Abstract
Cyclophosphamide is a commonly administered chemotherapeutic drug used to treat a variety of illnesses from cancer to lupus nephritis. However, despite its therapeutic effects the use of the treatment is limited by its propensity to cause urological side effects, namely the inflammatory disease interstitial cystitis. The mechanisms by which the drug causes this damage remains unknown but may be attributed to its urinary metabolites acrolein and chloroacetaldehyde but again, the direct effects of these metabolites on the urinary bladder remain elusive. The effect of cyclophosphamide administration was studied in a mouse model, whereby the drug was administered via multiple intraperitoneal doses over an 8-day period after which isolated whole bladder preparations and ex vivo afferent nerve recording were undertaken. The direct effects of in vitro application of acrolein and chloroacetaldehyde were also studied in separate sets of experiments using isolated whole bladder preparation and nerve recordings.The administration of cyclophosphamide caused an increase in voiding frequency in mice and decreased compliance and stretch-relaxation ability of isolated bladders. Pharmacological results indicate that purinergic and cholinergic changes may underlie this dysfunction. Furthermore, results also indicated changes to afferent nerve firing whereby capsaicin-insensitive fibres were increased in the cyclophosphamide treated animals. This was a novel finding, previously unobserved in the literature which may call attention to the ineffective use of capsaicin as a treatment of interstitial cystitis.
Intravesical administration of acrolein and chloroacetaldehyde caused various changes to the murine urinary bladder. Where acrolein caused increase maximal contraction to the muscarinic agonist carbachol, chloroacetaldehyde increased spontaneous activity, and both metabolites led to increased efferent nerve-evoked contractile activity to low threshold electrical field stimulation. These results also indicated changes to cholinergic and purinergic signalling mechanisms. Additionally, it was shown that contrary to current literature, chloroacetaldehyde may be the more toxic urinary metabolite of cyclophosphamide, as it increased high threshold nerve firing, which has commonly been attributed to pain experienced during the chemotherapy’s side effect and interstitial cystitis.
Overall, the findings indicate physiological and pharmacological changes to a number of urinary bladder mechanisms including purinergic and cholinergic signalling pathways, and afferent nerve activity. Therefore, the effects exerted by cyclophosphamide on the urinary bladder are complicated and can be attributed to the interaction of these functional changes, which may lead to interstitial cystitis.
Date of Award | 1 Dec 2022 |
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Original language | English |
Supervisor | Russ Chess-Williams (Supervisor), Donna Sellers (Supervisor) & Catherine McDermott (Supervisor) |