This proposal is to examine the pharmacokinetics and pharmacodynamics (drug concentration-time-effect relationship) of mitomycin C, thiotepa and doxorubicin which are used in the intravesical treatment of urinary bladder cancers. Studies 1 through 4 will be done in patients, and study 5 in rats. Studies 2, 4 and 5 are to be performed locally at Ohio State University and Roswell Park Memorial Institute, and studies 1 and 3 in collaboration with the Network organizations. 1. Establish the drug concentration-time profiles in blood and urine (bladder content), and the absorption rate of drugs from the bladder. Establish the effects of transurethral resection and disease staging on the drug absorption rate. A pharmacokinetic model is proposed to examine the drug transfer across the bladder tissue and the drug concentration in different layers of the bladderwall. 2. Study the drug distribution in different regions of the bladder and the depth of drug penetration in vivo using bladders removed from patients who receive total cystectomy shortly after drug instillation. 3. Correlate the drug concentration-time profiles in urine and bladder tissue with its antitumor effect and local toxicity. 4. Develop an in vitro chemosensitivity assay using freshly obtained human bladder tumor tissues grown in collagen gels. 5. The effects of pH and volume of bladder content, dwell time, size (molecular weight), acidity/basicity and/or concentration of drug on the extent and rate of drug absorption from bladder will be studied in female Fischer rats. Only the most critical determinants, selected based on the patient data in aim 1, will be examined. Results of these studies are expected to enhance the data base to optimized treatment conditions, e.g. drug concentration and dwell time, pH and volume of instillate. The pharmacokinetics of drug distribution in bladder tissue, and its relationship with the drug properties (i.e. permeability diffusion coefficient) and tissue blood flow may be used to identify candidate drugs for tumors located in superficial and deep layers of the bladder wall.
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