The Either Agmatine Antitumor Effect Of Pharmacodynamic Evaluation Mechanism

Agmatine, the analog of polyamine, which was formed by the decarboxylation of L-Arginine by the enzyme L-arginine decarboxylase, has been postulated to be an endogenous ligand for imidazoline receptors (I-R). Many biological functions of agmatine have been found such as neuron protection, influence on the release of hormones and neurotransmitters, antidepression and modulation on opioid functions. The recent discovery for the effect of agmatine on cell proliferation and differentiation has caused our interest in the effects of agmatine on tumor. However, there is no report about whether agmatine can inhibit the proliferation of tumor by now. In this experiment, we have studied the inhibitory effect of agmatine on the proliferation of tumor tissues in mice in vivo and tumor cells in culture in vitro for the first times. In addition, the possible mechanisms for the anti-proliferative effect of agmatine were studied at the same time.Section A: Pharmacological effects of agmatine on tumor cell lines in vitro1 A weak inhibitory effect of agmatine was found on the proliferation of ovaries cancer cell line (Ovca), gastric carcinoma cell line ( K562 ) and human erythroleukemia cell line (Kato-III) in the current experiments. However, in MCF cell line, agmatine inhibited the proliferation of the tumor cells in MTT assay and 3H-thymidine incorporation assay. These results inferred that agmatine had anti-proliferative effect on tumor cells, but this effect was specific for cell lines. Agmatine could inhibit the proliferation of MCF cell in the range of 1~1000u M in a concentration-dependent manner both in the MTT assay and 3H-thymidine incorporation test. The highest inhibitory rate was over 50%. The anti-proliferative effect of agmatine 1000 u M on MCF cell lines exhibited a time-dependent characteristic during 48 hours.2 In mice transplanted with S180 sarcoma and B16 melanoma tumor cell lines, the tumor weight was significantly reduced after the mice were treated with agmatine 5-40 mg.kg-1, and these efFects exhibited a dose-dependent manner.Section B: Possible mechanisms for the antiproliferation of agmatine on tumor cells1 Idazoxan, an antagonist of I-R, had no influence on the proliferation of MCF cellitself and had no action on the inhibitory effects of agmatine on the proliferation of MCF cells. This result indicated that the inhibitory effect of agmatine didn't due to the activation of I-R.2 As to MCF cells, agmatine (1-1000 u M) had no influence on the activity of LDH, which suggest that agmatine has no direct cell toxicity in vitro and the inhibitory effect of agmatine on the proliferation of MCF cells had nothing to do with the cell toxicity.3 Polyamines include putrescine, spermidine and spermine. Putrescine at the concentration of 0.01-1000 u M, had no inhibitory and facilitory effects on the MCF proliferation. When co-administrated with agmatine, putrescine (12.5-100 u M) reversed agmatine's inhibitory effect on MCF. Spermine and spermidine, at the concentration of 0.01-1 u M, had no inhibitory and facilitory effect on the proliferation of tumor cells. However, at the concentration of 1-100 u M, spermidine and spermine significantly inhibited the proliferation of tumor cells and enhanced the anti-proliferative effect of agmatine. These results implicated that agmatine had anti-proliferative effect on tumor cells and the possible mechanism might relate to interfere with the synthesis of polyamines.Section C: Conclusion1 Agmatine inhibited the proliferation of tumor cells, and this effect was specific fortumor cell lines.2 The anti-proliferative effect of agmatine on tumor cells didn't due to the activation of I-R and its cell toxicity.3 The possible mechanism for the anti-proliferative effect of agmatine on MCF cells might be relate to its influence on the synthesis of polyamines.