Introduction
2. Plant-Derived Anticancer Agents in Clinical Use (Figure 1)
3. Plant-Derived Anticancer Agents in Clinical Development (Figure 2)
4. Targeted Natural Products
5. Plant-Derived Antitumor Agents in Preclinical Development (Figure 3)
6. Cell Cycle Target Inhibition and Anticancer Drug Discovery
7. Conclusions
Glossary
Bibliography
Biographical Sketches
To cite this chapter

Summary

Plant-derived compounds have played an important role in the development of several
clinically useful anti-cancer agents. These include vinblastine, vincristine, the
camptothecin derivatives, topotecan and irinotecan, etoposide, derived from
epipodophyllotoxin, and paclitaxel (taxol®). Several promising new agents are in
clinical development based on selective activity against cancer-related molecular
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targets, including flavopiridol and combretastin A4 phosphate, and some agents which
failed in earlier clinical studies are stimulating renewed interest.

1. Introduction

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Plants have a long history of use in the treatment of cancer. Hartwell, in his review of
plants used against cancer, lists more than 3000 plant species that have reportedly been
used in the treatment of cancer. In many instances, however, the “cancer” is undefined,
or reference is made to conditions such as “hard swellings”, abscesses, calluses, corns,
warts, polyps, or tumors, to name a few. These symptoms would generally apply to
skin, “tangible”, or visible conditions, and may indeed sometimes correspond to a
cancerous condition. Many of the claims for efficacy in the treatment of cancer,
however, should be viewed with some skepticism because cancer, as a specific disease
entity, is likely to be poorly defined in terms of folklore and traditional medicine. This
is in contrast to other plant-based therapies used in traditional medicine for the
treatment of afflictions such as malaria and pain, which are more easily defined, and
where the diseases are often prevalent in the regions where traditional medicine systems
are extensively used. However, despite these observations, it is significant that over
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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
60% of currently used anti-cancer agents are derived in one way or another from natural
sources, including plants, marine organisms and micro-organisms. Indeed, molecules
derived from natural sources (so-called natural products), including plants, marine
organisms and micro-organisms, have played, and continue to play, a dominant role in
the discovery of leads for the development of conventional drugs for the treatment of
most human diseases.

While in past years, cancer has been regarded mainly as a group of diseases afflicting
the more developed countries, the incidence of various forms of cancer is now rapidly
rising worldwide. Reference to the World Health Organization database on cancer
incidence and mortality [http://www.who.int/cancer/resources/incidences/en/] indicates
substantial numbers of cases of major cancers in less developed countries (see Table 1).

Number of cases in the year 2000*
Cancer Type
More developed
Less developed
Total
countries
countries
All (except skin)
5,317,905
2,503,772
2,814,132
Breast 1,050,346
579,285
471,063
Colon/Rectum 498,574 318,694 180,059
Kidney 118,255
79,090
39,158
Leukemia 144,321
58,416
85,912
Liver 398,364
73,270
325,108
Lung 901,746
470,836
430,919
Melanoma 65,177
50,608
14,571
Oral Cavity
169,524
59,959
109,553
Ovary 192,379
91,307
101,060
Prostate 542,990
415,568
127,419
Stomach 558,458
208,282
350,176

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bers apply to all ages and males only, except for breast and ovary. The total
numbers often do not correspond to the sums of the more and less developed countries

Table 1. The number of cases in more developed/less developed countries as of the year
2000

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The search for anti-cancer agents from plant sources started in earnest in the 1950s with
the discovery and development of the vinca alkaloids, vinblastine and vincristine, and
the isolation of the cytotoxic podophyllotoxins (see Section 2). These discoveries
prompted the United States National Cancer Institute (NCI) to initiate an extensive plant
collection program in 1960, focused mainly in temperate regions. This led to the
discovery of many novel chemotypes showing a range of cytotoxic activities, including
the taxanes and camptothecins, but their development into clinically active agents
spanned a period of some 30 years, from the early 1960s to the 1990s. This plant
collection program was terminated in 1982, but with the development of new screening
technologies, the NCI revived the collections of plants and other organisms in 1986.
This time the focus was on the tropical and sub-tropical regions of the world, but it is
interesting to note that no new plant-derived clinical anti-cancer agents have, as yet,
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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
reached the stage of general use. However, as described in Sections 3 to 5, a number of
agents are in preclinical development.

2. Plant-Derived Anti-Cancer Agents in Clinical Use (see Figure 1)

The first agents to advance into clinical use were the so-called vinca alkaloids,
vinblastine (VLB) and vincristine (VCR), isolated from the Madagascar periwinkle,
Catharanthus roseus G. Don. (Apocynaceae), which was used by various cultures for
the treatment of diabetes. These drugs were first discovered during an investigation of
the plant as a source of potential oral hypoglycemic agents. While research investigators
could not confirm this activity, it was noted that extracts reduced white blood cell
counts and caused bone marrow depression in rats, and subsequently it was found that
the treatment of mice bearing a transplantable lymphocytic leukemia caused significant
life extension. This led to the isolation of VLB and VCR as the active agents, so their
discovery may be indirectly attributed to the observation of an unrelated medicinal use
of the source plant. It is interesting to note that though the plant was originally endemic
to Madagascar, the samples used in the discovery of VLB and VCR were collected in
Jamaica and the Philippines. More recent semi-synthetic analogues of these agents are
vinorelbine (VRLB) and vindesine (VDS). These agents are primarily used in
combination with other cancer chemotherapeutic drugs for the treatment of a variety of
cancers. VLB is used for the treatment of leukemias, lymphomas, advanced testicular
cancer, breast and lung cancers, and Kaposi’s sarcoma, and VCR, in addition to the
treatment of lymphomas, also shows efficacy against leukemias, particularly acute
lymphocytic leukemia in childhood. VRLB has shown activity against non-small-cell
lung cancer and advanced breast cancer. Of over 2069 anti-cancer clinical trials
recorded by the NCI as being in progress as of July 2004, over 160 are drug
combinations including these agents against a range of cancers.

The two clinically-active agents, etoposide (VM 26) and teniposide (VP 16-213), which
are semi-synthetic derivatives of the natural product, epipodophyllotoxin (an isomer of
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podophyllotoxin), may be considered as being more closely linked to a plant originally
used for the treatment of “cancer”. The Podophyllum species (Podophyllaceae), P.
peltatum Linnaeus (commonly known as the American mandrake or Mayapple), and P.
emodii Wallich from the Indian subcontinent, have a long history of medicinal use,
including the treatment of skin cancers and warts. P. peltatum was used by the
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Penobscot Native Americans of Maine for the treatment of “cancer”, and interest was
promoted by the observation in the 1940s that venereal warts could be cured by topical
application of an alcohol extract of the dried roots (called podophyllin). The major
active constituent, podophyllotoxin, was first isolated in 1880, but its correct structure
was only reported in the 1950s. Many closely related podophyllotoxin-like lignans were
isolated during this period, and several of them were introduced into clinical trials, only
to be dropped due to lack of efficacy and unacceptable toxicity. Extensive research at
Sandoz Laboratories in Switzerland in the 1960s and 1970s led to the development of
etoposide and teniposide as clinically effective agents which are used in the treatment of
lymphomas and bronchial and testicular cancers. Of 2069 anti-cancer clinical trials
recorded by the NCI as being in progress as of July 2004, over 150 are drug
combinations including etoposide against a range of cancers.

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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
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SAMPLE CHAPTER

Figure 1. Plant-derived anti-cancer agents in clinical use.

A more recent addition to the armamentarium of plant-derived chemotherapeutic agents
is the class of molecules called taxanes. Paclitaxel (taxol®) initially was isolated from
the bark of Taxus brevifolia Nutt. (Taxaceae), collected in Washington State as part of a
random collection program by the U.S. Department of Agriculture (USDA) for the
National Cancer Institute (NCI). The use of various parts of T. brevifolia and other
Taxus species (e.g. T. canadensis Marshall, T. baccata L.) by several Native American
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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
tribes for the treatment of some non-cancerous conditions has been reported, while the
leaves of T. baccata are used in the traditional Asiatic Indian (Ayurvedic) medicine
system, with one reported use in the treatment of “cancer”. Paclitaxel, along with
several key precursors (the baccatins), occurs in the leaves of various Taxus species, and
the ready semi-synthetic conversion of the relatively abundant baccatins to paclitaxel, as
well as active paclitaxel analogs, such as docetaxel (Taxotere®), has provided a major,
renewable natural source of this important class of drugs. Paclitaxel is used in the
treatment of breast, ovarian and non-small-cell lung cancer (NSCLC), and has also
shown efficacy against Kaposi sarcoma. Paclitaxel has also attracted attention in the
potential treatment of multiple sclerosis, psoriasis and rheumatoid arthritis. Docetaxel is
primarily used in the treatment of breast cancer and NSCLC. The importance of this
class of anti-cancer agents may be judged from the fact that 12 and 23 taxane analogs
are in clinical and preclinical development, respectively. In addition, of 2069 cancer
clinical trials recorded by the NCI as being in progress as of July 2004, 248 or close to
12% are listed as involving taxane-derived drugs, including 134 with paclitaxel
(Taxol®), 105 with docetaxel (Taxotere®), and 10 with miscellaneous taxanes, either as
single agents or in combination with other anti-cancer agents. In addition, 23 taxanes
are in preclinical development.

Another important addition to the anti-cancer drug armamentarium is the class of
clinically-active agents derived from camptothecin, which is isolated from the Chinese
ornamental tree, Camptotheca acuminata Decne (Nyssaceae), known in China as the
tree of joy. Camptothecin was discovered from extracts of plants originally collected by
the U. S. Department of Agriculture as a possible source of steroidal precursors for the
production of cortisone. The extract of C. acuminata was the only one of 1000 of these
plant extracts tested for anti-tumor activity which showed efficacy, and camptothecin
was isolated as the active constituent. Camptothecin (as its sodium salt) was advanced
to clinical trials by the NCI in the 1970s, but was dropped because of severe bladder
toxicity. However, extensive research was performed by several pharmaceutical
companies in a search for more effective camptothecin derivatives, and Topotecan
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tin®), developed by SmithKline Beecham (now Glaxo SmithKline), and
Irinotecan (CPT-11; Camptosar®), originally developed by the Japanese company,
Yakult Honsha, are now in clinical use. Topotecan is used for the treatment of ovarian
and small-cell lung cancers, while Irinotecan is used for the treatment of colorectal
cancers. Of the 2069 cancer clinical trials recorded by the NCI as being in progress, as
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of July 2004, 94 or approximately 4.5% are listed as involving camptothecin-derived
drugs, including 64 with irinotecan (CPT-11), 26 with topotecan, and 4 with other
miscellaneous analogues, either as single agents or in combination with other anti-
cancer agents. In addition, 15 other camptothecin derivatives are in preclinical
development.

Other plant-derived agents in clinical use are homoharringtonine, isolated from the
Chinese tree, Cephalotaxus harringtonia var. drupacea (Sieb and Zucc.)
(Cephalotaxaceae), and elliptinium, a derivative of ellipticine, isolated from species of
several genera of the Apocynaceae family, including Bleekeria vitensis A. C. Sm., a
Fijian medicinal plant with reputed anti-cancer properties. A racemic mixture of
harringtonine and homoharringtonine (HHT) has been used successfully in China for
the treatment of acute myelogenous leukemia and chronic myelogenous leukemia.
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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
Purified HHT has shown efficacy against various leukemias, including some resistant to
standard treatment, and has been reported to produce complete hematologic remission
(CHR) in patients with late chronic phase chronic myelogenous leukemia (CML).
Elliptinium is marketed in France for the treatment of breast cancer.

3. Plant-Derived Anticancer Agents in Clinical Development (Figure 2)

The flavone, flavopiridol is totally synthetic, but the basis for its novel structure is a
natural product, rohitukine, isolated by chemists at Hoechst India Ltd. in the early 1990s
from Dysoxylum binectariferum Hook. f. (Meliaceae), which is phylogenetically related
to the Ayurvedic plant, D. malabaricum Bedd., used for rheumatoid arthritis.
Rohitukine was isolated as the constituent responsible for anti-inflammatory and
immunomodulatory activity. A total synthesis was undertaken, and one of the over 100
analogues synthesized during structure-activity studies was flavopiridol, which was
found to possess tyrosine kinase activity and potent growth inhibitory activity against a
series of breast and lung carcinoma cell lines. It also showed broad spectrum in vivo
activity against human tumor xenografts in mice, and this led to its selection for
preclinical and clinical studies by the NCI in collaboration with Hoechst. It is currently
in 18 Phase I and Phase II clinical trials, either alone or in combination with other anti-
cancer agents, against a broad range of tumors, including leukemias, lymphomas and
solid tumors. While flavopiridol alone is probably not a viable treatment, use of the
compound in conjunction with other agents such as paclitaxel and cisplatin has led to
partial and complete remissions in a number of Phase I patients, leading to Phase II
studies in patients with a variety of paclitaxel-resistant tumors.

The combretastatins were isolated from the South African “bush willow”, Combretum
caffrum (Eckl. & Zeyh.) Kuntze (Combretaceae), collected in Southern Africa in the
1970s for the NCI by the USDA, working in collaboration with the Botanical Research
Institute of South Africa. These collections were part of a random collection program
aimed at the discovery of novel anti-cancer agents. Species of the Combretum and
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Terminalia genera, both of which belong to the Combretaceae family, are used in
African and Indian traditional medicine for the treatment of a variety of diseases,
including hepatitis and malaria. Several Terminalia species have reportedly been used in
the treatment of “cancer”. The combretastatins are a family of stilbenes which act as
anti-angiogenic agents, causing vascular shutdown in tumors and resulting in tumor
SAMPLE CHAPTER
necrosis. A water-soluble analogue, combretastatin A-4 phosphate (CA4), has shown
promise in early clinical trials. Of interest is the number of combretastatin (CA4)
mimics being developed. Three are in clinical trials, while 11 are in preclinical
development. This chemical class has served as a model for the synthesis of a host of
analogues containing the essential trimethoxy aryl moiety (see Figure 2) linked to
substituted aromatic moieties through a variety of two or three atom bridges including
heterocyclic rings and sulfonamides. This is an impressive display of the power of a
relatively simple natural product structure to spawn a prolific output of medicinal and
combinatorial chemistry.

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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman

Figure 2. Plant-derived anti-cancer agents in clinical development

An interesting agent in early clinical development is roscovitine which is derived from
olomucine, originally isolated from the cotyledons of the radish, Raphanus sativus L.
(Brassicaceae), but which is now produced synthetically. Olomucine stimulated interest
as a result of its inhibition of cyclin-dependent kinases (Cdk), proteins which play a
major role in cell cycle progression. Chemical modification of olomucine resulted in the
more potent inhibitor, roscovitine, which is in clinical development under the code
CYC202 by Cyclacel in Dundee, Scotland, and currently is in Phase II clinical trials in
Europe. Further development of this series, following synthesis of a focused library via
combinatorial chemistry techniques, has led to the purvalanols which were even more
potent, and are in preclinical development.

4. Targeting Natural Products

A recurring liability of natural products, at least in the area of cancer chemotherapy, is
that, although many are generally very potent, they have limited solubility in aqueous
solvents and exhibit narrow therapeutic indices. These factors have resulted in the
demi
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se of a number of pure natural products, such as the plant-derived agents,
bruceantin and maytansine, as promising leads. An alternative approach to utilizing
such agents is to investigate their potential as ‘warheads” attached to monoclonal
antibodies specifically targeted to epitopes on tumors of interest.

A promising case is that of maytansine. Maytansine (Figure 3) was isolated in the early
SAMPLE CHAPTER
1970s from the Ethiopian plant, Maytenus serrata (Hochst. Ex A. Rich.) Wilczek
(Celastraceae), again collected for the NCI through the USDA random collection
program. The yields were very low (2 x 10-5% based on plant dry weight), but its
extreme potency in testing against cancer cell lines permitted the production of
sufficient limited quantities for pursuit of preclinical and clinical development. Despite
very promising activity observed in preclinical animal testing, no significant efficacy
was observed in clinical trials, and it was dropped from further study in the early 1980s.
Related compounds, the ansamitocins, were subsequently isolated from a microbial
source, the Actinomycete, Actinosynnema pretiosum, and this posed the question as to
whether the maytansines are actually plant products, or are produced through an
association between a microbial symbiont and the plant; this is a topic of continuing
study. The microbial source of closely related compounds allows for easier production
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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
of larger quantities of this class of compounds, and this factor, together with their
extreme potency, has stimulated continued interest in pursuing their development. A
derivative of maytansine, DM1, conjugated with a monoclonal antibody (mAb)
targeting small-cell lung cancer cells, is being developed as huN901-DM1 by the U.S.
company, ImmunoGen, Inc. and British Biotech for the treatment of small-cell lung
cancer. Another conjugate, known as SB408075 or huC242-DM1 (also known as
Cantuzumab Mertansine), produced by the coupling of DM1 to huC242, a mAb directed
against the muc1 epitope expressed in a range of cancers, including pancreatric, biliary,
colorectal and gastric cancers, was being developed by Glaxo-SmithKline, and is
currently in Phase I clinical trials in the USA. DM1 has also been conjugated to J591, a
mAb targeting the prostate specific membrane antigen (PSMA), and is in clinical trials
against prostate cancer.

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SAMPLE CHAPTER
Figure 3. Plant-derived anti-tumor agents in preclinical development

Another case of considerable interest is that of thapsigargin (TG) (see Figure 3), isolated
from the umbelliferous plant, Thapsia garganica L. (Apiaceae), collected on the
Mediterranean island of Ibiza. Thapsigargin induces apoptosis (cell death) in quiescent
and proliferating prostate cancer cells, and acts by disrupting intracellular Ca2+ levels.
While TG does not show selectivity for prostate cancer cells, it has been conjugated to a
small peptide carrier to produce a water-soluble prodrug which is specifically activated
by prostate specific antigen (PSA) protease at metastatic prostate cancer sites.
Treatment of animals bearing prostate cancer xenograft tumors demonstrated complete
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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
tumor growth inhibition without significant toxicity. Given that the prodrug is stable in
human plasma, it holds promise as a treatment for human prostate cancer, and it is being
developed towards clinical trials with support from the NCI.

5. Plant-Derived Antitumor Agents in Preclinical Development (see Figure 3)

As mentioned above, a number of naturally-derived agents were entered into clinical
trials and were terminated due to lack of efficacy or unacceptable toxicity. The case of
maytansine (Section 3) illustrates how the emergence of novel technologies can revive
interest in these “older” agents. It is also worth remembering that the development of
effective drugs, such as paclitaxel (taxol®) and the camptothecin derivatives, topotecan
and irinotecan (see Section 2), required 20 to 30 years of dedicated research and
patience, and considerable resources, to ultimately prove their efficacy as clinical
agents.

Another example of an “old” drug of the same vintage as taxol® and camptothecin, and
having a possibility of revival, is bruceantin which was first isolated from a tree, Brucea
antidysenterica J. F. Mill. (Simaroubaceae), used in Ethiopia for the treatment of
“cancer”. Activity was observed in animal models bearing a range of tumors, but no
objective responses were observed in clinical trials, and further development was
terminated. Interest has been revived by the observation of significant activity against
panels of leukemia, lymphoma and myeloma cell lines, as well as in animal models
bearing early and advanced stages of the same cancers. This activity has been associated
with the down-regulation of a key oncoprotein (c-myc), and these data are being
presented as strong evidence supporting the development of bruceantin as an agent for
the treatment of hematological malignancies.

Betulinic acid is a lupane-type triterpene which has been isolated from many
taxonomically diverse plant genera. A major source is the birch tree, Betula spp.
(Betulaceae), which is also a primary source of its C28 alcohol precursor, betulin. It is
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interesting to note that the isolation of betulin was first reported in 1788. Betulinic acid
has been associated with a variety of biological activities, including antibacterial, anti-
inflammatory and anti-malarial, but the most important activities have been associated
with inhibition of the replication of strains of the human immunodeficiency virus (HIV),
and cytotoxicity against a range of cancer cell lines. Significant in vivo activity has been
observed in anim
SAMPLE CHAPTER
al models bearing human melanoma xenografts, and the NCI is
assisting in the development of systemic and topical formulations of the agent for
potential clinical trials.

The family of bis-indoles known generically as indirubins are the main constituents of
Mu Lan (Indigofera tinctoria L.), (Leguminosae) a product from the Chinese Materia
Medica used to treat chronic myelogenous leukemia. The indirubins are the product of
non-enzymatic dimerization of isatin and indoxyl—indole-derived molecules found in a
large number of indigo-producing plants. These compounds are also produced by
bacteria and are found in gastropod mollusks. In fact, in the latter case, they are the
source of the purplish-red dye known from antiquity as “Tyrian Purple”. It is interesting
to note that they were the first human-used compounds identified as inhibitors of cyclin
dependent kinases (Cdks), key regulatory proteins in the cell cycle referred to in the
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ETHNOPHARMACOLOGY - Plants as a Source of Anti-Cancer Agents - G. M. Cragg and D. J. Newman
discussion of olomucine and roscovitine in Section 3 above. Other substituted indirubins
have been synthesized, and the 3’-monooxime and 5-bromo derivative (Figure 3), show
comparable activity to other known Cdk inhibitors, such as flavopiridol and roscovitine
discussed earlier, and are candidates for preclinical development.

Triterpenoid acids, such as oleanolic and ursolic acid which are common plant
constituents, are known to possess weak anti-inflammatory and anti-tumor activities.
Attempts to synthesize new analogues with increased potencies have led to the synthesis
of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its methyl ester, which
have potent in vitro and in vivo anti-tumor activity against a wide range of tumors,
including breast carcinomas, leukemias, and pancreatic carcinomas. Of particular
interest is the significant activity of CDDO against epithelial ovarian carcinoma (EOC)
cell lines, including lines which were resistant to clinically used agents such as cisplatin.
Since EOC is the leading cause of death from gynecologic cancers, further evaluation of
CDDO in the treatment of these cancers is being pursued.

Species of the genus Tabebuia (Bignoniaceae) have a history of use in the Amazonian
region for the treatment of several diseases, including syphilis, fevers, malaria,
cutaneous infections, and stomach disorders. Claims for clinical efficacy in the
treatment of cancers started in the 1960s, particularly in Brazil, and this led to
widespread sales of the stem bark and trunk wood of T. impetiginosa (Mart. Ex DC.)
Standl. (synonym T. avellanedae Lorentz ex Griseb.), T. rosea (Bertol.), and T.
serratifolia (Vahl) Nicholson in health food stores under various names such as pau
d’arco or lapacho. They possess numerous bioactive compounds, but the
naphthaquinones, particularly lapachol and β-lapachone, have received most attention.
Lapachol showed significant in vivo anti-tumor activity in some early mouse models
and was advanced to clinical trials by the NCI in the 1970s, but they were terminated
due to unacceptable levels of toxicity. Recently, β-lapachone has stimulated renewed
interest in this class of compounds due to its significant activity against a range of tumor
cell lines, including breast, leukemia and prostate lines, and several multidrug resistant
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(MDR) lines. In addition, this class of compounds has been shown to be potent
inhibitors of Cdc25 phosphatases, dephosphorylating enzymes that play a key role in
cell cycle progression.

Consumption of Veratrum californicum by pregnant sheep has long been associated
with the developm SAMPLE CHAPTER
ent of birth defects in lambs, including cyclopia in severe cases.
These teratogenic effects have been found to be due to presence of alkaloids of the
jervine class, in particular, cyclopamine, and are due to the specific inhibition of
vertebrate cellular responses to the Hedgehog (Hh) family of secreted growth factors.
While the Hedgehog cell signaling pathway normally is quiescent in adult cells,
aberrant activation of the pathway in adults has been implicated in many cancers,
including cancers of the pancreas, prostate, lung (small cell), and brain (glioma).
Cyclopamine blocks the activation of this pathway, and analogues are in various stages
of preclinical development.

The resistance developed by many cancer patients to treatment with standard anti-
cancer agents is a serious problem encountered in cancer chemotherapy. Resistance to a
drug may develop in a cell population through repeated exposure to treatment with that
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