The novel heterodinucleoside dimer 5-FdU-NOAC is a potent cytotoxic drug and a p53-independent inducer of apoptosis in the androgen-independent human prostate cancer cell lines PC-3 and DU-145
✍ Scribed by R.M.C. Cattaneo-Pangrazzi; H. Schott; R.A. Schwendener
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 323 KB
- Volume
- 45
- Category
- Article
- ISSN
- 0270-4137
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✦ Synopsis
BACKGROUND. We analyzed the cytotoxic properties of the new heterodinucleoside phosphate dimer 5-FdU-NOAC, which is composed of the cytotoxic drugs 5-FdU and N 4octadecyl-1--D-arabinofuranosylcytosine (NOAC) against human prostate tumor cells. METHODS. 5-FdU-NOAC effects on cell proliferation, cell cycle distribution, thymidylate synthase activity, and apoptosis were investigated in vitro in the two human prostate carcinoma cell lines DU-145 and PC-3 and compared to cells treated with the corresponding single drugs 5-FdU and NOAC. RESULTS. Treatment of the cells with 5-FdU-NOAC resulted in IC 50 values of 3.9-5 M and in a complete inhibition of cell proliferation at 200 M after 96 hr compared to 5-FdU, where 10% of the cells remained resistant. Flow cytometric analysis revealed cell cycle perturbations in S-phase only in the DU-145 cells. 5-FdU-NOAC caused 50% inhibition of thymidylate synthase after 90 min at 0.6 M in both cell lines. Apoptotic cell fractions in DU-145 (66%) and in PC-3 (34%) cells were found after treatment with 5-FdU-NOAC for 96 hr. DNA fragmentation further confirmed the induction of apoptosis. CONCLUSIONS. 5-FdU-NOAC inhibits thymidylate synthase and cell cycle progression causing proliferation arrest and apoptosis in DU-145 and PC-3 cells, suggesting a potential role of 5-FdU-NOAC for the treatment of prostate cancer.