Presentation Authors: Wei Phin Tan*, Andrew Chang, Gregory Barton, Wiguins Etienne, Brant A Inman, Durham, NC
Introduction: Hyperthermia (heating to 43Â°C) activates the innate immune system and improves bladder cancer (BC) chemosensitivity. In this study, we evaluated the impact of convective hyperthermia on intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models.
Methods: Forty 60 kg female swine were anesthetized and catheterized with a 3-way, 16-F catheter. The Combat BRS device was used to heat the porcine bladders to a target temperature of 43Â°C with recirculating intravesical MMC (2 mg/mL) at doses of 40mg, 80mg and 120mg. Dwell-heat time ranged from 30 to 120 minutes, after which rapid necropsy with immediate flash freezing of tissues (bladder, lymph nodes, liver, kidney, spleen, heart and lung) occurred. Blood and urine were collected longitudinally. Serum and tissue MMC concentrations were measured by liquid chromatography tandem-mass spectrometry (Agilent 1200 â€“ Applied Biosciences/SCIEX API 5500 QTrap). Data acquisition and quantification was performed by Analyst 1.6.2 software.
Results: As shown in the Table, 3 factors increased MMC absorption into the bladder: dwell time, drug concentration, and the presence of heat. Bladder MMC concentrations were, in general, significantly higher in pigs that underwent convective hyperthermia than in those that did not (it is uncertain why this relationship was not present at the 120 mg dose with 1-hour dwell time). The relationship between bladder penetration of drug and heating showed a weak linear relationship with dose (Kendallâ€™s tau = 0.35). In the hyperthermia arm, drug penetration saturated at 80 mg dose, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Importantly, convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, lymph node tissue and plasma and is therefore not expected to result in excess toxicity in humans, even at the 120 mg dose.
Conclusions: Convective bladder hyperthermia using the Combat BRS device increases MMC penetration into the bladder wall but does not result in an increase of MMC levels in the liver, heart, kidney, spleen, lung, lymph node tissue and plasma. The use of hyperthermia may saturated drug delivery and allow lower doses. These data support the use of the Combat BRS device to improve MMC penetration into the bladder wall.
Source of Funding: NCI P01 CA42745.Ruth L. Kirschstein Institutional National Research Service Award (T32)