Is vincristine neurotoxicity related to genotype?
Research type
Research Study
Full title
Is vincristine neurotoxicity related to genotype?
IRAS ID
178792
Contact name
Boo Messahel
Contact email
Sponsor organisation
University of Cambridge
Duration of Study in the UK
0 years, 5 months, 31 days
Research summary
Vincristine is a chemotherapeutic drug with a wide application in paediatric cancer and has many side effects. One of the most severe is a characteristic peripheral neurotoxicity, including muscle weakness and loss of sensation. The only known cure is to discontinue treatment with vincristine or to decrease the dose or frequency of treatment.
African-American children are known to have a poorer overall prognosis than Caucasian children in Non-Hodgkins Lymphoma, Wilms Tumour and Acute Lymphoblastic Leukaemia.
It has been hypothesised that the CYP3A family of enzymes are responsible for vincristine metabolism but the mechanism is not well understood, nor is the widely reported variability in its pharmacokinetics. The CYP3A5 enzyme is highly polymorphic and displays racial variance. High CYP3A5 expression is thought to be consistent with increased metabolism of Vincristine. African-American children have been previously shown to have higher expression of CYP3A5. It is plausible that the high expression of CYP3A5 could cause increased metabolism of vincristine explaining the poorer prognosis of African-American children compared to Caucasian children with Acute Lymphoblastic Leukaemia.
This study aims to genotype all children presenting to Addenbrookes will be placed on a chemotherapy regime that contains vincristine to demonstrate that decreased expression of these enzymes lead to increased neurotoxicity. Conversely, as a secondary outcome, we aim to demonstrate that those with increased expression and an increased metabolism of vincristine have a poorer event free survival and overall survival. This could potentially lead to tailored dosing of vincristine based on the individual’s genotyping in the future.References:
1. Moudi M, Go R, Yien CYS, Nazre M. Vinca Alkaloids. International Journal of Preventative Medicine. 2013;4(11):1231-5.
2. Gidding CEM, Kellie SJ, Kamps WA, de Graaf SSN. Vincristine revisited. Critical reviews in Oncology and Haematology. 1999;29:267-87.
3. Downing KH. Structural basis for the interaction of tubulin with proteins and drugs that affect microtubule dynamics. Annual Reviews in Cell and Developmental Biology. 2000;16:89-111.
4. Wang LG, Liu XM, Kreis W, Budman DR. The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemotherapy and Pharmacology. 1999;44:355-61.
5. Xie H-G, Wood AJ, Kim RB, Stein CM, Wilkinson GR. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics. 2004;5(3):243-72.
6. Hartman A, van Schaik RHN, van der Heiden IP, Broekhuis MJC, Meier M, den Boer ML, et al. Polymorphisms in genes involved in vincristine pharmacokinetics or pharmacodynamics are not related to impaired motor performance in children with leukemia. Leukemia Research. 2010;34(2):154-9. Epub 2009 May 20.
7. Moore A, Pinkerton R. Vincristine: can its therapeutic index be enhanced? Paediatric Blood and Cancer. 2009;53:1180-7.
8. Guilhaumou R, Solas C, Bourgarel-Rey V, Quaranta S, Rome A, Simon N, et al. Impact of plasma and intracellular exposure and CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms on vincristine-induced neurotoxicity. Cancer Chemotherapy and Pharmocology. 2011;68:1633-8. Epub 4October 2011.
9. Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, Hall SD. Selective metabolism of vincristine in vitro by CYP3A5. Drug metabolism and disposition. 2006;34(8):1317-27. Epub 2006 May 5.
10. Renbarger JL, McCammack KC, Rouse CE, Hall SD. Effect of race on vincristine-associated neurotoxicity in pediatric acute lymphoblastic leukemia patients. Pediatric Blood and Cancer. 2008;50:769-71.REC name
East of England - Cambridge South Research Ethics Committee
REC reference
17/EE/0130
Date of REC Opinion
30 May 2017
REC opinion
Further Information Favourable Opinion