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.

Abstract

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.

• Authors: R M Cattaneo-Pangrazzi, H Schott, R A Schwendener
• Journal: The Prostate (Prostate) Vol. 45 Issue 1 Pg. 8-18 (Sep 15 2000) ISSN: 0270-4137 [Print] United States
• PMID: 10960838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2000 Wiley-Liss, Inc.

Chemical References

• 2'-deoxy-5-fluorouridylyl-(5'-5')-N(4)-octadecyl-1-arabinofuranosylcytosine
• Androgens
• Antimetabolites, Antineoplastic
• Enzyme Inhibitors
• Prodrugs
• Tumor Suppressor Protein p53
• Floxuridine
• Cytarabine
• N(4)-oleylcytosine arabinoside
• Fluorodeoxyuridylate
• Thymidylate Synthase
• Phosphoric Diester Hydrolases
• Phosphodiesterase I

Topics

• Androgens (physiology)
• Antimetabolites, Antineoplastic (blood, pharmacokinetics, toxicity)
• Apoptosis (drug effects, physiology)
• Biotransformation
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cytarabine (analogs & derivatives, blood, pharmacokinetics, toxicity)
• Dimerization
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (toxicity)
• Floxuridine (blood, pharmacokinetics, toxicity)
• Fluorodeoxyuridylate (analogs & derivatives, toxicity)
• Humans
• Hydrolysis
• Male
• Neoplasms, Hormone-Dependent (drug therapy, pathology)
• Phosphodiesterase I
• Phosphoric Diester Hydrolases (metabolism)
• Prodrugs (chemistry, pharmacokinetics, toxicity)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Thymidylate Synthase (antagonists & inhibitors)
• Tumor Cells, Cultured (drug effects)
• Tumor Suppressor Protein p53 (physiology)