This competitive renewal application is to define the pharmacokinetics and pharmacodynamics of the drugs commonly used in intravesical therapy, in order to optimize the treatment regimen. Results of our studies on mitomycin C (MMC) indicate several treatment conditions which need optimization and a low sensitivity of high stage, high grade and rapidly proliferating tumors to MMC. A.l. Pharmacokinetics of intravesical therapy in patients. Our studies of the pharmacokinetics of MMC yielded important information to optimize the treatment protocols. We propose to establish, for doxorubicin and thiotepa, (a) drug concentration-time profiles in blood and urine, (b) extent and rate of systemic absorption of drugs from bladder, and (c) effects of transurethral resection and disease staging on drug absorption. A.2. Drug distribution in normal and tumor tissues. We will study the drug distribution in different region; of the bladder and the depth of drug penetration in vivo using bladders removed from dogs and from patients who receive drug instillation at the time of total cystectomy. This will indicate whether effective drug concentrations are achieved at the tumor sites. A.3. Determinants of drug absorption from bladder. Variables including the pH and volume of urine, dwell time, size (molecular weight), acidity/basicity and concentration of a drug can influence the drug absorption from bladder and potentially affect the target site specificity of intravesical therapy in patients. Because patient studies are not always feasible, we propose to study the effect of the selected variables on drug absorption kinetics in animals. Our MMC studies suggest the dog as the most suitable animal model. A.4. Chemosensitivity and pharmacodynamic studies in vitro. An in vitro chemosensitivity assay using patient bladder tumor explants has been established. The proliferative activity of explants is parallel to the tumor pathobiology. We found a 60-fold difference in the IC of MMC in explants from different patients, and an inverse relationship between the IC and exposure time. The data also suggest a correlation between tumor sensitivity to MMC and prognostic factors such as DNA ploidy, tumor grade and tumor stage. The pharmacodynamics, correlation of IC with potential prognostic factors, and the effect of pH will be determined. A.5. Evaluate activity of new drugs and combinations for high stage and rapidly proliferating tumors. We found that high stage and rapidly proliferating tumors were less sensitive to MMC than the less malignant tumors. Clinically, MMC is less effective against T2 tumors than Ta and T1 tumors. The high stage and rapidly proliferating tumors are of high risk with respect to recurrence, progression to invasive disease, metastasis, and poor survival. We propose to evaluate the activity of new drugs and combinations for these tumors, and to establish the pharmacodynamics as stated in A.4.
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