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Systemic vincristine exposure in childhood affects lower urinary tract function in a sex-specific manner
Nao Iguchi, PhD1, Sarah L. hecht, MD2, Dexiang Gao, PhD1, Duncan T. Wilcox, MBBS, MD3, Anna P. Malykhina, PhD1, Nicholas G. Cost, MD3.
1University of Colorado AMC, Aurora, CO, USA, 2Doernbecher Children's Hospital, Portland, OR, USA, 3Children's Hospital Colorado, Aurora, CO, USA.

BACKGROUND: Vincristine (VCR) is one of the most common chemotherapy agents used in pediatric oncology. Despite well-known VCR-induced peripheral neuropathy (VIPN), there has been limited investigation into the potential impact of VIPN on lower urinary tract (LUT) function. The objective of this study was to investigate the effects of systemic VCR exposure in childhood on LUT function by using a juvenile murine model.
METHODS: Using IACUC approved protocols, CD-1 mice (3.5-wk-old) received an intraperitoneal injection of 0.5 mg/kg of VCR twice per week for 4 weeks. Control mice were treated with the same volume and schedule of saline. Physiological recordings of LUT and detrusor function were conducted by in vivo, cystometry in conscious unrestrained mice as well as an in vitro organ bath using bladder strips at 5 weeks after the last treatment. Manual Von Frey tests were conducted to evaluate the degree of VIPN. Bladder morphology was examined by light and fluorescence microscopy. Changes in gene expression in the bladders and the lumbosacral dorsal root ganglia (Ls-DRG) were examined at the mRNA and protein levels.
RESULTS: Cystometry revealed that VCR exposure induced increased functional bladder capacity, micturition volume, and non-void contractions. Cystometry also demonstrated sex dimorphic changes in response to VCR; an elevation of maximal intravesical pressure at micturition in females but not in males, and a significant increase in bladder compliance in males compared to the control mice (Table 1). An increase in basal activity was observed in bladder strips from males who received VCR, suggesting that VCR induced detrusor overactivity. Manual von Frey tests revealed that VCR exposure induced mechanical hyposensitivity in both sexes of mice compared to those in the control groups. Molecular studies revealed that VCR exposure induced downregulations of a serotonin receptor (Htr3b) in the bladder and of voltage gated Ca channel (Cav1.2) in the Ls-DRG, specifically in female mice. Both genes are suggested to play important roles in sensory nerve excitation. In males, multiple genes associated with inflammation were upregulated in both the bladders and Ls-DRG of mice exposed to VCR compared to the control group, suggesting that VCR induced neuroinflammation in male mice.
CONCLUSIONS: Our results suggest that that systemic VCR exposure in juvenile period impact on voiding behaviors which appears to be attributed to an altered sensitivity of sensory neuron involved in voiding via sex-dimorphic mechanisms. These changes might clinically present as gender-specific signs or symptoms of LUT dysfunction, which was suggested in our recent DVSS survey study in childhood cancer survivors who received VCR and/or doxorubicin (Table 2). follow-up urological assessment may be of benefit for pediatric cancer patients treated with VCR.


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