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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Specialized Center (P50)
Project #
3P50DE011921-05S1
Application #
6471778
Study Section
Project Start
2000-08-01
Project End
2002-07-31
Budget Start
Budget End
Support Year
5
Fiscal Year
2001
Total Cost
$103,677
Indirect Cost
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Cohen, Ezra E W; Rosner, Marsha Rich (2009) MicroRNA-regulated feed forward loop network. Cell Cycle 8:2477-8
Cohen, Ezra E W; Zhu, Hongyan; Lingen, Mark W et al. (2009) A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle. Cancer Res 69:65-74
Logemann, Jeri A; Pauloski, Barbara Roa; Rademaker, Alfred W et al. (2008) Swallowing disorders in the first year after radiation and chemoradiation. Head Neck 30:148-58
Huang, R Stephanie; Duan, Shiwei; Kistner, Emily O et al. (2008) Genetic variants contributing to daunorubicin-induced cytotoxicity. Cancer Res 68:3161-8
Zhang, Wei; Duan, Shiwei; Kistner, Emily O et al. (2008) Evaluation of genetic variation contributing to differences in gene expression between populations. Am J Hum Genet 82:631-40
Shukla, Sunita J; Duan, Shiwei; Badner, Judith A et al. (2008) Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis. Pharmacogenet Genomics 18:253-62
Logemann, Jeri A; Rademaker, Alfred W; Pauloski, Barbara Roa et al. (2006) Site of disease and treatment protocol as correlates of swallowing function in patients with head and neck cancer treated with chemoradiation. Head Neck 28:64-73
Cohen, Ezra Eddy Wyssam; Lingen, Mark W; Zhu, Bangmin et al. (2006) Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase. Cancer Res 66:6296-303
Milano, Michael T; Vokes, Everett E; Kao, Johnny et al. (2006) Intensity-modulated radiation therapy in advanced head and neck patients treated with intensive chemoradiotherapy: preliminary experience and future directions. Int J Oncol 28:1141-51
Pasche, Boris; Knobloch, Thomas J; Bian, Yansong et al. (2005) Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA 294:1634-46

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