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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
Author(s) -
CattaneoPangrazzi R.M.C.,
Schott H.,
Schwendener R.A.
Publication year - 2000
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/1097-0045(20000915)45:1<8::aid-pros2>3.0.co;2-l
Subject(s) - apoptosis , prostate cancer , inducer , cancer research , cytotoxic t cell , prostate , androgen , medicine , cytotoxicity , cancer , oncology , biology , in vitro , gene , biochemistry , hormone
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‐β‐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 μM and in a complete inhibition of cell proliferation at 200 μM 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 μM 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. Prostate 45:8–18, 2000. © 2000 Wiley‐Liss, Inc.