This proposal will exploit the improved efficacy of 5-fluorouracil (FUra) after biochemical modulation by benzylacyclouridine (BAU) for the treatment of prostate cancer. Prostate cancer is a major health problem in American males. Effective treatment is lacking, particularly for those whose disease is resistant to hormonal manipulation. 5-fluorouracil (FUra) is among the most active anticancer agents available for this disease, but trials with FUra alone have shown limited effect. Combination with other anticancer agents causes more toxicity without improving efficacy. Benzylacyclouridine (BAU), a potent uridine phosphorylase inhibitor, nontoxic by itself, is able to modulate fluoropyrimidine metabolism. Preclinical studies have demonstrated enhancement of FUra antineoplastic activity by BAU against human prostate carcinomas PC-3 and LNCaP in vitro and in vivo Moreover, a rapid and innovative ill vitro/in vivo predictive sensitivity assay has been developed which correlates well with these results. Biochemical studies have shown that BAU increases FUra incorporation into DNA and in addition, potentiates inhibition of thymidine incorporation by FUra. These results indicate that enhancement of FUra cytotoxicity by BAU is associated with increased fluoropyrimidine incorporation into nucleic acids. Furthermore, preclinical toxicologic studies of BAU have shown no significant host toxicity. Consequently, these encouraging findings have led to a phase I trial of BAU. Minimal toxicity (grade I-H) has been observed and dose escalation to determine the MTD and MED of BAU as a single oral dose is proceeding. Preliminary pharmacodynamic studies show evidence of uridine phosphorylase inhibition even at current dose levels. Completion of this portion of the trial will be followed by phase IB studies of BAU given as multiple oral doses to sustain elevations in plasma uridine levels over 24 hours. Preclinical and phase I studies will then be translated into a pilot study of BAU in combination with FUra for the treatment of prostate cancer. This will establish the MTD for BAU- FUra therapy and provide information on response. Inhibition of uridine phosphorylase and enhancement of FUra incorporation by BAU will be correlated with clinical response. Finally, primary tumor specimens from patients will be used to measure FUra incorporation into nucleic acids by GC-MS and to establish permanent cell lines. These biochemical studies and new primary and metastatic prostate cancer cell lines will provide confirmation of the mechanism of FUra cytotoxicity and lead to further improvements in therapy.
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| Yee, L K; Chu, E; Pan, B C et al. (1998) Benzylacyclouridine enhances 5-fluorouracil cytotoxicity against human prostate cancer cell lines. Pharmacology 56:80-91 |
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