Inhibitory effects of the nucleoside analogue gemcitabine on prostatic carcinoma cells

Abstract

Gemcitabine (2≺,2≺difluoro‐2≺deoxycytidine, dFdC) is a synthetic antimetabolite of the cellular pyrimidine nucleotide metabolism. In a first series of in vitro experiments, the drug showed a strong effect on the proliferation and colony formation of the human androgen‐sensitive tumor cell line LNCaP and the androgen‐insensitive cell lines PC‐3 and DU‐145. Maximal inhibition occurred at a dFdC concentration as low as 30 nM. In contrast to the cell lines which were derived from metastatic lesions of prostate cancer patients, no inhibitory effects were found in normal primary prostatic epithelial cells at concentrations up to 100 nM. The effect of gemcitabine was reversed by co‐administration of 10–100 μM of its natural analogue deoxycytidine. In view of a future clinical application of this anti‐tumor drug in advanced prostatic carcinoma, we have compared the effect of gemcitabine on prostatic tumor cells with that on bone marrow granulopoietic‐macrophagic progenitor cells, because neutropenia is a common side effect of gemcitabine treatment. The time course of action on the two kinds of cells was markedly different. Colony formation of tumor cells was inhibited by two thirds at a gemcitabine concentration of about 3.5 nM. The same effect on granulopoietic‐macrophagic progenitor cells required a concentration of 9 nM. Co‐administration of deoxycytidine to gemcitabine‐treated tumor cell cultures completely antagonized the effect of gemcitabine whereas addition of deoxycytidine after 48 hr of gemcitabine treatment could not prevent gemcitabine action on the tumor cells. In contrast, more than half of the granulopoietic‐macrophagic progenitor cells could still be rescued by deoxycytidine administration after 48 hr. These findings and the marked difference in the susceptibility of neoplastic and normal prostatic cells suggest that gemcitabine is a promising substance which should be further evaluated as to its efficacy in the treatment of advanced prostatic carcinoma. © 1996 Wiley‐Liss, Inc.

Switch from antagonist to agonist of the androgen receptor blocker bicalutamide is associated with prostate tumour progression in a new model system

“…They were grown in medium containing 10% CS FCS for 24 h. After this period, the concentration of CS FCS was reduced to 5% and either androgen or one of the non-steroidal anti-androgens (hydroxyflutamide, bicalutamide) was added. Proliferative response was assessed after 72 h. The MTT assay was performed as recently described by Cronauer et al (1996).…”

3,3′,5-Triiodo-l-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy

“…It has been reported, indeed, that in some human solid tumors, cells were blocked in the S phase depending on the exposure time and chemotherapeutic concentration (Cronauer et al 1996, Ng et al 2000. In contrast, other authors reported an arrest in G 1 phase only depending on the dFdCyd concentration.…”

Induced Expression of Androgen Receptor in Androgen Independent Prostate Cancer Cells Using an I kappa B alpha Super Repressor""

“…This study provides important new insights into the effects of inhibiting NF-KB in TNF-a-insensitive prostate cancer cells. A wide range of intracellular components are implicated in TNF-a-induced cell killing, including pertussis toxin-sensitive guanine nucleotide binding protein (34), phospholipase A2 (35), phospholipase D activation (36), and DNA damage (37). Despite which receptor sets off the cytotoxic effect, the various intracellular signals activated by TNF-a lead to activation of NF-KB (4).…”

“…A study by Cronauer et al examine gemcitabine as a single agent in the in vitro treatment of the PC-3, DU-145 and LNCaP human prostate cancer cell Ones (34). Their results demonstrated gemcitabine had a strong effect on the prostate cancer cell lines, but did not effect normal epithelial cell growth (34).…”

“…A study by Cronauer et al examine gemcitabine as a single agent in the in vitro treatment of the PC-3, DU-145 and LNCaP human prostate cancer cell Ones (34). Their results demonstrated gemcitabine had a strong effect on the prostate cancer cell lines, but did not effect normal epithelial cell growth (34). Our laboratory has previously demonstrated the synergistic activity of several chemotherapeutic combinations for the treatment of hormone refractory prostate cancer both in preclinical studies and in clinical trials (35)(36)(37)(38)(39).…”