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

Scientific classification

Kingdom:  Plantae

(unranked):  Angiosperms
(unranked):  Eudicots
(unranked):  Asterids
Order:  Gentianales
Family:  Apocynaceae
Genus:  Catharanthus

 

Species:

·   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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25.     Deborah A. Thomas, Andreas H. Sarris, Jorge Cortes,Stefan Faderl, Susan O’Brien, Francis J. Giles, Guillermo Garcia-Manero, Maria A. Rodriguez, Fernando Cabanillas, Hagop Kantarjian, Phase II Study of Sphingosomal Vincristine in Patients with Recurrent or Refractory Adult Acute Lymphocytic Leukemia; CANCER January 1, 2006 / Volume 106 / Number 1,120-127.

 

Received on 30.06.2010

Accepted on 07.07.2010        

© A&V Publication all right reserved

Research Journal of Pharmacognosy  and Phytochemistry. 2(5): Sept.-Oct. 2010, 347-353