Vincristine -Potent Mitotic Inhibitor
Kishu
Tripathi1 and T. Siva Kumar2
1Institute of Pharmaceutical
Sciences and Research Center, Bhagwant University, Ajmer,
Rajasthan.
2Nandha College of Pharmacy, Tamil
Nadu.
ABSTRACT:
Vincristine is a vinca alkaloid obtained from Catharanthus and is a potent mitotic inhibitor.
KEYWORDS: Vincristine, mitotic inhibitor
INTRODUCTION:
Catharanthus: An evergreen
shrub, it grows to a height of 1m with a spread of 1m. The stem is short, erect
and branching; the leaves are glossy green, oval, 5cm long and opposite
acuminate; the flowers are soft pink, tinged with red, 5 petalled,
open, tubular and 4cm across, appearing in spring and autumn. A native of
tropical Africa and Madagascar, it prefers rich, well drained, moist soils in a
protected, sunny position, and is drought and frost tender. Propagation is by
seed and by cuttings.
Catharanthus pusillus
Kingdom: Plantae
(unranked): Angiosperms
(unranked): Eudicots
(unranked): Asterids
Order: Gentianales
Family: Apocynaceae
Genus: Catharanthus
· Catharanthus coriaceus Markgr.
Madagascar.
· Catharanthus lanceus (Bojer ex
A.DC.) Pichon. Madagascar.
· Catharanthus longifolius (Pichon)
Pichon. Madagascar.
· Catharanthus ovalis Markgr.
Madagascar.
· Catharanthus pusillus (Murray) G.Don.
Indian subcontinent.
· Catharanthus roseus (L.) G.Don.
Madagascar.
· Catharanthus scitulus (Pichon) Pichon. Madagascar.
· Catharanthus trichophyllus (Baker) Pichon.
Madagascar.
Vincristine (brand name, Oncovin), also
known as leurocristine, is a vinca alkaloid from the Catharanthus
roseus (Madagascar periwinkle), formerly Vinca rosea and
hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.
methyl (1R,9R,10S,11R,12R,19R)-
11-(acetyloxy)- 12-ethyl- 4-[(13S,15S,17S)-
17-ethyl- 17-hydroxy- 13-(methoxycarbonyl)-
1,11-diazatetracyclo[13.3.1.04,12.05,10] nonadeca- 4(12),5,7,9-tetraen- 13-yl] - 8-formyl-
10-hydroxy- 5-methoxy- 8,16-diazapentacyclo [10.6.1.01,9.02,7.016,19]
nonadeca- 2,4,6,13-tetraene- 10-carboxylate
Chemical data:
Formula C46H56N4O10
Mol. mass 824.958 g/mol
Pharmacokinetic data
Bioavailability n/a
Protein binding ~75%
Metabolism Hepatic Half life 19 to 155 hours
Excretion Mostly biliary, 10%
in urine
Therapeutic
considerations:
Pregnancy cat. D(AU) D(US)
Legal status ℞ Prescription only
Routes Exclusively intravenous
History: Having
been used as a folk remedy for centuries, studies in the 1950s revealed that C.
roseus contained 70 alkaloids, many of which are
biologically active. While initial studies for its use in diabetes mellitus
were disappointing, the discovery that it caused myelosuppression (decreased activity of the bone
marrow) led to its study in mice with leukemia, whose lifespan was prolonged by
the use of a vinca preparation. Treatment of the
ground plant with Skelly-B defatting
agent and an acid benzene extract led to a fraction termed "fraction
A". This fraction was further treated with aluminium oxide,
chromatography, trichloromethane, benz-dichloromethane
and separation by pH to yield vincristine1.
Vincristine was approved by the United States Food
and Drug Administration (FDA) in July 1963 as Oncovin.
The drug was initially discovered by a team lead by Dr. J.G. Armstrong; it was
then marketed by Eli Lilly and Company.
Mode of action: Tubulin is a structural protein which polymerizes to action
microtubules. The cell cytoskeleton and mitotic spindle, amongst other things,
are made of microtubules. Vincristine binds to
tubulin dimers, inhibiting
assembly of microtubule structures. Disruption of the microtubules arrests
mitosis in metaphase. The vinca alkaloids
therefore affect all rapidly dividing cell types including cancer cells, but
also intestinal epithelium and bone marrow.
Uses: Vincristine is delivered via intravenous infusion for use
in various types of chemotherapy regimens. Its main uses are in non-Hodgkin's
lymphoma as part of the chemotherapy regimen CHOP, Hodgkin's lymphoma as part
of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen, in
acute lymphoblastic leukemia, and in treatment for nephroblastoma
(Wilms tumor, a kidney tumor common in children). It
is also used to induce remission in ALL with Dexamethasone
and L Asparginase. Vincristine
is occasionally used as an immunosuppressant, for example, in treating
thrombotic thrombocytopenic purpura (TTP) or chronic
idiopathic thrombocytopenic purpura (ITP). It is used
in combination with prednisone to treat childhood leukemia.
Side effects: The main
side-effects of vincristine are peripheral
neuropathy, hyponatremia, constipation and hair
loss.Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. One of the first symptoms of peripheral
neuropathy is foot drop: a person with a family history of foot drop and/or
Charcot-
Marie-Tooth disease (CMT) may benefit from genetic
testing for CMT before taking vincristine2. Accidental injection of vinca alkaloids into the spinal canal (intrathecal
administration) is highly dangerous, with a mortality rate approaching 100%.
The medical literature documents cases of ascending paralysis due to massive
encephalopathy and spinal nerve demyelination,
accompanied by intractable pain, almost uniformly leading to death; a handful
of survivors were left with devastating neurological damage
with no hope of recovery. Rescue treatments consist of
washout of the cerebrospinal fluid and administration of protective medications3.
A significant series of inadvertent intrathecal vincristine
administration occurred in China in 2007 when batches of cytarabine and methotrexate (both often used intrathecally)
manufactured by the company Shanghai Hualian were
found to be contaminated with vincristine4.
Biosynthetic Information
Forms a Basis for Efficient Synthesis 01 the Vinblastine-Vincristine
Family:
From a large number of
investigations involving enzymes obtained from a stable cell line of Catharanthus roseus and
the alkaloids catharanthine (1) and vindoline (3), we have unravelled
the structures of the important late stage intermediates in the biosynthetic
pathway of the clinical anticancer drugs vinblastine (7,
R=CH ) and vincristine (7, R=CHO). Fig.
summarizes the overall sequence involved. From these data, a highly efficient
and commercially important "one-pot" process for the synthesis of the
clinical drugs was developed (Fig.). The overall process, involving five
separate chemical reactions itnd providing a 40% overall
yield of vinblastine,demands
that eiich reaction must proceed with yields in
excess of 80%. A recent review5 summarizes
these extensive studies and provides citations to pertinent earlier references.
Instrumental Analysis:
A simple and rapid method
for the identification of Vinca
alkaloids from a crude extract of Catharanthus roseus G. Don
(Apocynaceae) by direct-injection electrospray
ionisation (ESI) and tandem mass spectrometry (MS/MS)
has been developed. The alkaloids vindoline, vindolidine, vincristine
and vinblastine were evaluated in a commercial
extract of C.
roseus using this method. Catharanthine
and its isomers 19S-vindolinine and vindolinine were
detected in the commercial product by direct injection ESI/MS/MS and confirmed
by preparation and by HPLC-ESI/MS. For the characterisation
of different fragment fingerprints, ESI/MS/MS is a
sensitive, rapid and convenient technique by which to identify some
constituents in complex and mixed plant extracts6.
Brain tumor:
The extensive Evans blue
staining within the brain tumor is shown in Fig. This demonstrates that the
blood brain barrier around the tumor was open to macromolecules as large as
albumin, which is bound to the Evans blue. The vincristine
concentrations in femtomoles per milligram (mean and
95% CI) determined by quantitative autoradiography in the brain tumor, normal
brain, liver, and s.c. tumor
of each animal are presented in Fig. These data demonstrate that 50-_Ci
injections into the ipsilateral carotid resulted in
concentrations of vincristine in the i.c. tumor after 20 min that were 6-fold lower than those
in liver, and 2-fold lower than those in the s.c
tumors. This is the reverse of the normal pattern after intra-arterial drug
administration7. Levels in ipsilateral
normal brain were also negligible.The 10-min time
point in the third animal, which received vincristine
into the dominant contralateral carotid, demonstrated
no additional retention of vincristine in the brain
or i.c. tumor. Liver concentrations in this animal
were 11-fold higher than those in brain, consistent with the known short
initial half-life, prompt tissue binding, and rapid hepatic excretion of
vincristine8.
Results of P-gp Immunohistochemistry:P-gp was detected in liver, a finding consistent with its
role in biliary excretion of vincristine.
It was not detected on tumor cells in brain or s.c. locations. However, it was detected on capillary
endothelium in brain tumor and normal brain and was not detected in capillary
endothelium in s.c. tumors.
This is demonstrated in Figs. 1B–D.
Fig.9. Evans blue staining and immunohistochemistry results. A. Albumin macromolecules,
bound to Evans blue, penetrate the bloodbrain barrier
of the i.c. tumor and the s.c
tumor, but not normal brain. B–D. JSB1 immunocytochemistry
for P-gp. Staining is demonstrated in cerebral
capillaries of the tumor (arrow, B) and in the liver (arrow, C), but not in the
tumor cells in either location or in the s.c.
capillaries (D); 40_magnification.
DISCUSSION:
The findings suggest that
normal brain and tumors implanted within the brain are poorly penetrated by vincristine,even when it is given
as an intracarotid bolus. This occurs despite evidence
that the blood-brain barrier is quite disrupted, allowing Evans blue bound to
albumin, with MW 60,000, to enter the tumor. The molecular weight of vincristine is 930.This lack of penetration is unexpected,
given the lipid solubility of vincristine and its
ready penetration of peripheral nerves. This is likely explained by the
presence of pumps (P-gp or other related drug efflux
pumps) on the cerebral capillaries but not in the peripheral nervous system.
Our results do not rule out other steric factors that
may hinder penetration of this large molecule. This lack of penetration
explains the rarity of central neurotoxicity when vincristine
is administered systemically, despite its profound neurotoxicity if
administered into the CSF. The poor penetration of vincristine
into brain tumors suggests that it is unlikely that this drug adds
substantially to the efficacy of brain tumor regimens. Vincristine
is also associated with significant toxicities. Peripheral and autonomic
neuropathy is an additional burden to a group of patients already at risk of
problems with mobility and sensation due to the tumor itself and to other
drugs, including steroids. In addition, the pharmacology of vincristine
in patients with gliomas might be significantly
affected by the coadministration of cytochrome P450–inducing anticonvulsant drugs. As with
other chemotherapy agents, this drug interaction would be expected to reduce
the systemic levels of vincristine, further
diminishing the chances that this drug contributes to the therapy of this
patient population9-11. The limitations of this study include the
small number of animals and the lack of plasma space correction for the
different organs. This may lead to an underestimate of levels in the normal
brain, since it is less vascular than the i.c. tumor,
liver, and s.c. tumor.
Penetration of drugs may also be affected by regional differences in vascularity of the 9L model, although this is a feature of
human glioblastoma also, as demonstrated by regional
difference in perfusion with MRI. It is also possible that seizures may have
affected permeability, although these would be expected to increase rather than
reduce observed drug levels12.
Fig.10. Vincristine
levels in each animal (fmol/mg, mean and 95%
confidence intervals) determined by quantitative autoradiography. Levels in the
liver are significantly higher than those in other organs, with normal brain
being the lowest in each animal.
Vincristine Cytotoxicity potentiated by Bryostatin 1
Administering VCR 24 h after
Bryol to SCID mice bearing DLCL tumors improves
antitumor activity. Bryol by itself showed some
activity when given at the maximum tolerated dose by the SCID mice (75 ı.tg/kg). In previous
work, we have demonstrated that a Bryol dose of 100 fig/kg was toxic to SCID mice (22). However, even at
a lower dose of 50 rig/kg, which had no significant antitumor activity,Bryol decreased Pgp and down-regulated mdrl
RNA expression,as measured by flow cytometry and quantitative PCR assay. This effect on
tndri expression may be a mechanism by
which Bryol potentiates VCR action. This conclusion
is supported by the increased uptake of [3HIVCR and daunorubicin
fluorescence by WSU-DLCL2 cells after prior exposure to Bryol
compared with control cells13.
Reversal of multidrug
resistance in vincristine-resistant human gastric
cancer cell line SGC7901/VCR by LY980503
Cells of a human
gastric cancer cell line, SGC7901, and its VCR-resistant variant, SGC7901/VCR,
were cultivated with LY980503 and /or doxorubicin (DOX). The cytotoxicity of drugs in vitro was assayed by MTT method.
Based on the flow cytometric technology, the uptake
of DOX was detected in these cells by measuring DOX -associated mean
fluorescence intensity (MFI). SGC7901/VCR cells were 23.5 times more resistant
to DOX in comparison with SGC7901 cells. LY980503 at the concentrations of 2.0 μmol/L -10 μmol/L
had no obvious cytotoxicity to SGC7901 and
SGC7901/VCR cells. After simultaneous treatment with LY980503 at the
concentrations of 2.0, 4.0 and 10 μmol/L, the IC50 of
DOX to SGC7901/VCR cells decreased from 1.6 ± 0.12 μmol/L
to 0.55 ± 0.024, 0.25 ± 0.032 and 0.11 ± 0.015 μmol/L,
respectively, thus, increasing the DOX sensitivity by 2.9-fold (P < 0. 05),
6.4-fold (P < 0. 01) and 14.5-fold (P < 0. 01), respectively. In the
uptake study of DOX, simultaneous incubation of SGC7901/VCR cells with LY980503
significantly increased the DOX -associated MFI in SGC7901/VCR cells. No such
results were found in parental SGC7901 cells14.
Vincristine degradation by serum from leukemic patients: role of myeloperoxidase
Myeloperoxidase (MPO) has been shown to catalyze the in vitro
degradation of vincristine (VCR). Given that MPO is a
lysosomal enzyme that can be released into the
circulation by both normal activated and leukemic myeloid cells, we investigated
the possibility that sera from patients with acute myeloblastic
leukemia (AML) might exhibit an increased capacity to degrade VCR. 31 serum
samples (23 from patients with acute myeloblastic
leukemia and 8 from patients with other conditions) were analyzed after
incubation with (3H)VCR by using HPLC. Sera
from patients with AML demonstrated an increased ability to breakdown VCR when
compared to either normal sera or to sera from patients with lymphoid leukemias. VCR degradation was significantly increased by
adding hydrogen peroxide, an electron donor for MPO, to the sera and was almost
completely inhibited by adding 1 mM acetaminophen, an
inhibitor of MPO. VCR peroxidation in the presence of
hydrogen peroxide correlated both with the number of leukemic blasts in the
circulation at the time the sera were obtained and with serum MPO
concentrations determined by an immunoassay. These data suggest that the
inactivity of VCR in AML may be due in part to its rapid peroxidation
to inactive species by the MPO of leukemic myeloblasts15.
The
consequences of the effects of the chemotherapeutic drug (vincristine)
in organs and the influence on the bioavailability of two radio-biocomplexes used for bone evaluations in balb/c female mice The development of animal model to
evaluate the toxicological action of compounds used as pharmaceutical drugs is
desired. The model described in this work is based on the capability of drugs
to alter the bioavailability of radiopharmaceuticals (radiobiocomplexes)
labeled with technetium-99 m(99mTc). There are
evidences that the bioavailability or the pharmacokinetic of radiobiocomplexes can be modified by some factors, as
drugs, due to their toxicological action in specific organs. Vincristine is a natural product that has been utilized in
oncology. The vincristine effect on the
bioavailability of the radiobiocomplexes
99mTc-methylene diphosphonic acid (99mTc-MDP) and
99mTc-pyrophosphate (99mTc-PYP) in Balb/c female mice
was evaluated. The fragments of kidney were processed to light microscopy and
transmission electron microscopy. The aim of this work was to study at
structural and ultrastructural levels the alterations
caused by vincristine in organs. One hour after the
last dose of vincristine, 99mTc-PYP or 99mTc-MDP was
injected, the animals were sacrificed and the percentage of radioactivity
(%ATI) was determined in the isolated organs. Concerning 99mTc-PYP, the %ATI (i)decreased in spleen, thymus,
lymph nodes (inguinal and mesentheric), kidney, lung,
liver, pancreas, stomach, heart and brain and (ii)increased in bone and
thyroid. Concerning 99mTc-MDP, the %ATI (iii)decreased
in spleen, thymus, lymph nodes (inguinal and mesentheric),
kidney, liver, pancreas,stomach, heart, brain, bone,
ovary and uterus. In conclusion, the toxic effect of vincristine
in determined organs could be responsible for the alteration of the uptake of
the studied radiobiocomplexes16.
Penetration of intra-arterially administered vincristine in experimental brain tumor
Vincristine
is an integral part of the “PCV” regimen that is commonly administered to treat
primary brain tumors. The efficacy of vincristine as
a single agent in these tumors has been poorly studied. This study was designed
to determine whether vincristine enters normal rat
brain or an intracranially or subcutaneously
implanted glioma and to assess the presence of the
efflux pump P-glycoprotein (P-gp) on tumor and
vascular endothelial cells. The 9L rat gliosarcoma
was implanted intracranially and subcutaneously in
three Fischer 344 rats. On day 7, [3H] vincristine
(50 μCi, 4.8 μg)
was injected into the carotid artery, and the animals were euthanized 10 or 20
min later. Quantitative autoradiography revealed that vincristine
levels in the liver were 6- to 11-fold greater than in the i.c.
tumor, and 15- to 37-fold greater than in normal brain, the reverse of the
expected pattern with intra-arterial delivery. Vincristine
levels in the s.c. tumor
were 2-fold higher than levels in the i.c. tumor. P-gp was detected with JSB1 antibody in vascular endothelium
of both normal brain and the i.c. tumor, but not in
the tumor cells in either location, or in endothelial cells in the s.c. tumor. These results
demonstrate that vincristine has negligible
penetration of normal rat brain or i.c. 9L glioma despite intra-arterial delivery and the presence of
blood-brain barrier dysfunction as demonstrated by Evan’s blue. Furthermore,
this study suggests that P-gp-mediated efflux from
endothelium may explain these findings. The lack of penetration of vincristine into brain tumor and the paucity of
single-agent activity studies suggest that vincristine
should not be used in the treatment of primary brain tumors17.
Phase II Study of Sphingosomal Vincristine in Patients with Recurrent or Refractory Adult
Acute Lymphocytic Leukemia
The vinca alkaloid vincristine has
significant activity against lymphomas and acute lymphocytic leukemia (ALL).1 Vincristine induces cytotoxicity
by binding to tubulin, resulting in microtubule depolymerization and metaphase arrest.2,3 These events lead
to apoptosis of cells undergoing mitosis.4 In human leukemia cell lines, vincristine induced apoptosis in vitro in proportion to the
concentration and time of exposure of the drug.4–6 The dose intensity and
delivery of conventional vincristine is limited by
the disruption of axonal microtubules after vincristine
binds to neuronal tubulin. This results in
significant neurotoxicity at doses higher than the “capped”dose
of 2.0 mg18-24.
Outcomes with
salvage therapy for patients with recurrent or refractory acute lymphocytic
leukemia (ALL) are poor, with complete response (CR) rates reported to be
20–30% and a median survival ranging from 2–6 months. New agents are needed to
reduce the recurrence rate after frontline chemotherapy .Vincristine
is an important component of ALL therapy. In animal models, the encapsulation
of vincristine into sphingomyelin
liposomes or “sphingosomes”
for injection (SV) has improved efficacy compared with conventional vincristine. A Phase II clinical trial of single-agent SV
given at a dose of 2.0 mg/m2 every 2 weeks was conducted in patients
with recurrent or refractory ALL. Approximately half of the 16 patients who
received SV had a first CR duration of less than 1 year, 19% had failed
standard induction chemotherapy, and 50% had Philadelphia chromosome-positive
disease. SV was the first salvage attempt in 69% of the patients .The overall
response rate in the 14 evaluable patients was 14% (1 CR and 1 partial
response). Five patients (36%) had transient reductions in bone marrow leukemia
infiltrate with subsequent regrowth of the leukemia
between SV infusions. Toxicity with limited treatment (median number of doses
was two; range, one to five doses) was minimal with expected peripheral
neuropathy25.
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Received
on 30.06.2010
Accepted on 07.07.2010
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Research Journal of Pharmacognosy and Phytochemistry.
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