Vincristine-induced neuropathy is the main dose-limiting side effect.[10] Chemotherapy-induced peripheral neuropathy can be severe, and may be a reason to reduce or avoid using vincristine. The symptoms are progressive and enduring tingling numbness, pain and hypersensitivity to cold, beginning in the hands and feet and sometimes affecting the arms and legs.[11] 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) should avoid vincristine.[12] A 2021 study has suggested that anakinra can reduce the neuropathy.[13][14]
Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. 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. Several patients have survived after aggressive and immediate intervention. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.[15] Children may do better following this injury. One child, who was aggressively treated at the time of the injection, recovered almost completely with only mild neurological deficits.[16] 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 vincristine.[17]
The overuse of vincristine may also lead to drug resistance by overexpression of the p-glycoprotein pump (Pgp). There is an attempt to overcome resistance by the addition of derivatives and substituents to the vincristine molecule.[18]
Mechanism of action
Vincristine works partly by binding to the tubulin protein, stopping the tubulin dimers from polymerizing to form microtubules, causing the cell to be unable to separate its chromosomes during the metaphase.[19] The cell then undergoes apoptosis.[20] The vincristine molecule inhibits leukocyte production and maturation.[21] A downside, however, to vincristine is that it does not only affect the division of cancer cells. It affects all rapidly dividing cell types, making it necessary for the very specific administration of the drug.[22]
Chemistry
The natural extraction of vincristine from Catharanthus roseus is produced at a percent yield of less than 0.0003%. For this reason, alternate methods to produce synthetic vincristine are being used.[23] Vincristine is created through the semi-synthesis coupling of indole alkaloids vindoline and catharanthine in the vinca plant.[24] It can also now be synthesized through a stereocontrolled total synthesis technique which retains the correct stereochemistry at C18' and C2'. The absolute stereochemistry at these carbons is responsible for vincristine's anticancer activity.[23]
The liposome encapsulation of vincristine enhances the efficacy of the vincristine drug while simultaneously decreasing the neurotoxicity associated with it. Liposome encapsulation increases vincristine's plasma concentration and circulation lifetime in the body, and allows the drug to enter cells more easily.[25]
History
Some members of Eli Lilly's vincristine research team
Having been used as a folk remedy for centuries, studies in the 1950s revealed that the rosy periwinkle Catharanthus roseus contained over 120 alkaloids, many of which are biologically active, the two most significant being vincristine and vinblastine. Its use as an anti-tumor, anti-mutagenic agent is well documented in the ancient Ayurveda system of medicine and in the folk culture of Madagascar and Southern Africa.[26] It was not found to be anti-diabetic in double blinded controlled studies.[27] 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 Skellysolve-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 vincristine.[28]
Vincristine was approved by the US Food and Drug Administration (FDA) in July 1963 under the trade name Oncovin and was marketed by Eli Lilly and Company. The drug was initially developed by a team at Lilly Research Laboratories in Indianapolis where it was demonstrated that vincristine cured artificially induced leukemia in mice and remission of acute leukemias of childhood.[29]
Production of vincristine required one ton of dried periwinkle leaves to produce one ounce of vincristine. The periwinkle was grown on a ranch in Texas.[30]
Society and culture
Suppliers
Until recently, two generic drug makers were suppliers of vincristine in the United States: Teva and Pfizer. In 2019 Teva stopped producing vincristine, leaving Pfizer as the only company in production.[citation needed] Teva has said that they will restart production, and expect it to be available in 2020.[31]
Shortage
In October 2019 an impending shortage was reported; no adequate substitute is known for treating childhood-cancers.[32] By 2022, the shortage of vincristine continued.[33]
Controversy
Pharmaceutical bioprospecting
Vincristine's origins are debated as an example of pharmaceutical bioprospecting in the fields of ethnobotany and ethnomedicine. Some consider the Catharanthus roseus plant from which vincristine is derived, and its folk remedies to be endemic to Madagascar, and that Madagascar was denied royalties from vincristine sales.[34] However, Catharanthus roseus has a documented history in folk medicine treatments in other locations. In 1963, Lilly researchers acknowledged that the plant was used in Brazil to treat hemorrhage, scurvy, toothaches, and chronic wounds; in the British West Indies to treat diabetic ulcers; and in the Philippines and South Africa as an oral hypoglycemic agent – but not as a treatment for cancer.[35]
Catharanthus roseus has been a cosmopolitan species since before the Industrial Revolution and the plant's use in folk remedies suggested general bioactivity for diabetes treatment, not cancer. In the mid-eighteenth century, botanist Judith Sumner recorded the arrival of Catharanthus roseus at London's Chelsea Physic Garden from the Jardin des plantes in Paris. It's unclear how the plant first arrived in Paris and the details of its origins in Madagascar beyond reports of its transport from Madagascar by early European explorers. Vincristine was initially distributed at cost to increase accessibility, though later switched to a for-profit model to recover the costs of production and development. According to Michael Brown, vincristine may not be a tidy example of pharmaceutical bioprospecting, but it demonstrates how pharmaceuticals with a history of use in folk medicine have intellectual property claims which are difficult to untangle.[36]
Vincristine and confusion with other drugs in administration
Vincristine has been involved in a number of medical errors. Multiple instances of vincristine having been administered improperly, after having been confused with other drugs, have occurred. If delivered into the spine (intrathecal) it causes paralysis and usually death.
In 2003 two Australian oncology pharmacists recommended a solution. The suggested procedure is to prepare and administer vincristine in a small volume mini-bag rather than a syringe thus physically preventing the vincristine syringe being accidentally attached to a spinal needle. Acceptance of this safer procedure has been slow.[37]
Research
In 2012, the FDA approved a liposomal formulation of vincristine branded as Marqibo.[38][39][40] Marqibo was voluntarily withdrawn from the US market in November, 2021.[41]
A nano-particle bound version of vincristine was under development as of 2014.[42]
In 1995 and 2006 Malagasy agronomists and American political ecologists studied the production of Catharanthus roseus around Fort Dauphin and Ambovombe and its export as a natural source of the alkaloids used to make vincristine, vinblastine and other vinca alkaloid cancer drugs. Their research focused on the wild collection of periwinkle roots and leaves from roadsides and fields and its industrial cultivation on large farms.[43][44][45]
References
^"Vincristine". Dictionary.com. Random House, Inc. Archived from the original on 9 November 2014. Retrieved 9 November 2014.
^ abcdefghBrayfield A, ed. (13 December 2013). "Vincristine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Archived from the original on 8 April 2020. Retrieved 15 April 2014.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^Qweider M, Gilsbach JM, Rohde V (March 2007). "Inadvertent intrathecal vincristine administration: a neurosurgical emergency. Case report". Journal of Neurosurgery. Spine. 6 (3): 280–3. doi:10.3171/spi.2007.6.3.280. PMID17355029.
^Zaragoza MR, Ritchey ML, Walter A (January 1995). "Neurourologic consequences of accidental intrathecal vincristine: a case report". Medical and Pediatric Oncology. 24 (1): 61–2. doi:10.1002/mpo.2950240114. PMID7968797.
^Anticancer Drugs Targeting Tubulin and Microtubules. Elsevier. 2015-01-01. ISBN9780444626493.
^Jordan MA (January 2002). "Mechanism of action of antitumor drugs that interact with microtubules and tubulin". Current Medicinal Chemistry. Anti-Cancer Agents. 2 (1): 1–17. doi:10.2174/1568011023354290. PMID12678749.
^Plotkin M (1993). Tales of a Shaman's Apprentice: An Ethnobotanist Searches for New Medicines in the Amazon Rain Forest. New York: Penguin Books. pp. 15–16.
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