| Drug delivery and dosing regimen compose two major limitations for anticancer drug efficacy: This dissertation is focused on these two aspects to optimize cancer chemosensitization.; The work presented in this dissertation reflects a multidisciplinary approach towards the development and study of regional prostate cancer chemotherapy. Formulation studies (Chapter 2) were performed using biodegradable polymers. A Poly(lactide-co-glycolide) cylindrical matrix containing paclitaxel was developed for localized prostate cancer chemotherapy. The macro-porous PLGA matrix was used to increase paclitaxel release. The formulation was evaluated in PC-3 tumor bearing mice (Chapter 3). Results showed the formulation could inhibit tumor growth, while paclitaxel penetration was limited. And host toxicity was monitored by body weight change. No long-term toxicity was observed.; Traditionally, the Maximum Tolerated Dose paradigm has been employed to treat cancer patients. However, our tab has found an unconventional dose-response relationships of a grow factor inhibitor, suramin. The preclinical in vitro and in vivo studies showed that suramin reversed FGF-induced chemoresistance in a narrow therapeutic range from ∼10--50 muM, with antagonism occurring above this concentration. Hence, a good understanding of the pharmacokinetics of suramin is important for the successful performance of preclinical studies in rodents, and clinical studies in animal and human patients. We studied the interspecies pharmacokinetics of suramin in mice, rats, dogs, and humans (Chapter 4) The parameters of interest were correlated across species as a function of bodyweight using the allometric equation. The steady-state volume of distribution (Vdss), total body clearance (CL), product of clearance and Maximum Life Potential (CL*MLP), and Area Under the Curve (AUC) correlated well across species. The dienetichron plot, an allometric scaling plot, which transforms clock time and absolute physical parameters into forms that become species invariant, was used to predict the suramin concentration profile in human patients and the simulation was validated using data from our phase I study in Non-Small Cell Lung Cancer patients. A Phase I trial evaluated the effectiveness of low dose suramin in pet dogs with naturally occurring tumors (Chapter 5). For a better understanding of suramin pharmacodynamics, tissue distribution of low-dose suramin was studied on s.c. tumor-bearing mice (Chapter 6). (Abstract shortened by UMI.)... |
