zimeldine and 6-nitroquipazine

Growth stimulation of a variety of cell types by the neurotransmitter serotonin has been reported. We have examined the effects of three serotonin-uptake inhibitors, 6-nitroquipazine, zimelidine and fluoxetine (Prozac, Eli Lilly Co., Indianapolis, Indiana) on human prostate carcinoma cell lines. In vitro, all 3 of these compounds inhibited the proliferation of PC-3, DU-145 and LNCaP cells in a dose-dependent manner. Also, all 3 compounds blocked the uptake of a radiolabeled analog of serotonin by the prostate carcinoma cell lines. The order of potency for inhibition of growth as well as for serotonin uptake was fluoxetine > zimelidine > 6-nitroquipazine. The growth of subcutaneous, PC-3 xenografts in athymic nude mice was significantly inhibited by fluoxetine. These results implicate biogenic amines such as serotonin in the growth of prostate carcinoma cells and indicate the potential use of serotonin-uptake inhibitors for the treatment of prostate cancer.

Topics: Animals; Carcinoma; Cell Division; Dose-Response Relationship, Drug; Fluoxetine; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mice, Nude; Neoplasm Transplantation; Prostatic Neoplasms; Quipazine; Selective Serotonin Reuptake Inhibitors; Soft Tissue Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured; Zimeldine

[3H]6-Nitroquipazine bound to rat lung membranes at 37 degrees with a dissociation constant (Kd) of 0.310 +/- 0.13 nM and a maximal number of binding sites (Bmax) of 1752 +/- 334 fmol/mg protein (mean +/- SD, N = 4). The binding was saturable, of high affinity and sodium dependent. Drug inhibition studies indicated that [3H]6-nitroquipazine binding in the lung is similar to that already reported in the rat brain and human platelets. Scatchard analysis indicated that 5-hydroxytryptamine (5-HT) inhibited [3H]6-nitroquipazine binding to rat lung membranes in a competitive manner. The present results suggest that [3H]6-nitroquipazine binding sites in the rat lung are associated with the uptake system of 5-HT.

Topics: Animals; Biological Transport; Desipramine; Imipramine; Kinetics; Lung; Male; Maprotiline; Membranes; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Stereoisomerism; Temperature; Tritium; Zimeldine