Leave a message
Loading [Contrib]/a11y/accessibility-menu.js

Chemotherapy medication of Vincristine and Vinblastine

Research Article | DOI: https://doi.org/10.31579/2640-1053/007

Chemotherapy medication of Vincristine and Vinblastine

  • Rico Moha 1*
  • Lujain B 1
  • Armando T 1

1 Hygiene and Tropical Medicine, Jordan

*Corresponding Author: Rico Moha Hygiene and Tropical Medicine, Jordan

Citation: Rico Moha , Lujain B, Armando T. Chemotherapy medication of Vincristine and Vinblastine. J Cancer Research and Cellular Therapeutics, Doi: 10.31579/2640-1053/007

Copyright: © 2017 Rico Moha . This is an open-access article distributed under the terms of The Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 30 January 2017 | Accepted: 20 February 2017 | Published: 04 March 2017

Keywords: acute leukemia, Chemotherapy medication

Abstract

Cancers treated with Vincristine and vinblastine include: acute leukemia, Hodgkin's and non- Hodgkin's lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, Wilms' tumor, multiple myeloma, chronic leukemias, thyroid cancer, brain tumors, non-small cell lung cancer, bladder cancer, melanoma, and testicular cancer andIt is also used to treat some blood disorders. It is given by injection into a vein.

Vincristine and vinblastine exhibit differential activity against tumors and normal tissues. In this work, a number of cultured cell lines were assayed for their sensitivity to the antiproliferative and cytotoxic effects of the two drugs following short-term (4 hr) or during continuous exposures. Differential activity was not seen when cells were subjected to continuous exposures. The concentrations of Vincristine and vinblastine, respectively, that inhibited growth rates by 50% were: mouse leukemia L1210 cells, 4.4 and 4.0 nw; mouse lymphoma S49 cells, 5 and 3.5 nM; mouse neuroblastoma cells, 33 and 15 nw; HeLa cells, 1.4 and 2.6 nw; and human leukemia HL-60 cells, 4.1 and 5.3 nM. In contrast, differential toxicity was seen when cells were subjected to 4-hr exposures and transferred to drug-free medium: the 50% growth-inhibitory concentrations for Vincristine and vinblastine, respectively, for inhibition (a) of proliferation of L1210 cells were 100 and 380 nM and of HL-60 cells were 23 and 900 nM and (b) of colony formation of L1210 cells were 6 and >600 nM and of HeLa cells were 33 and 62 nM. Uptake and release of [3H]- vincristine and [3H]vinblastine were examined in L1210 cells under the conditions of growth experiments. Uptake of both drugs was dependent on the pH of culture media, and signifi cantly greater amounts of [3H]vinblastine than of [3H]vincristine were associated with cells after 4-hr exposures to equal concen trations of either drug. When cells were transferred to drug-free medium after 4-hr exposures, vinblastine was released much more rapidly from cells than was Vincristine, and by 0.5 hr after resuspension of cells, the amount of Vincristine associated with the cells was greater than the amount of vinblastine and remained so for up to at least 6 hr.

Introduction

Vinblastine is a vinca alkaloid and a chemical analogue of vincristine It binds tubulin, thereby inhibiting the assembly of microtubules. Vinblastine treatment causes M phase specific cell cycle arrest by disrupting microtubule assembly and proper formation of the mitotic spindle and the kinetochore, each of which are necessary for the separation of chromosomes during anaphase of mitosis. Toxicities include bone marrowsuppression (which is dose-limiting), gastrointestinal toxicity, potent vesicant (blister-forming) activity, and extravasation injury (forms deep ulcers). Vinblastine paracrystals may be composed of tightly-packed unpolymerized tubulin or microtubules.

Vinblastine is reported to be an effective component of certain chemotherapy regimens, particularly when used with bleomycin, and methotrexate in VBM chemotherapy for Stage IA or IIA Hodgkin lymphomas. The inclusion of vinblastine allows for lower doses of bleomycin and reduced overall toxicity with larger resting periods between chemotherapy cycles.

Vinblastine is a component of a number of chemotherapy regimens, including ABVD for Hodgkin lymphoma. It is also used to treat histiocytosis according to the established protocols of the Histiocytosis Association.

Vincristine and vinblastine are potent mitotic inhibitors that have been used clinically in the treatment of a variety of neo plasms. The sensitivity of cells to short-term (1- and 4-hr) exposures was also determined for both drugs. Although there were differences in sensitivity to vincristine and vinblastine between cell lines, there was little or no difference in sensitivity to the 2 drugs within a given cell line during continuous exposures. In contrast, after exposures of 4 hr or less, L1210 and HL-60 cells were much more sensitive to vincristine than to vinblastine. Experiments were undertaken to determine if the difference in sensitivity of L1210 cells to vincris tine and vinblastine after short exposures was due to differences in uptake and/or release of the drugs by cells. Others have observed that vinblastine associates with and is released more quickly from rat platelets than vincristine. Radiolabeled vincristine and vinblastine were utilized in assaying uptake and release of drugs from the cells during and following 4-hr exposures. The results obtained suggest that rapid release of vinblastine by cells is the reason for its lesser toxicity, compared with vincristine, after 1- or 4-hr exposures.

Mechanism of Action

Figure

Microtubule-disruptive drugs like vinblastine, colcemid, and nocodazole have been reported to act by two mechanisms.[16] At very low concentrations they suppress microtubule dynamics and at higher concentrations they reduce microtubule polymer mass. Recent findings indicate that they also produce microtubule fragments by stimulating microtubule minus-end detachment from their organizing centers. Dose-response studies further indicate that enhanced microtubule detachment from spindle poles correlate best with cytotoxicity.

Isolation and synthesis

Vinblastine may be isolated from the Madagascar Periwinkle (Catharanthus roseus), along with several of its precursors, catharanthine and vindoline. Extraction is costly and yields of vinblastine and its precursors are low, although procedures for rapid isolation with improved yields avoiding auto-oxidation have been developed. Enantioselective synthesis has been of considerable interest in recent years, as the natural mixture of isomers is not an economical source for the required C16’S, C14’R stereochemistry of biologically active vinblastine. Initially, the approach depends upon an enantioselective Sharpless epoxidation, which sets the stereochemistry at C20. The desired configuration around C16 and C14 can then be fixed during the ensuing steps. In this pathway, vinblastine is constructed by a series of cyclization and coupling reactions which create the required stereochemistry. The overall yield may be as great as 22%, which makes this synthetic approach more attractive than extraction from natural sources, whose overall yield is about 10%.[18]Stereochemistry is controlled through a mixture of chiral agents (Sharpless catalysts), and reaction conditions (temperature, and selected enantiopure starting materials).

Materials and methods

Drugs. VCR sulfate and VLB sulfate formulated for clinical use were obtained from Shionogi and Co., Ltd., Osaka, Japan, and [3H]VCR sulfate (2.8 Ci/mmol) was purchased from the Radiochemical Centre, Amersham, Buckinghamshire, England. Verapamil was kindly supplied by the Eisai Co., Ltd., Tokyo, Japan. Animals and Tumors. Adult female BALB/c x DBA/2Cr F, (hereafter called CD2Fi) mice weighing 20 to 23 g were used in experiments; DBA/2Cr mice were the carriers of P388 leukemia and its VCR-resistant subline. CD2F, and DBA/2Cr mice and P388 leukemic cells were supplied by Simonsen Laboratories, Inc., Gilroy, Calif., under the auspices of the National Cancer Institute, NIH, Bethesda, Md. P388/VCR was kindly supplied by the Mammalian Genetics and Animal Pro duction Section, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Md. Evaluation of Antitumor Activity. One-tenth ml of diluted ascites fluid containing 106 P388 or P388/VCR cells was transplanted i.p. into CD2F, mice. Verapamil and VCR or VLB were dissolved in 0.9% NaCI solution. Except as otherwise indicated, both drugs were mixed, and the mixture was admin istered at a constant rate of 0.01 ml/g body weight i.p. daily for 10 days starting from the day after the tumor inoculation. Doses of verapamil and VCR (or VLB) were in the range of 50 to 125 mg/kg and 1 to 200 jug/kg, respectively. Antitumor activity was expressed by: (a) T/C; (b) at each dosage of VCR and VLB, the mean survival time of the treated group divided by the mean survival time of the group of mice treated with VCR or VLB alone. Five mice were used for each experimental group. Cell Culture and Drug Treatment. P388 and P388/VCR ascites cells were harvested from the peritoneal cavity of each tumor-bearing DBA/2Cr mouse. The cells were maintained in plastic dishes (Corning Glass Works, Corning, N. Y.) in Roswell Park Memorial Institute Medium 1640 supplemented with 10

Results and Discussion

The ICso values for the 2 drugs for a given cell line were similar, with the exception of neuroblastoma, which exhibited ICso values for vincristine that were 2-fold greater than those seen for vinblas tine. For each of the other 4 cell lines, the survival curves (the percentage of doublings of drug-treated cells relative to control cells over 48 or 96 hr plotted as a function of drug concentration) were basically the same for vincristine and vinblastine, indicating that, under conditions of continuous exposure, vincristine and vinblastine were equally toxic. Survival curves are presented in Chart 1 for HL-60 cells. When the effects of short (4-hr) exposures to the 2 drugs on proliferation rates were compared.vincristine was more toxic than vinblastine against all of the cell lines except neuroblastoma

blastine after 24-hr exposures, a result that was consistent with the effects seen when growth rates were determined during continuous exposure. After 1-hr exposures, HeLa cells were about twice as sensitive to the cytotoxic effects of vincris tine than to those of vinblastine. The biological studies described above indicated that differ ential toxicity of the Wnca alkaloids was seen when cells were subjected to pulse exposures to drug, but not during continuous exposures. Experiments were undertaken with L1210 cells to determine if differences in uptake and release of the drugs by cells during and after 4-hr exposures could account for differen tial toxicity. Since vinblastine and vincristine are partially ionized at physiological pH (pK«sare 5.0 to 5.5 and 7.4), the relationship between uptake and pH was examined in the ex periment presented in Chart 4. When L1210 cells were incubated for 4 hr with either drug at 50 nM, drug uptake increased as the pH increased from 5.5 to 7.5, concomitant with a loss of charge on drug molecules. Subsequent uptake experiments presented in this study were conducted at pH 7.4. The experiments of Chart 4 also indicated that L1210 cells accumulated significantlymore vinblastine than vincristine during 4-hr exposures. When drug accumulation was expressed as the ratio of apparent intracellular concentration7 to extracellular concentration of drug, both vinblastine and vincristine were "concentrated" by cells, presumably through binding to cellular components. The de pendence of uptake on the extracellular concentration of vinblas tine or vincristine is presented in Chart 5, where it is apparent that the uptake of vinblastine was greater than that of vincristine at all of the concentrations tested. The time courses of uptake and of release of vinblastine and vincristine were investigated by measuring cellular accumulation

References

a