PHARMACOLOGY OF ANTICANCER AGENTS

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The overall objective of this project is to delineate the role of pharmacokinetics and -dynamics in the therapy of oral cancers. There is strong evidence that 5-FU pharmacokinetics represent a major determinant of response to 5-FU-based induction chemotherapy in oral cancers. Similarly, intracellular activities of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (S), the major enzymes contributing to 5- FU anabolism and catabolism, respectively, have been implicated to be of importance for response and toxicity of 5-FU-based induction chemotherapy. However, induction chemotherapy has not been shown to impact on overall survival of these patients in large randomized studies. Concomitant chemoradiation therapy on the other hand has been shown to prolong survival and disease-free survival. To date, pharmacokinetics of 5-FU or other-drugs have not been examined in this setting. The goal of this project is to elucidate a possible contribution of pharmacokinetics to outcome parameters in clinical trials of concomitant chemoradiotherapy. We will aim at correlating pharmacokinetics with response and survival in patients with advanced oral cancer treated on three clinical protocols and establish mathematical models to optimize dosing in individual patients on subsequent clinical trials. We will also attempt to correlate DPD and TS activity with 5-FU pharmacokinetics, clinical toxicity, response and survival. We will seek to correlate DPD activity in peripheral blood mononuclear cells (PBMC) with its activity in tumor tissues to verify the use of PBMC's as surrogate tissue. Recently, the DPD inhibitor, ethynyluracil, has been developed as a modulator of 5-FU. The administration of ethynyluracil in combination with 5-FU results in a much prolonged 5-FU half-life thus increasing systemic exposure to the drug following its IV-bolus or oral administration; they may also increase 5-FU cytotoxicity. We will explore the contribution of ethynyluracil to 5-FU pharmacokinetics and -dynamics in chemoradiotherapy studies (using exclusively orally administered drugs). DPD activity will be determined prior to chemotherapy and at day 4 following ethynyluracil to study the impact of this modulator on tumoral and PBMC DPD activity. Coincident with this study will be an analysis of plasma uracil concentrations. It is our hope that these studies will teach us how to introduce new 5-FU modulators in a rational fashion into the clinic with the goal of increasing cure rates while minimizing the clinical toxicity resulting from chemoradiotherapy of oral cancer.