Chemistry:Vinblastine

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Short description: Chemotherapy medication
Vinblastine
Vinblastine2DCSD.svg
Vinblastine ball-and-stick.png
Clinical data
Trade namesVelban, Velbe, others
Other namesvincaleukoblastine
AHFS/Drugs.comMonograph
MedlinePlusa682848
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration		intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailabilityn/a
MetabolismLiver (CYP3A4-mediated)
Elimination half-life24.8 hours (terminal)
ExcretionBiliary and kidney
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
FormulaC46H58N4O9
Molar mass810.989 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer.[1] This includes Hodgkin's lymphoma, non-small-cell lung cancer, bladder cancer, brain cancer, melanoma, and testicular cancer.[1] It is given by injection into a vein.[1]

Most people experience some side effects.[1] Commonly it causes a change in sensation, constipation, weakness, loss of appetite, and headaches.[1] Severe side effects include low blood cell counts and shortness of breath.[1] It should not be given to people who have a current bacterial infection.[1] Use during pregnancy will likely harm the baby.[1] Vinblastine works by blocking cell division.[1]

Vinblastine was isolated in 1958.[2] An example of a natural herbal remedy that has since been developed into a conventional medicine, vinblastine was originally obtained from the Madagascar periwinkle.[3] It is on the World Health Organization's List of Essential Medicines.[4]

Medical uses

Vinblastine is a component of a number of chemotherapy regimens, including ABVD for Hodgkin lymphoma.[5] It is also used to treat histiocytosis according to the established protocols of the Histiocytosis Association.

Side effects

Adverse effects of vinblastine include hair loss, loss of white blood cells and blood platelets, gastrointestinal problems, high blood pressure, excessive sweating, depression, muscle cramps, vertigo and headaches.[6][1] As a vesicant, vinblastine can cause extensive tissue damage and blistering if it escapes from the vein from improper administration.[7]

Pharmacology

Vinblastine is a vinca alkaloid[8][2][9] and a chemical analogue of vincristine.[10][11] It binds tubulin, thereby inhibiting the assembly of microtubules.[12] 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 marrow suppression (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.[13]

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.[14]

Mechanism of action

The complex of tubulin and vinblastine. Vinblastine is shown in yellow.

Microtubule-disruptive drugs like vinblastine, colcemid, and nocodazole have been reported to act by two mechanisms.[15] 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.[16] But research into the mechanism is still ongoing as recent studies also show vinblastine inducing apoptosis that is phase-independent in certain leukemias.[17]

Pharmacokinetics

Vinblastine appears to be a peripherally selective drug due to limited brain uptake caused by binding to P-glycoprotein.[18][19]

Isolation and synthesis

Vinblastine may be isolated from the Madagascar Periwinkle (Catharanthus roseus), its only known biological producer,[20] along with several of its precursors, catharanthine and vindoline. Large scale extraction procedures for vinblastine from the leaves of Catharanthus roseus have been developed [21],[22],[23]The biosynthetic pathway for vinblastine and its precursors, particularly catharanthine, still remains partially unknown.[20].It was first proposed that vinblstine may arise by coupling reactions involving an Iboga alkaloid catharanthine and the Aspidosperma alkaloid vindoline, and this biomimetic approach was then employed for the partial synthesis of vinblastine and its analogues.[24][25] 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%.[26] Stereochemistry is controlled through a mixture of chiral agents (Sharpless catalysts), and reaction conditions (temperature, and selected enantiopure starting materials).[27] Due to difficulty of stereochemical restraints in total synthetic processes, other semi-synthetic methods from precursors, catharanthine and vindoline, continue to be developed.[28]

History

Vinblastine was first isolated by Robert Noble and Charles Thomas Beer at the University of Western Ontario from the Madagascar periwinkle plant. Vinblastine's utility as a chemotherapeutic agent was first suggested by its effect on the body when an extract of the plant was injected in rabbits to study the plant's supposed anti-diabetic effect. (A tea made from the plant was a folk-remedy for diabetes.) The rabbits died from a bacterial infection, due to a decreased number of white blood cells, so it was hypothesized that vinblastine might be effective against cancers of the white blood cells such as lymphoma.[29] It was approved by FDA in 1965.[12]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Vinblastine Sulfate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/vinblastine-sulfate.html. 
  2. ↑ 2.0 2.1 The evolution of drug discovery : from traditional medicines to modern drugs (1. Aufl. ed.). Weinheim: Wiley-VCH. 2011. p. 157. ISBN 9783527326693. https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA157. 
  3. ↑ Textbook of Drug Design and Discovery (Third ed.). CRC Press. 2002. p. 550. ISBN 9780415282888. https://books.google.com/books?id=EL-UI6t8omQC&pg=PA550. 
  4. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02. 
  5. ↑ "Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study". Annals of Oncology 15 (12): 1798–1804. December 2004. doi:10.1093/annonc/mdh465. PMID 15550585. 
  6. ↑ "Vinblastine sulfate- vinblastine sulfate injection". 31 December 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f073b58e-56d6-4c8d-a2ce-b37719402d77. 
  7. ↑ "Vinblastine". https://chemocare.com/chemotherapy/drug-info/vinblastine.aspx. 
  8. ↑ "The Catharanthus alkaloids: pharmacognosy and biotechnology". Current Medicinal Chemistry 11 (5): 607–628. March 2004. doi:10.2174/0929867043455846. PMID 15032608. 
  9. ↑ "Africa's gift to the world". Botanical Miracles: Chemistry of Plants That Changed the World. CRC Press. 2016. pp. 46–51. ISBN 9781498704304. https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA46. 
  10. ↑ "Modifications on the basic skeletons of vinblastine and vincristine". Molecules 17 (5): 5893–5914. May 2012. doi:10.3390/molecules17055893. PMID 22609781. 
  11. ↑ "Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties". Accounts of Chemical Research 48 (3): 653–662. March 2015. doi:10.1021/ar500400w. PMID 25586069. 
  12. ↑ 12.0 12.1 "Preclinical Pharmacology and Structure-Activity Studies of Epothilones". The Epothilones: An Outstanding Family of Anti-Tumor Agents: From Soil to the Clinic. Springer Science & Business Media. 2009. pp. 157–220. ISBN 9783211782071. https://books.google.com/books?id=FfCfFgWenSAC&pg=PA158. 
  13. ↑ "Two ultrastructurally distinct tubulin paracrystals induced in sea-urchin eggs by vinblastine sulphate". Journal of Cell Science 20 (1): 79–89. January 1976. doi:10.1242/jcs.20.1.79. PMID 942954. http://jcs.biologists.org/content/20/1/79.full.pdf. 
  14. ↑ "Vinblastine, bleomycin, and methotrexate chemotherapy plus irradiation for patients with early-stage, favorable Hodgkin lymphoma: the experience of the Gruppo Italiano Studio Linfomi". Cancer 98 (11): 2393–2401. December 2003. doi:10.1002/cncr.11807. PMID 14635074. 
  15. ↑ "Microtubules as a target for anticancer drugs". Nature Reviews. Cancer 4 (4): 253–265. April 2004. doi:10.1038/nrc1317. PMID 15057285. 
  16. ↑ "Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs". The Journal of Biological Chemistry 285 (42): 32242–32250. October 2010. doi:10.1074/jbc.M110.160820. PMID 20696757. 
  17. ↑ "Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed". Molecular Cancer Therapeutics 9 (4): 791–802. April 2010. doi:10.1158/1535-7163.MCT-10-0028. PMID 20371726. 
  18. ↑ "P-Glycoprotein, a gatekeeper in the blood-brain barrier". Adv Drug Deliv Rev 36 (2–3): 179–194. April 1999. doi:10.1016/s0169-409x(98)00085-4. PMID 10837715. 
  19. ↑ "P-glycoprotein-mediated efflux transport of anticancer drugs at the blood-brain barrier". Ther Drug Monit 20 (5): 588–90. October 1998. doi:10.1097/00007691-199810000-00024. PMID 9780140. 
  20. ↑ 20.0 20.1 "Biosynthesis and regulation of terpenoid indole alkaloids in Catharanthus roseus". Pharmacognosy Reviews 9 (17): 24–28. January 2015. doi:10.4103/0973-7847.156323. PMID 26009689. 
  21. ↑ A Rapid Procedure for the Isolation of Vinblastine from the Leaves of Catharanthus roseus, Atta-ur-Rahman, J. Fatima and A.N. Mistry, Pakistan Patent No. 128340, dated 14-2-1984
  22. ↑ A New Procedure for the Isolation of Vinblastine from the Leaves of Catharanthus roseus, Atta-ur-Rahman and M. Bashir, Pakistan Patent No. 128636, dated 21-10-1984.
  23. ↑ A New Procedure for the Isolation of Vinblastine from the Leaves of Catharanthus roseus, Atta-ur-Rahmanand M. Bashir, Pakistan Patent No. 128638, dated 18-4-1983.
  24. ↑ Methods for the Syntheses of Vinblastine, 20-Epivinblastine (Vinrosidine), 15-Hydroxy-20-Deoxyvinblastine, Vincristine and other Novel Intermediates, Atta-ur-Rahman, Pakistan Patent No. 126852, dated 14-2-1978.
  25. ↑ “Synthetic Approaches to Vinblastine and Vincristine - Anticancer Alkaloids of Cathranthus roseus”, Atta-ur-Rahman, Z. Iqbal and Habib Nasir. In "Studies in Natural Products Chemistry, Stereoselective Synthesis", ed. Atta-ur-Rahman, Elsevier Science Publishers,Amsterdam, pp. 805-884, Vol. 14, (1994);complete copy of 1978 patent of first synthesis of vinblastine available therein
  26. ↑ "Enantioselective Syntheses of Vinblastine, Leurosidine, Vincovaline, and 20'-epi-Vincovaline". Journal of Organic Chemistry 56 (2): 513–528. 1991. doi:10.1021/jo00002a008. 
  27. ↑ "Total Synthesis of (+)-Vinblastine: Control of the Stereochemistry at C18′". The Chemical Record 10 (2): 101–118. 2009. doi:10.1002/tcr.200900025. PMID 20394103. 
  28. ↑ "A simplified procedure for indole alkaloid extraction from Catharanthus roseus combined with a semi-synthetic production process for vinblastine". Molecules 12 (7): 1307–1315. July 2007. doi:10.3390/12071307. PMID 17909486. 
  29. ↑ "Role of chance observations in chemotherapy: Vinca rosea". Annals of the New York Academy of Sciences 76 (3): 882–894. December 1958. doi:10.1111/j.1749-6632.1958.tb54906.x. PMID 13627916. Bibcode: 1958NYASA..76..882N. 

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