The aim of the present study was to evaluate sex differences in tumorigenesis by assessing the number of Ki‑67‑positive cells [Ki‑67(+)] in urethane‑induced mice lung tumors and the effect of sodium valproate (NaVP) in BALB/c mice. Gonad-intact and gonadectomized female and male mice were divided into the following groups: i) Treated with urethane, ii) treated with urethane and NaVP and iii) gonad‑intact or gonadectomized control. Urethane (total 50 mg/mouse) was injected intraperitoneally. The NaVP 0.4% solution was administered orally for 6 months. Histologically, lung tumors were divided into adenomas and adenocarcinomas and assessed immunohistochemically using antibodies against Ki‑67. The Ki‑67(+) was calculated per one mm2 of a tumor. In adenomas, Ki‑67(+) in the urethane‑treated gonad‑intact males was significantly higher than in females (P=0.001) and in castrated males (P<0.01); Ki‑67(+) in adenomas of the urethane‑treated gonad‑intact males was significantly higher than in urethane‑NaVP‑treated ones (P<0.04). No significant differences were found in analogous female groups. In adenocarcinomas, Ki‑67(+) in urethane‑treated gonad‑intact males was significantly higher than in females and gonadectomized mice of both sexes (P<0.001), and in ovariectomized females was significantly higher than in ovary‑intact group (P=0.01). A significantly higher number of Ki‑67(+) cells were observed in gonad‑intact adenocarcinomas of the urethane‑NaVP‑treated females compared with the urethane‑treated ones (P<0.001). Comparing between urethane‑NaVP‑treated gonadectomized males and females in adenocarcinomas, determined that Ki‑67(+) was significantly lower in females (P=0.005). In adenocarcinomas, Ki‑67(+) in urethane‑NaVP‑treated gonadectomized males and females was significantly lower than in gonad‑intact mice of the same sex (P<0.001). In summary, gonadectomy with NaVP treatment decreased Ki‑67(+) in adenocarcinomas for mice of both sexes. The results of the present study indicate sex‑related differences in mice lung tumorigenesis, and a sex‑related effect of NaVP on progression in urethane‑induced BALB/c mice lung tumors.

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