Sodium Valproate Enhances the Urethane-Induced Lung Adenomas and Suppresses Malignization of Adenomas in Ovariectomized Female Mice

Abstract

In the present study, the possible effect of sodium valproate (NaVP) on urethane-induced lung tumors in female mice has been evaluated. BALB/c mice (n = 60; 4-6 weeks old, females) were used in the following groups: (1) urethane-treated; (2) urethane-NaVP-treated; (3) only NaVP-treated; (4) control. In the same groups, ovariectomized female mice (n = 60) were investigated. Urethane was given intraperitoneally, with a total dose of 50 mg/mouse. In NaVP-treated mice groups, 0.4% aqueous solution of NaVP was offered to mice ad libitum. The duration of the experiment was 6 months. The number of tumors per mouse in ovariectomized mice and in those treated with urethane and NaVP was significantly higher than in mice treated with urethane only (8.29 ± 0.58 versus 6.0 ± 0.63, p < 0.02). No significant difference in the number of tumors per mouse was revealed while comparing the nonovariectomized urethane- and urethane-NaVP-treated groups (p = 0.13). A significant decrease of adenocarcinoma number in ovariectomized mice treated with a urethane-NaVP as compared with ovariectomized mice treated with urethane only was found (p = 0.031). NaVP together with low estrogen may have a protective effect on the malignization of adenomas in ovariectomized mice.

Figure 1

Lung specimens. (a) Control. (b) Urethane-induced lung tumors (white arrowheads). (c) Adenoma, magnification ×4, H & E staining. There are no signs of pressure to surrounding tissues; alveoli are well preserved (black arrowheads). (d) Adenocarcinoma, magnification ×4, H & E staining. Compression of surrounding alveoli (black arrowheads). Invasion to the lumen of bronchiole (black arrows). (e) adenoma, magnification ×40, H & E staining. All nuclei are of similar size and shape; no nucleoli are present (black arrowheads). Cells are of similar size and shape (black arrows). (f) Adenocarcinoma, magnification ×40, H & E staining. Pleomorphic nuclei (black arrowheads), mitotic figures (black arrow), and different cell shapes and sizes (white arrowheads). Scale bar: (c and d) 200 μm; (e and f) 20 μm.

Figure 2

Number of tumors in intact and ovariectomized mice groups. (a) Total number of tumors on the surface of the lungs. ^∗ p < 0.02 in comparison with the ovariectomized urethane-treated group. (b) Tumors in accordance with tumor diameter. ^∗∗ p < 0.05 in comparison with the ovariectomized urethane-treated group.