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Anticancer Alkaloids of Catharanthus roseus: Transition from Traditional to Modern Medicine

Authors:
RAJESH ARORA, POONAM MALHOTRA, AJAY K MATHUR,
ARCHNA MATHUR, CM GOVIL, PS AHUJA
CHAPTER 21
Anticancer Alkaloids of
Catharanthus roseus: Transition from
Traditional to Modern Medicine
INTRODUCTION
Catharanthus is an important medicinal plant
distributed throughout the world. The interest in
this plant emanates due to the fact that it contains
more than 120 terpenoid indole alkaloids (TIAs),
several of which exhibit strong pharmacological
properties. The plant has been used in traditional
medicine since ages in various parts of the world.
A number of alkaloids isolated from this plant are
already in clinical use, e.g. ajmalacine – an anti-
hypertensive alkaloid, and vincristine and vinblas-
tine – the antineoplastic bisindole alkaloids. The
successful transition of this plant’s economic utility
from traditional to modern medicine has indeed
set an example that is worth-emulating.
Catharanthus roseus: The Wonderful Plant with
Multifarious Activities
The genus name, Catharanthus, means “pure flower”.
Catharanthus roseus (often synonymous with Vinca
rosea; though certain authors disagree with the
proposition that Catharanthus and Vinca are one and
the same; Khoury, 1993) is a perennial plant that
commonly grows in tropical countries. The plant is
referred to with a variety of names in various
countries (Table 21.1). Seven species of the genus
are known from Madagascar; one is restricted to
India and Sri Lanka, while one species is cultivated
in China. The plant is believed to be a native of the
West Indies. Catharanthus is more commonly known
as Madagascar periwinkle. The plant grows in warm
ABSTRACT
Catharanthus roseus is an important medicinal plant found in various parts of the world. The Catharanthus
alkaloids have been used in traditional medicine since ages for treating a variety of ailments. The serendipitous
discovery of antineoplastic property of Catharanthus alkaloids in the 1950s has had far reaching effects in
clinical oncology and has paved the path for the discovery of a number of plant-derived anticancer drugs.
The Catharanthus alkaloids are of wide importance in clinical medicine and vincristine (VCR) and vinblastine
(VLB) form an essential component of standard chemotherapy regimens. VCR and VLB are indispensable
components of virtually every curative regimen for metastatic malignancy and are extensively used in adjuvant
and neoadjuvant drug regimens. The transition from traditional to modern medicine in case of Catharanthus
has been rapid. Leads obtained from Catharanthus have proved that natural products indeed are reliable
sources of medicine and can solve several of the health problems being faced by humans. There is a need to
discover several such agents from nature’s storehouse for the benefit of humanity.
Keywords: Catharanthus roseus, periwinkle, anticancer alkaloids, traditional medicine, modern medicine,
alkaloids, vincristine, vinblastine.
Anticancer Alkaloids of Catharanthus roseus 293
regions of the world and especially in the Southern
United States.
Table. 21.1 Some common names of Catharanthus in
different countries.
S. Country Common name(s)
No.
1. Bangladesh Nayantara
2. Brazil Boa-noite, Congorca
3. Cook Islands Tiare-tupapaku-kimo
4. Dominica Caca poule
5. French Guiana Pervenchede de Madagascar
6. Guatemala Chatilla
7. Guyana Periwinkle
8. India Ainskati, Billaganneru, Nayantara,
Nityakalyani, Periwinkle, Sada
bahar, Sadaphul, Ushamanjairi
9. Jamaica Periwinkle
10. Japan Nichinich-so, Nichinichi-so
11. Kenya Maua
12. Madagascar Madagascan periwinkle
13. Mexico Ninfa
14. Pakistan Sada-bahar
15. Peru Chavelita
16. Philippines Atay-biya, Chichirica, Kantotan,
Periwinkle, Tsitsirika
17. Rodrigues Islands Saponaire
18. Sri Lanka Mini-mal, Patti-poo
19. Thailand Phaeng phoi farang, Phang-puai-
fa-rang
20. USA Periwinkle
21. Venda Liluvha
22. Vietnam Dua can
23. West Indies Brown man’s fancy, Consumption
bush, Old maid, Periwinkle, Pink
flower, Ram goat rose, Red rose,
Sailors flower, White tulip
The plant has, since a long time, been used to treat
a wide variety of diseases. Europeans used the plant
for minor ailments like headache to a remedy for dia-
betes. Some of its alkaloids are approved as
antineoplastic agents to treat leukemia, Hodgkin’s
disease, malignant lymphomas, neuroblastoma,
rhabdomyosarcoma, Wilms’ tumor, and other
cancers. Its vasodilating and memory-enhancing
properties have experimentally been indicated to
alleviate vascular dementia and Alzheimer’s disease.
The plant also has antihypertensive and antispasmodic
properties.
However, smoking dried leaves of the plant
may cause side effects like incoordination,
prickling of the skin and hallucinations. Excessive
use may result in kidney and nervous system
problems.
Ayurvedic medicines prepared from the stem,
leaves and roots of the plant are used to treat
diabetes, hypertension, asthma, gastro-intestinal
problems, and problems in female sexuality.
Catharanthus is generally a short lived plant. It is
mainly cultivated as an ornamental plant in the
tropical and subtropical world. It grows to about 2
feet in length. It is highly branched and develops a
woody base. The leaves of the plant are petiolate,
oblong in shape, thick and leathery in texture, while
the arrangement is opposite or alternate (Virmani et
al, 1978). The Vincas are mildly poisonous. Flowers
of the plant are single and never double. Most
modern varieties show overlapping petals. The
flowers can be pink, white or a mixture of both and
are sometimes pale pink in colour with a dark violet
dot in the center. Catharanthus flowers come in various
hues. The plant normally grows 8 to 18 inches in
length and a 1-foot spread, although the trailing types
spread upto 2 feet. The chromosome number for all
Cathranthus species is 2n= 16. However, tetraploid
plants grow more fast and the flowers are reported
to be bigger in size (Virmani et al, 1978).
Catharanthus roseus: A Symbol of Hope for
Cancer Patients
The plant is widely used in anticancer therapy and
The National Cancer Council of Malaysia (Majlis
Kanser National, MAKNA) uses the periwinkle logo
as its symbol of hope for cancer patients (Loh,
2008).
Botanical Classification
Kingdom: Plantae
Division: Magnoliophyta
Class: Magnoliopsida
Order: Gentianales
Family: Apocynaceae
Genus: Catharanthus
Species: roseus
Different Species of Catharanthus roseus
The genus Catharanthus comprises 8 species, which
are shown in Fig. 21.1.
294 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
Growth Conditions
Catharanthus prefers sunny, hot conditions and
blooms all through the summer until frost appears.
The related plants, Vinca minor and Vinca major, are
evergreen vining ground plants. They are
propagated from cuttings and not from the seed
unlike Catharanthus. Another member of the family,
Vinca vine (Vinca major), is a trailing vine having
soft green variegated leaves.
Mode of Propagation
Catharanthus plants are self-propagating in nature
(from seed). The seeds need total darkness to
germinate. Cuttings from mature plants also have
capability to develop roots.
Culture
C. roseus grows best in poor, well-drained soils.
Flowering is not encouraged in too fertile soils.
Flowers of the plant drop off when they finish
blooming.
Light
Full sun or partial shade is supportive for the growth
and alkaloid yield (Virmani et al, 1978).
Moisture
Watering of the plant is moderately advisable during
the growing season. However, it is relatively
drought resistant once established. The plant is
sensitive to overwatering.
Uses in Traditional Medicine
Since time immemorial, this plant has been used for
treating varied number of diseases. Some of them
are illustrated in Fig. 21.2. The plant was introduced
in Europe during the mid-1700s. At that time, it
was cultivated as an ornamental. The plant has
found wide application in folk medicine. Extracts
of the plant have been used for ailments like ocular
inflammation, diabetes and hemorrhage to as
diverse as treating insect stings and cancers.
In Madagascar also, extracts of the plant were
used, for hundreds of years, for the treatment of
diabetes, as hemostatics and tranquilizers, to lower
blood pressure, and as disinfectants. The side effect
of using the extracts was hair loss.
In India, juice from the leaves of the plant was
used to treat wasp stings. In Hawaii, the plant was
boiled and used to stop bleeding. In China, it has
various uses such as an astringent, diuretic and cough
remedy. In Central and South America, it was used
to comfort lung congestion, inflammation and sore
throats. In the Caribbean, flower extract is used to
treat eye irritation and infections. Catharanthus was
also regarded as a magic plant as Europeans thought
it could ward off evil spirits, while the French
referred to it as “violet of the sorcerers.”
The plant came to the notice of the Western
researchers in the 1950’s when they came to know
of a tea Jamaicans used to drink to treat diabetes.
Uses in Modern Medicine
Catharanthus Alkaloids: The Anticancer Arsenal
Derived from Plants
Alkaloids are naturally occurring chemical com-
pounds containing basic nitrogen atoms. Extracts of
Catharanthus have significant anticancer activity
against numerous cell types. The greatest activity is
seen against multi-drug resistant tumor types, which
suggests that there are compounds in Catharanthus
that work in association with antineoplastic elements
by inhibiting resistance to them.
A plethora of alkaloids are produced by C. roseus,
several of which are accumulated in various parts of
the plant (Figs 21.3 and 21.4). These terpenoid indole
alkaloids (TIAs) are synthesized via operation of
secondary metabolism pathways. Several studies have
Fig. 21.1: Various species of the genus Catharanthus.
Anticancer Alkaloids of Catharanthus roseus 295
Fig. 21.2: Different parts of Catharanthus roseus that have been used in traditional systems of medicine
for treating various diseases.
Fig. 21.3: Catharanthus alkaloids from various parts of the plant. (For color version, see Plate 5)
296 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
Fig. 21.4: Classification of Catharanthus alkaloids (Johnson et al, 1963).
pointed out the involvement of signal components,
such as receptors, Ca2+ influx, medium alkalinization,
oxidative burst, and several others for enhanced
production of secondary metabolites, i.e. the alkaloids
by increased transcription of related genes. It has
already been proven in C. roseus that the abiotic
elicitor UV-B induces the formation of dimeric TIAs.
TIAs provide protection against microbial
infection, herbivores and abiotic environmental
stresses such as UV irradiation. Vincristine and
vinblastine are the dimeric alkaloids, while ajmalicine
and serpentine are anti-hypertensive monomeric
alkaloids. The antitumor dimeric alkaloids accumu-
lating in the leaves of Vinca plants are composed of
catharanthine and vindoline monomers and are
exclusively found in the aerial parts. These alkaloids
are mainly used in modern medicine as immuno-
suppressive and antitumor agents.
Catharanthus roseus contains alkaloids such as
vinblastine, vincristine (named after Vinca) and their
derivatives. These are produced by the stem of the
plant as a milky sap, which is poisonous if ingested.
Plant contains about 0.86% of alkaloids in roots;
0.67% in leaves and 0.31% in stems. Vincristine is
used as the chemotherapeutic agent for Hodgkin’s
lymphoma, while vinblastine is used for childhood
leukemia. Vincristine is used more than vinblastine,
but the plant produces a higher amount of vinblastine.
It is, however, possible to convert vinblastine into
vincristine chemically or using microorganisms.
Catharanthus alkaloids arrest cancer cell
proliferation by binding to tubulin in the mitotic
spindle. Catharanthus alkaloids also induce apoptosis
(programmed cell death). They also inhibit spread
of various other types of cancers like those of breast,
ovary, lung, colon, rectum, testis, neuroblastoma,
Hodgkin’s disease and leukemia. Another use of
the periwinkle extracts and derivatives such as
Vinpocetine, is as nootropic drugs (substances that
enhance human cognitive abilities- the functions and
capacities of the brain). Vinpocetine, a semisynthetic
derivative of vincamine, is commercially known as
Cavinton or Intelectol and its chemical name is ethyl
apovincaminate.
Vinblastine and vincristine were the first
naturally synthesised products whose structures
were determined by X-ray and also they were
among the first for which X-ray of a heavy atom
derivative was used to establish their absolute
configuration. Vindoline, a major alkaloid of the
plant, constitutes the complex half of vinblastine
and contributes as both a natural and synthetic
precursor.
The medicinally useful Catharanthus alkaloids are
low-volume, high-value compounds and difficulties
in their synthetic derivatization has created immense
interest in exploring biotechnological routes for their
enhanced production (Arora, 1998; Arora et al, 2005).
Catharanthus alkaloids form an integral part of
chemotherapy regimen and are either used singly
Anticancer Alkaloids of Catharanthus roseus 297
or in combination (Table 21.2). All Catharanthus
alkaloids in clinical use are administered
intravenously (IV). After injection, they are
eventually metabolized by the liver and excreted.
The main side effects of these drugs are peripheral
neuropathy, hair loss, hyponatremia and consti-
pation. Semi-synthetic Catharanthus alkaloids, e.g.
vinorelbine and vinflunine have been developed to
improve the therapeutic index (Wargin and Lucas,
1994). Vinorelbine and vinflunine exert their
antitumor effect by binding to tubulin. These
compounds reduce microtubule dynamics and
assembly resulting in cell cycle arrest at the
metaphase/anaphase transition (Jordan et al, 1991;
Wilson et al, 1999). Both vinorelbine and vinflunine
have been shown to be useful in the treatment of
non-small cell lung, metastatic breast and bladder
cancer (Depierre et al, 1991; Bennouna et al, 2006;
Mano, 2006).
An inadequately studied area with respect to
Catharanthus alkaloids is their possible use in
combination with or as an adjunct to radiation
therapy (McCormack, 1990; Simoens et al, 2008). A
few drugs have been shown to clinically render
radiation-resistant tumors sensitive to radiation
therapy. The usefulness of the Catharanthus alkaloids
in this area has not been adequately investigated so
far (Simoens et al, 2008).
Catharanthus Alkaloids in Clinical Use
Vinblastine (VLB)
Vinblastine (Fig. 21.5) is the official generic name
for the alkaloid formerly known as vincaleuko-
blastine. It is a colorless compound. The sulphate
derivative (VLB), which is used in the clinic, is a
white to slightly yellow, hygroscopic crystalline
compound that is soluble in water and methanol. It
is an anti-mitotic drug widely used medically to
treat different kinds of cancers, e.g. breast cancer,
non-small cell lung cancer, head and neck cancer,
Hodgkin’s lymphoma and testicular cancer.
Mode of Action
Vinblastine was first isolated by Robert Noble and
Charles Thomas Beer from the Madagascar
periwinkle plant. Vinblastine’s utility as a
chemotherapeutic agent was first discovered when
it was crushed into a tea. Consumption of this tea
led to a decreased number of white blood cells;
therefore, it was hypothesized that vinblastine might
be effective against cancers of the white blood cells
such as lymphoma.
Vinblastine is a chemical analogue of vincristine.
It binds to tubulin, thereby inhibiting the assembly
of microtubules. It is M phase cell cycle-specific and
is an integral component of a plethora of chemo-
therapy regimens, including ABVD (Adriamycin,
Bleomycin, Vinblastine, Dacarbazine) for Hodgkin’s
lymphoma. Vinblastine is a component of the
regimen of choice for the treatment of metastatic
testicular cancer. In the treatment of testicular
carcinomas, vinblastine in association with other
antitumor agents often results in a cure rate of over
90% in patients. In adult Hodgkin’s lymphoma, the
Catharanthus alkaloids have raised the 5 year
survival chances to 98% (Meyers, 2007). Vinblastine
has been shown to combat cancer by interfering
with glutamic acid metabolism. Vinblastine is also
used in the treatment of Kaposi’s sarcoma, mycosis
fungoides and carcinoma of the breast.
Uses
VLB, when used in encapsulated form in multilamellar
liposomes (composed of phosphatidylcholine and
phosphatidylserine residues), showed substantial
enhancement of antitumor activity against VLB-
resistant cells. This strategy can be useful in
overcoming the problem of multidrug resistance
(MDR). Solid VLB can be safely stored at room
temperature within sealed ampoules in dark
conditions in an inert atmosphere.
Fig. 21.5: Chemical structure of vinblastine.
298 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
Toxicity and Side Effects
Toxicities of VLB include bone marrow suppression
(which is dose-limiting), gastrointestinal toxicity,
potent vesicant (blister-forming) activity, and
extravasation injury (forms deep ulcers). Patients
with bacterial infections are not prescribed this drug.
Vinblastine has been shown to be embryotoxic and
mutagenic in animal studies and is also carcinogenic
and, therefore, should not be used in pregnancy.
Breast feeding is also not recommended because of
its potential secretion into breast milk.
Vincristine (VCR)
Vincristine (brand name, Oncovin), is also known
as leurocristine (Fig. 21.6). VCR is a Vinca
(Catharanthus roseus) alkaloid and hence its name. In
most commercial preparations, VCR appears as a
colourless fluid. It is a mitotic inhibitor, and is
extensively used in cancer chemotherapy. Vincristine
was approved by the United States Food and Drug
Administration (FDA) in July 1963 (Farnsworth,
1985) as Oncovin.
Mode of Action
Vincristine binds to tubulin dimer, which is a
structural protein, inhibiting assembly of micro-
tubule structures. Disruption of the microtubules
arrests mitosis in metaphase stage of the cell cycle.
The Catharanthus alkaloids affect all rapidly dividing
cell types including cancer cells, intestinal epithelium
and bone marrow.
Both VCR and VLB are active at submicromolar
concentrations ranging from 10 nM upto 1 µM. These
drugs bind to the growing ends of microtubules
resulting in an “end-capping” or the “poisoning”
effect. It has also been noticed that at higher
concentrations (> 10 µM), these compounds also
cause tubulin aggregation, which results in the
formation of tubulin paracrystals (Foye, 1995).
Formula – C46H56N4O10
Mol Mass 824.958 g/mol
Metabolism Hepatic
Excretion Mostly biliary, 10% in urine
Uses
Vincristine is delivered by intravenous infusion for
use in various types of chemotherapy regimens. VCR
is used for treating non-Hodgkin’s lymphoma as an
integral constituent of the chemotherapy regimen
CHOP (Cyclophosphamide, Adriamycin (hydroxy-
doxorubicin), Vincristine, and Prednisone). It is also
employed for treating Hodgkin’s lymphoma, as part
of MOPP (Mechlorethamine, Vincristine, Pro-
carbazine, Prednisone), COPP, BEACOPP, or the
less popular Stanford V chemotherapy regimen, in
acute lymphoblastic leukemia, and also in the
treatment of nephroblastoma (Wilms’ tumor).
Toxicity and Side Effects
The main side effects of vincristine are peripheral
neuropathy, hyponatremia, constipation and hair
loss. Injection of Catharanthus alkaloids into the
spinal canal (intrathecal administration) can be lethal.
There are cases of ascending paralysis due to massive
encephalopathy and spinal nerve demyelination,
accompanied by intractable pain, finally leading to
death. In some patients, breathing problems or a
lung spasm may precipitate after the drug is
administered. Secondary cancers may also
occasionally develop in certain patients if they
receive the drug along with other anticancer drugs
that may act as carcinogens.
Multiple Drug Resistance is a major obstacle in
the cancer treatment specifically regarding two
Fig. 21.6: Chemical structure of vincristine.
Anticancer Alkaloids of Catharanthus roseus 299
drugs, VLB and VCR. Some of the other side
effects of the alkaloids like vinblastine and
vincristine are leukopenia, thrombopenia, para-
sthesias, motor weakness, depression, psychoses,
neuromyopathy, peripheral neuritis and convul-
sions, etc.
Vincristine and vinblastine are used in a variety
of chemotherapeutic regimens for adults, including
paediatric patients (Tables 21.2 and 21.3).
Vindesine
Vindesine, VDS (Foye, 1995), (Fig. 21.7) is an anti-
mitotic Catharanthus alkaloid used in chemotherapy.
When the commercially available powder of
vindesine is dissolved it appears like a colorless
fluid. Vindesine is used to treat several different
types of cancer, including leukaemia, lymphoma,
melanoma, breast cancer, and lung cancer.
Toxicity and side effects of vindesine are similar
to those of vinblastine. Vindesine is marketed
under the names Eldisine and Fildesin and is used
mainly to treat melanoma and lung cancers
(carcinomas) and, with other drugs, to treat uterine
cancers.
Formula -C43H55N5O7
Mol mass -753.926 g/mol
Metabolism -Hepatic
Excretion -Biliary and renal.
Vinorelbine
Vinorelbine (VNLB, VRL) (Fig. 21.8) is the first
5´NOR semi-synthetic Catharanthus alkaloid. It is
obtained by semi-synthesis from Catharanthus
alkaloids like vindoline and catharanthine, via
Polonovski fragmentation strategy. It was disco-
vered in mid-1990s by the Pierre Fabre Company.
Vinorelbine (Navelbine or Noranhydrovinblastine)
is an anti-mitotic chemotherapy drug that is given
as a treatment for some types of cancer, including
breast cancer and non-small cell lung cancer. It
appears as a colorless fluid. So far, it seems to have
a wider range of antitumor activity than any other
Catharanthus alkaloid. It is assumed to be less of a
nerve poison than vindesine.
Side Effects
Vinorelbine produces a number of side-effects in
patients that can limit its clinical application, e.g.
constipation, lowered resistance to infection,
bleeding, anaemia, nausea, diarrhea, numbness or
tingling in hands or feet, tiredness and a general
feeling of weakness, inflammation of the vein into
which it was injected. Infrequently, severe
hyponatremia is observed. Amongst the less
common effects hair loss and allergic reactions have
been reported in some patients.
Vinflunine (VFL)
Vinflunine (Fig. 21.9) was discovered by Prof Jean-
Claude Jacquesy. It is a promising second generation
anticancer drug derived from the Catharanthus
Fig. 21.7: Chemical structure of vindesine.
Fig. 21.8: Chemical structure of vinorelbine.
300 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
alkaloid vinorelbine (Etievant et al, 1999). It was
developed by Laboratoires Pierre Fabre. Vinflunine
is a relatively novel alkaloid uniquely fluorinated,
using superacid chemistry (Kruczynski et al, 1998;
Kruczynski, 2001), in a little exploited region of the
catharanthine moiety. In vitro investigations have
confirmed the mitotic-arresting and tubulin-
interacting properties of vinflunine shared by other
Catharanthus alkaloids (Kruczynski et al, 2001; Yun-
San Yip et al, 2008). Classically, its mechanism of
action involves slowing down of the metaphase-to-
anaphase transition, resulting in blocking of cancer
cells in mitosis, and eventually induction of
apoptosis (Pourroy et al, 2006). In vitro studies have
indicated least potency of vinflunine in comparison
to other Catharanthus alkaloids, while in vivo studies
in a range of transplantable murine and human
tumor models in mice have shown that vinflunine
was markedly superior to vinorelbine. It was also
noticeable that vinflunine induced considerably
prolonged inhibitory effects on tumor growth, in
human and mice models, than did vinorelbine under
in vivo experimental conditions (McIntyre and
Castaner, 2004). Phase I evaluation of vinflunine
have been completed in Europe. Appreciable activity
has been observed in phase II studies, majorly in
the treatment of transitional cell carcinoma of the
urothelial tract, non–small cell lung cancer, and breast
cancer. Vinflunine has currently entered phase III
trial assessment in patients suffering with (second
line) transitional cell carcinoma of the urothelium
and first-line advanced breast cancer (Bennouna et
al, 2008). Research is being carried out on this
compound for the treatment of bladder cancer.
Vinflunine and Vinorelbine: A Comparison
Vinflunine has a great structural similarity with
vinorelbine. But the selective induction of the two
fluorine atoms seems to influence the drugs
characteristics in the following ways (Simoens et al,
2008):
i. VFL’s potency with respect to both inhibition
of cell proliferation and mitotic block is lower
than VRL.
ii. VFL shows relatively low in vitro cytotoxic
potency, but has exhibited higher in vivo activity
against human tumour experimental models.
iii. VFL also has a 3-16 fold lower overall binding
affinity for tubulin than VRL. This difference
partially indicates that high concentrations of
the drug are required to block mitosis and cell
proliferation. The NMR study of Fabre et al
(2002) showed the presence of specific binding
sites and showed a different affinity of VFL
and VRL to the tubulin dimer at physiological
temperatures. This may account for their
different toxicity.
iv. The peak intracellular drug concentrations at the
mitotic IC50 value are highest for VFL (4.2 ± 0.2
µM as compared to 1.3 ± 0.1 µM for VRL). This
indicates that intracellular binding reservoir(s)
could be responsible for VFL’s high efficacy to
some extent, by providing a reservoir for excess
drug and enabling its gradual release. VFL also
induces significantly smaller spirals (tubulin
aggregates) than VRL. This lower overall binding
affinity for tubulin, together with the smaller
spirals, the shorter relaxation times and the
gradual release, suggest that VFL may show
reduced neurotoxicity as compared to VRL.
v. VFL seems to be a much less potent inducer of
drug resistance when compared to VRL.
Upon experimentally determining, the radios-
ensitising effects of both semisynthetic Catharanthus
Fig. 21.9: Chemical structure of vinflunine.
Anticancer Alkaloids of Catharanthus roseus 301
Table 21.2: Overview of Catharanthus alkaloids, their properties and use in chemotherapy regimens (Adapted with significant
modification from: Baquiran Delia C. Cancer Chemotherapy Handbook. Lippincott, Philadelphia; Second Edition, 2001;
344-74).
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
Ajmalicine – – – Plant, Callus C21H24N2O3
Tissue
Akuammine – – – Plant C20H26N2O4
Carosidine – – – Leaf, Root Dimeric
Carosine – – – Leaf, Flower C46H56N4O10
Catharanthine – – – Plant, Callus C21H24N2O2
Tissue
Catharicine – – – Leaf, Flower C46H52N4O10
Catharine – – – Aerial Parts C46H52N4O9.CH3OH
Isoleurosine – – – Leaf C46H60N4O9
Lochnenidine – – – Leaf C20H24N2O8
Lochnericine – – – Plant C21H24N2O2
Lochneridinine – – – Leaf C22H26N2O4
Lochnerine – – – Plant C20H24N2O2
Neoleurocristine – – – Plant C46H56N4O12
Neoleurosidine – – – Aerial Parts C46H62N4O11
Perivine – – – Plant C20H24N2O2
Pleurosine – – – Aerial Parts C46H56N4O10
Reserpine – – – Plant, Callus C33H40N2O9
Tissue
Serpentine – – – Plant, Callus C21H22N2O3
Tissue
Sitsirikine-1/2 – – – Plant C21H26N2O3.
H2SO4 1/2H2SO4
Tetrahydroal- – – – Plant, Root, C21H24N2O3
stonine Flower
Vinblastine VL or VLB Exal,Velban, ABV (Doxorubicin, Phenytoin- Plant C46H56N4O9
or VBL Velbe, Velsar Bleomycin, VLB)– decreases
Kaposi’s sarcoma.serum phenytoin
levels.
ABVD (Doxorubicin, Mitomycin-
Bleomycin, VLB causes acute
and/or Dacarbazine) pulmonary
Hodgkin’s reactions.
lymphoma.
BCVPP (Carmustine,
Cyclophosphamide,
Contd...
302 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
VLB, Procarbazine,
Prednisone)–
Hodgkin’s lymphoma
ChLVPP (Chlorambucil,
VLB, Procarbazine,
Prednisone)–
Hodgkin’s lymphoma.
ChlVPP/EVA (ChlVPP
with Etoposide, VCR
and Doxorubicin)–
Hodgkin’s lymphoma.
CISCA/VB
(Cyclophosphamide
Doxorubicin, Cisplatin
alternating with VLB,
Bleomycin)–Germ
Cell tumors
CMV (Cisplatin,
Methotrexate, VLB)–
Bladder cancer.
CVD (Cisplatin, VLB,
Dacarbazine)–
Malignant melanoma
CVPP (Lomustine,
VLB, Procarbazine,
Prednisone)–
Hodgkin’s lymphoma.
EVA (Etoposide, VLB,
Doxorubicin)–
Hodgkin’s lymphoma.
MOPP/ABV
(Mechlorethamine,
VCR, Procarbazine,
Prednisone, Bleomycin,
VLB, Doxorubicin)–
Hodgkin’s lymphoma.
MVAC (Methotrexate,
Doxorubicin, VLB,
Cisplatin)–Bladder
cancer.
MVP (Mitomycin, VLB,
Cisplatin)–nonsmall
cell, lung cancer.
MVPP (Mechlorethamine
(nitrogen mustard), VLB,
Contd...
Contd...
Anticancer Alkaloids of Catharanthus roseus 303
Procarbazine, Prednisone)
Hodgkin’s disease.
NOVP (Mitoxantrone,
VCR, VLB, Prednisone)
Hodgkin’s disease.
PVB (Cisplatin, VLB,
Bleomycin)–Testicular
Cancer, adenocarcinoma.
STANFORD V
(Mechlorethamine,
Doxorubicin, VLB, VCR,
Bleomycin, Etoposide,
Prednisone)–Hodgkin’s
lymphoma.
VATH (VLB, Doxorubicin,
Thiotepa, Fluoxymestrone)
Breast Cancer.
VDP (VLB, Dacarbazine,
Cisplatin)–Malignant
melanoma.
VIP (VLB or Etoposide,
Ifosfamide, Cisplatin,
Mesna)–Testicular
cancer.
VM (Mitomycin, VLB)–
Breast cancer.
Vincamicine – – – Leaf Dimeric
Vincarodine – – – Leaf C44H52N4O10
Vincristine Leurocristine, Oncovin, BOMP (Bleomycin, Mitomycin- Plant C46H56N4O10
VCR Vincasar PES, VCR, Cisplatin, cause Acute
Kyocristine, Mitomycin)– pulmonary
Vincosid, Cervical Cancer.reactions.
Vincrex
CAL-G (Cyclophos- Digoxin-
phamide, decrease
Daunorubicin, VCR, serum
Prednisone with digoxin levels.
Asparaginase or
Pegaspargase)–
Acute lymphocytic
leukemia (ALL).
CAV or VAC
(Cyclophosphamide,
Doxorubicin, VCR)–
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
Contd...
Contd...
304 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
Lung Cancer (small
cell)
CAVE (Etoposide
in addition to CAV)–
small cell lung
cancer.
CEV (Cyclophos-
phamide, Etoposide,
VCR)–small cell lung
cancer.
CHOP (Cyclophos-
phamide,
Doxorubicin,
VCR, Prednisone)–
non-Hodgkin’s
lymphoma
CHOP/BLEO (alongwith
CHOP Bleomycin)–non-
Hodgkin’s lymphoma.
CMFVP
(Cyclophosphamide,
Methotrexate,
Fluorouracil,
Prednisone, VCR)–
breast cancer.
COB (cisplatin, VCR,
Bleomycin)–head
and neck cancer.
CODE (Cisplatin,
VCR, Doxorubicin,
Etoposide)–small
cell lung cancer.
COMLA
(Cyclophosphamide, VCR,
Methotrexate, Leucovorin,
Cytarabine)–non-
Hodgkin’s lymphoma.
COMP
(Cyclophosphamide,
VCR, Methotrexate,
Prednisone)–
pediatric Hodgkin’s
lymphoma.
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
Contd...
Contd...
Anticancer Alkaloids of Catharanthus roseus 305
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
COP
(Cyclophosphamide,
VCR, Prednisone)–
non-Hodgkin’s
lymphoma.
COPE
(Cyclophosphamide,
VCR, Cisplatin,
Etoposide)–small
cell lung cancer.
COPP/CMOPP
(Cyclophosphamide,
VCR, Procarbazine,
Prednisone)–non/
Hodgkin’s lymphoma.
CVP (Cyclophosphamide,
VCR, Prednisone)–
non-Hodgkin’s
lymphoma, chronic
lymphocytic leukemia(CLL).
CYVADIC
(Cyclophosphamide,
VCR, Doxorubicin,
Dacarbazine)–
sarcoma of bony or
soft tissue.
DVP (Daunorubicin,
VCR, Prednisone)–
acute lymphocytic
leukemia.
M-2 (VCR,
Carmustine,
Cyclophosphamide,
Melphalan,
Prednisone)–
multiple myeloma.
MACOP-B
(Methotrexate,
Leucovorin,
Doxorubicin,
Cyclophosphamide,
VCR, Bleomycin,
Prednisone)–non-
Hodgkin’s lymphoma.
Contd.
Contd...
306 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
m-BACOD
(Methotrexate,
Leucovorin,
Bleomycin,
Doxorubicin,
Cyclophosphamide,
VCR,
Dexamethasone)–
non-Hodgkin’s
lymphoma.
MOPP
(Mechlorethamine,
VCR, Procarbazine,
Prednisone)–
Hodgkin’s
lymphoma.
NOVP (Mitoxantrone,
VCR, VLB,
Prednisone)–
Hodgkin’s
lymphoma.
OPA (VCR,
Prednisone,
Doxorubicin)–
Hodgkin’s
lymphoma.
OPPA (VCR,
Procarbazine,
Prednisone,
Doxorubicin)–
Hodgkin’s
lymphoma.
PCV (Lomustine,
Procarbazine, VCR)
non-small cell
Lung cancer.
POC (Prednisone,
Methyl-CCNU, VCR)
brain tumor
ProMACE/cytaBOM
(Prednisone,
Doxorubicin,
Cyclophosphamide,
Etoposide, Cytarabine,
Bleomycin, VCR,
Methotrexate,
Leucovorin)–non-
Hodgkin’s lymphoma.
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
Contd...
Contd...
Anticancer Alkaloids of Catharanthus roseus 307
PVDA (Prednisone in
addition to VDA)–
acute lymphocytic
leukemia.
STANFORD V
(Mechlorethamine,
Doxorubicine, VLB,
VCR, Bleomycin,
Etoposide,
Prednisone)–
Hodgkin’s
lymphoma.
VAC PULSE (VCR,
Dactinomycin,
Cyclophosphamide)
Sarcoma.
VAC STANDARD
(VCR, Dactinomycin,
Cyclophosphamide)
soft tissue
sarcoma.
VACAdr-IfoVP (VCR,
Dactinomycin,
Doxorubicin,
Cyclophosphamide,
Ifosfamide,
Etoposide)–bony
and soft tissue
sarcoma.
VAdrC (VCR,
Doxorubicin,
Cyclophosphamide)
bony and Soft
tissue sarcoma.
VAD (VCR,
Dactinomycin,
Doxorubicin)–
Wilms’ tumor.
VBAP (VCR,
Carmustine,
Doxorubicin,
Prednisone)–
multiple myeloma.
VCAP (VCR,
Cyclophosphamide,
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
Contd...
Contd...
308 Herbal Medicine: A Cancer Chemopreventive and Therapeutic Perspective
Alkaloid Abbreviation/ Commercial Combination Interaction with Site of Chemical Formula
Other Name Name Regimens other Drugs Origin
and Use
Doxorubicin
Prednisone)–
multiple myeloma.
VDA (VCR,
Daunorubicin,
Asparaginase)–
acute lymphocytic
leukemia.
”8 IN 1"
(Methylprednisone,
VCR, Methyl-CCNU,
Procarbazine,
Hydroxyurea,
Cisplatin,
Cytarabine,
Cyclophosphamide/
Dacarbazine)–brain
tumors.
Vindesine VDS Eldisine, Mitomycin-
Fildesin, causes acute
desacetyl pulmonary
vinblastine. reactions.
Methotrexate-
increases
methotrexate
plasma clearance.
Vindolicine – – – Leaf, Flower C25H32N2O62
Vindolidine – – – Leaf C48H64N4O10
Vindoline – – – Plant, Callus C26H32N2O6
Tissue
Vindolinine-2HC1 – – – Plant, Leaf C21 H24N2O2.2HCl
Vinleurosine – – – C46H58N4O9
Vinorelbine VNLB, VRL Navelbine NP (Vinorelbine, Mitomycin-
Cisplatin)–non- causes acute
small cell lung pulmonary
cancer.reactions.
VC (Vinorelbine, Cisplatin-
Cisplatin)–non-increases
small cell lung granulocytopenia.
cancer.
Vinrosidine – – – Dimeric
Virosine – – – Plant, Root C22 H26N2O4
Contd...
Anticancer Alkaloids of Catharanthus roseus 309
Table 21.3: Some commonly used chemotherapy regimens, including Catharanthus alkaloids, for pediatric use (Combination
chemotherapy regimens have been adapted with modification from: Baquiran Delia C. Cancer Chemotherapy Handbook.
Lippincott, Philadelphia; Second Edition, 2001; 344-74).
Alkaloid Combination Regimens
Vincristine (VCR) COMP (Cyclophosphamide, VCR, Methotrexate, Prednisone) – Pediatric Hodgkin’s lymphoma.
COPP/CMOPP (Cyclophosphamide, VCR, Procarbazine, Prednisone) – Non/Hodgkin’s Lymphoma.
DVP (Daunorubicin, VCR, Prednisone) – Acute lymphocytic leukemia.
MOPP (Mechlorethamine, VCR, Procarbazine) – Brain tumors.
OPPA (VCR, Procarbazine, Prednisone, Doxorubicin) – Hodgkin’s lymphoma.
POC (Prednisone, Methyl-CCNU, VCR) – Brain tumor.
PVDA (Prednisone in addition to VDA) – Acute lymphocytic leukemia.
VACAdr-IfoVP (VCR, Dactinomycin, Doxorubicin, Cyclophosphamide, Ifosfamide, Etoposide) – Bony and
soft tissue Sarcoma.
VAdrC (VCR, Doxorubicin, Cyclophosphamide) – Bony and soft tissue Sarcoma.
VAD (VCR, Dactinomycin, Doxorubicin) – Wilms’ tumor.
VDA (VCR, Daunorubicin, Asparaginase) – Acute lymphocytic leukemia.
alkaloids were observed to be comparable and
nearly always cell line-specific and concentration-
dependent. Due to the more favorable toxicity
profile of vinflunine, it might be more promising
than vinorelbine for chemoradiation studies.
CONCLUSION
Catharanthus alkaloids and their semisynthetic
derivatives have been used in the clinic since a long
time and continue to benefit innumerable cancer
patients. The case of Catharanthus has been a
successful one, where a lead from a plant has reached
the bedside in modern medicine. Several other
anticancer drugs of plant origin have yielded success
stories, e.g. Taxol, combretastatins, camptothecin,
etc. but the case of Catharanthus stands apart in
view of its serendipitious discovery. There is a need
to discover several such agents from nature’s
storehouse, given to us in the form of gift as plants.
Plant-derived molecules can serve as an inimitable
template for the synthesis of more potent anticancer
drugs. Whether the Catharanthus alkaloids will serve
this purpose or not in the future can’t be predicted,
but certainly the leads obtained so far have shown
promise for plants.
Dr John PN Rossazza of the University of Iowa,
USA has appositely summarized the need for more
research on Catharanthus alkaloids by saying “We
believe that serendipitous winds continue to blow us
through uncharted waters-but that somewhere there will
lie calm seas and a new archipelago where new generations
of Catharanthus alkaloid drugs- and those who need them-
will live happily ever after.”
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... These alkaloids stop the cell cycle and trigger apoptosis by preventing microtubule assembly [57]. The other alkaloids include vindesine 30, vinorelbine 31 and vinflunine 32 [58]. Vindesine effectively impedes the progression of cells into metaphase mitosis by impeding the tubulin mitotic function. ...
... In Table 2 (Ref. [56,58,60,62,63]), the chemical structures of key anticancer alkaloids are presented, with systematic numbering corresponding to the text and highlighting their anticancer activity. ...
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Cancer is a hard-to-treat disease with a high reoccurrence rate that affects health and lives globally. The condition has a high occurrence rate and is the second leading cause of mortality after cardiovascular disorders. Increased research and more profound knowledge of the mechanisms contributing to the disease’s onset and progression have led to drug discovery and development. Various drugs are on the market against cancer; however, the drugs face challenges of chemoresistance. The other major problem is the side effects of these drugs. Therefore, using complementary and additional medicines from natural sources is the best strategy to overcome these issues. The naturally occurring phytochemicals are a vast source of novel drugs against various ailments. The modes of action by which phytochemicals show their anti-cancer effects can be the induction of apoptosis, the onset of cell cycle arrest, kinase inhibition, and the blocking of carcinogens. This review aims to describe different phytochemicals, their classification, the role of phytochemicals as anti-cancer agents, the mode of action of phytochemicals, and their role in various types of cancer.
Book
Continuing the high standards set by the widely acclaimed first and second volumes of Medicinal Plants of the World: Chemical Constituents, Traditional and Modern Medicinal Uses, Ivan A. Ross now comprehensively documents in Volume 3 the medicinal value of 16 major plant species widely used around the world in medical formulations. The plants for this volume are Camellia sinenis, Cannabis sativa, Cocos nucifera, Coffea arabica, Daucus carota, Ferula assafoetida, Hordeum vulgare, Larrea tridentata, Nicotiana tabacum, Olea europaea, Oryza sativa, Plantago ovata, Saccharum officinarum, Serenoa repens, Sesamum indicum, and Zingiber officinale. The author's exhaustive summary of available scientific data for each plant provides detailed information on how the plant is used in different countries, describing its traditional therapeutic applications and what is known from its use in clinical trials. Additional material presented includes a botanical description with a color photo of each plant for identification, the common names used for the plant throughout the world, and a listing of the plant's known chemical constituents. A comprehensive bibliography cites the literature available from a wide range of disciplines. Medicinal Plants of the World: Chemical Constituents, Traditional and Modern Medicinal Uses, Volume 3, offers a unique collection of vital scientific information for pharmacologists, herbal medicine practitioners, drug developers, phytochemists, medicinal chemists, phytologists, toxicologists, and researchers who want to explore the many uses of plant materials for medicinal and related purposes. Its wealth of significant information will reveal little-known facts about these plants and open new horizons of application for the many novel drugs and drug candidates found in them.
Chapter
This chapter describes the biochemical pharmacology, cellular pharmacology, preclinical pharmacology, preclinical toxicology, clinical pharmacology, and clinical toxicology of antitumor bisindole alkaloids from Catharanthus. Despite the close structural resemblance of vinblastine, vincristine, and vindesine, the profiles of biological activities of the compounds are not identical. Vinblastine treatment is much less likely to result in neurotoxicity than the treatment with vincristine; on the other hand, vinblastine produces much more perturbation of bone marrow function than vinblastine. Vincristine is more effective than vinblastine in the treatment of acute leukemia in children. Vincristine and vinblastine interfere with the mitotic process by producing arrest of cell division in metaphase. These drugs interact with tubulins, dimeric cellular proteins that play several critical roles in cell structure and function, including the organization of chromosomes on a matrix (spindle), which is an essential feature of normal cell division. The toxicological profile for vindesine includes effects observed with both vinblastine and vincristine. Among the effects observed with vindesine are bone marrow depression, alopecia, and peripheral neurotoxicity.
Article
Ve have used a structure-activity approach to investigate whether the Vinca alkaloids inhibit cell proliferation primarily by means of their effects on mitotic spindle microtubules or by another mechanism or by a combination of mechanisms. Five Vìnca alkaloids were used to investigate the relationship in Urla cells between inhibition of cell proliferation and blockage of mitosis, alteration of spindle organization, and depolymeri- zation of microtubules. Indirect immunofluorescence staining of micro- tubules and 4,6-diamidino-2-phenylindole staining of chromatin were used to characterize the effects of the drugs on the distributions of cells in stages of the cell cycle and on the organization of microtubules and chromosomes in metaphase spindles. The microtubule polymer was iso lated from cells and quantified using a competitive enzyme-linked im- munoadsorbent assay for tubulin. We observed a nearly perfect coinci dence between the concentration of each Vinca derivative that inhibited cell proliferation and the concentration that caused 50% accumulation of cells at metaphase, despite the fact that the antiproliferative potencies of the drugs varied over a broad concentration range. Inhibition of cell proliferation and blockage of cells at metaphase at the lowest effective concentrations of all Vinca derivatives occurred with little or no micro- tubule depolymerization or spindle disorganization. With increasing drug concentrations, the organization of microtubules and chromosomes in arrested mitotic spindles deteriorated in a manner that was common to all five congeners. These results indicate that the antiproliferative activity of the Vinca alkaloids at their lowest effective concentrations in Ik-la cells is due to inhibition of mitotic spindle function. The results suggest further that the Vinca alkaloids inhibit cell proliferation by altering the dynamics of tubulin addition and loss at the ends of mitotic spindle microtubules rather than by depolymerizing the microtubules. The spe cific alterations of spindle microtubule dynamics appear to differ among the five Vinca congeners, and such differences may be responsible for differences in the antitumor specificities of the drugs.
Article
This paper describes a bioassay for the quantitative determination of the antimitotic principle(s) present in the periwinkle plant using mice bearing Ehrlich ascites carcinoma (EAC). The method proved accurate, specific, simple and cheap. It could be of great value for the phytochemical screening of plants intended to discover new active compounds capable of arresting mitosis of tumor cells in the metaphase.
Article
Navelbine (vinorelbine, NVB) is the first semisynthetic 5'-nor-vinca-alkaloid selected for clinical trial. NVB has been shown to have a good level of activity against different experimental solid tumors in animals, with low neurotoxicity. In the phase II study, 78 patients with an inoperable non-small-cell lung cancer (NSCLC) were treated with NVB at a weekly dose of 30 mg/m2. No patient had previously received chemotherapy. Twenty-three of the 78 eligible patients showed a partial response (29.4% with a 95% confidence limits: 19.5-39.5). Eight patients were not evaluable and the percentage of partial response were 32.8% in the evaluable patients group. The median response duration was 34 weeks, and the median survival time for the overall population reached 33 weeks. Grade 3-4 leukopenia was seen in 12.5% of cycles. No thrombocytopenia occurred. At the dosage schedule used, NVB seems a very promising agent in the treatment of NSCLC.
Article
Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) is a semisynthetic vinca alkaloid agent that has been structurally modified on the catharanthine nucleus to impart increased lipophilicity. As a result, vinorelbine appears to possess a higher therapeutic index and different pharmacokinetic properties from other marketed vinca alkaloids. Vinorelbine has been quantified in biologic matrices by measurement of total radioactivity, radioimmunoassay, and high-performance liquid chromatography. Because it is specific for the parent drug, high-performance liquid chromatography has generated the most reliable pharmacokinetic data. Vinorelbine is highly bound to platelets and lymphocytes, and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins. The drug undergoes significant metabolism and elimination via the liver and metabolites are excreted primarily in the bile. Two likely vinorelbine metabolites, vinorelbine N-oxide and deacetylvinorelbine, have been isolated and identified in human urine and very low concentrations appeared in plasma. Urinary excretion of unchanged drug accounts for less than 20% of an intravenous dose, with fecal elimination accounting for an additional 30% to 60%. The pharmacokinetic profile of vinorelbine after intravenous bolus or infusion is characterized by triexponential decay. Initial rapid decay is due primarily to distribution into tissues in the peripheral compartments. There is a prolonged terminal phase due to relatively slow efflux of the drug from peripheral compartments, which results in a long terminal phase half-life, with average values ranging from 27.7 to 43.6 hours. Plasma clearance of vinorelbine is high, approaching hepatic blood flow in humans, and its volume of distribution is large, indicating extensive extravascular distribution. In comparison to vinblastine or vincristine, vinorelbine has a higher clearance and a larger volume of distribution than either drug, and a half-life shorter than vinblastine but longer than vincristine. There is no relationship between the age of the patient and the pharmacokinetic parameters of vinorelbine, and coadministration of cisplatin does not appear to influence the pharmacokinetics of vinorelbine. Vinorelbine is the first vinca alkaloid to show promising efficacy following oral administration, and this has led to the development of a liquid-filled, soft-gelatin capsule dosage form. The absolute bioavailability of vinorelbine from this dosage form was 27% when intravenous doses of 30 mg/m2 were compared with oral doses of 100 mg/m2.