Antiproliferative activity and toxicity of 2-methoxyestradiol in cervical cancer xenograft mice

Abstract

2-Methoxyestradiol (2-ME) is considered to be an effective anticancer compound for many types of tumors. We have previously demonstrated that 2-ME inhibits the growth of human cervical cancer HeLaS3 cellsin vitro. In this study, we investigated the antitumoral effects of 2-ME on human cervical carcinoma in severe combined immune deficient (SCID) mice. The potential side effects of 2-ME on the SCID mice were also investigated. SCID mice were injected with HeLaS3 cells (3 × 106to 4 × 106/mouse) and a 15-day administration of 2-ME followed after a 1-week cell implantation. Tumor weight, volume, body weight, and blood chemistry were determined. Tumor tissues were examined with an antibody against the proliferative cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Liver, spleen, kidney, heart, and lung were screened by pathologic examinations. 2-ME (75 mg/kg p.o.) inhibited growth of human cervical carcinoma by 34% (P< 0.05) as compared with control. Necrosis was found in both 2-ME–treated and untreated tumor tissues, but the necrotic area was larger in 2-ME–treated mice. A low expression of proliferative cell nuclear antigen and an increased number of apoptotic cells were found in 2-ME–treated tumor sections as compared to those in controls. No significant difference was detected in blood chemistry. In addition, the liver showed hyperplastic Kupffer cells, hydropic swelling of hepatocytes, and liquefactive necrosis. The spleen showed an increased number of megakaryocytes and apoptotic cells after 2-ME treatment. Thus, 2-ME has an antitumor effect on human cervical carcinoma, and it is toxic to liver and spleen in this mouse model.