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.
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(4)-octadecyl-1-beta-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 microM and in a complete inhibition of cell proliferation at 200 microM 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 microM 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.
Cattaneo-Pangrazzi
R M
RM
Department of Pathology, University Hospital, Zurich, Switzerland.
Schott
H
H
Schwendener
R A
RA
D000728:Androgens / Q000502:physiology; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001711:Biotransformation; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity; D005467:Floxuridine / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives / Q000633:toxicity*; D006801:Humans; D006868:Hydrolysis; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000473:pathology; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C413287:2'-deoxy-5-fluorouridylyl-(5'-5')-N(4)-octadecyl-1-arabinofuranosylcytosine; D000728:Androgens; D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D011355:Prodrugs; D016159:Tumor Suppressor Protein p53; D005467:Floxuridine; D003561:Cytarabine; C065145:N(4)-oleylcytosine arabinoside; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I