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
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
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.