Lower urinary tract dysfunction could be a late effect of vincristine treatment in childhood, a mouse study
Nao Iguchi, PhD1, Ali Teimouri, MD1, Duncan Wilcox, MD2, Anna Malykhina, PhD1, NIcholas G. Cost, MD2.
1University of Colorado AMC, Aurora, CO, USA, 2Children's Hospital of Colorado, Aurora, CO, USA. BackgroundVincristine (VCR) is one of the most common chemotherapy agents used in pediatric patients with cancer and is well known to cause peripheral neuropathy, however, no translational studies have been conducted to evaluate the impact of this possible peripheral neuropathy on bladder function. Our recent study showed a higher rate of LUT dysfunction (LUTD) in childhood cancer survivors who received VCR and/or doxorubicin than healthy cohort, warranting further investigation. The current study aims to investigate the impact of systemic vincristine exposure in childhood impacts on lower urinary tract function using a murine model.
METHODSWith IACUC approval, juvenile male CD-1 mice received an ip injection of 750µg/kg of VCR twice per week for 4 weeks. Five weeks after the last treatment, LUT and detrusor function were evaluated by void spot assay, awake cystometry and in vitro physiological recordings using bladder strips, and bladder histology. Twenty-four-hour urine samples were collected and urinary creatinine, ATP, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were measured.
RESULTSVCR induced a decrease in urinary frequency shown in both void spot assay and awake cystometry, besides frequent non-void contractions were observed. VCR exposure induced a decrease in the detrusor contractility mediated by activation of either nerves or myocytes in the bladder strips. Bladder histology was comparable between control and VCR groups except the increased number of mast cells in VCR group (11.7± 1.8 vs. 47.5 ± 9.9, p=0.003). Histamine induced a 5-fold higher increase in the basal tone of the bladder strips from VCR group compared to the control (p=0.030), which was diminished in the presence of Trpv1 channel blocker, capsazepine. The volume of 24-hr urine output was smaller in VCR group (0.6 ± 0.2 vs. 1.9 ± 0.2 ml in the control group, p<0.001), but no statistical differences were detected in the level of molecules in urine tested.
CONCLUSIONSSystemic vincristine exposure impacted lower urinary tract function that appears to be associated with mast cell-histamine and Trpv1 channel activation in the bladder. Our results suggest that systemic vincristine exposure in childhood cancer survivors may impact LUT function and thus we recommend follow-up urological assessment of these children who receive vincristine.
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