Sixty percent of prostate cancers are organ-confined. Current local forms of therapy, namely surgery or radiotherapy, produce significant long-lasting side effects. This application is based on the hypothesis that intraprostatic chemotherapy represents a promising treatment option by achieving effective drug concentrations locally while minimizing systemic exposure. Preliminary studies demonstrate that doxorubicin concentrations effective against human prostate tumors can be achieved in the dog prostate after intraprostatic injection while plasma concentrations are non-toxic. The objectives of the application are: 1) to establish the effective CxT of doxorubicin using in vitro cultures of human prostate tumors, 2) to study the intraprostatic drug distribution and absorption kinetics in vivo in dogs and humans, 3) to develop a mathematical model of pharmacokinetic and pharmacodynamic parameters to predict the drug CxT in prostate tissue based on the plasma concentration and the relationship between prostate CxT and treatment outcome, and 4) to determine the validity of the model and to generate preliminary clinical information on the efficacy of intraprostatic doxorubicin in patients with prostate cancer.
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