The novel heterodinucleoside dimer 5-FdU-NOAC is a potent cytotoxic drug and a p53-independent inducer of apoptosis in the androgen-independent humanprostate cancer cell lines PC-3 and DU-145

Citation
Rmc. Cattaneo-pangrazzi et al., The novel heterodinucleoside dimer 5-FdU-NOAC is a potent cytotoxic drug and a p53-independent inducer of apoptosis in the androgen-independent humanprostate cancer cell lines PC-3 and DU-145, PROSTATE, 45(1), 2000, pp. 8-18
Citations number
42
Categorie Soggetti
Urology & Nephrology","da verificare
Journal title
PROSTATE
ISSN journal
02704137 → ACNP
Volume
45
Issue
1
Year of publication
2000
Pages
8 - 18
Database
ISI
SICI code
0270-4137(20000915)45:1<8:TNHD5I>2.0.ZU;2-Z
Abstract
BACKGROUND. We analyzed the cytotoxic properties of the new heterodinucleos ide phosphate dimer 5-FdU-NOAC, which is composed of the cytotoxic drugs 5- FdU and N-4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) against huma n 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 IC50 values of 3.9-5 mu M and in a complete inhibition of cell proliferation at 200 mu M a fter 96 hr compared to 5-FdU, where 10% of the cells remained resistant. Fl ow 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 mu M in both cell lines. Apoptotic cell fractions in D U-145 (66%) and in PC-3 (34%) cells were found after treatment with 5-FdU-N OAC for 96 hr. DNA fragmentation further confirmed the induction of apoptos is. CONCLUSIONS. 5-FdU-NOAC inhibits thymidylate synthase and cell cycle progre ssion 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 can cer. (C) 2000 Wiley-Liss, Inc.