ABSTRACT
OBJECTIVE: Topotecan, a novel topoisomerase-1 inhibitor, is a drug that appears to be effective against platinum-resistant ovarian cancers. However, the molecular mechanisms by which Topotecan treatment inhibits cancer cell proliferation are unclear. We investigated whether Topotecan increases the efficacy of Cisplatin in platinum-resistant ovarian cancer models in vitro and in vivo. METHODS: We used Cisplatin-resistant Caov-3 cells and Cisplatin-sensitive A2780 cells. We examined the effect of Cisplatin and Topotecan on the cell viability of Caov-3 and A2780 cells by MTS assay. We examined the Akt kinase activity, VEGF and HIF-1α expression after Cisplatin and Topotecan by a Western blot analysis. Moreover, we also evaluated the effects of Cisplatin and Topotecan on the intraabdominal dissemination of ovarian cancer in vivo. RESULTS: Topotecan significantly inhibited Cisplatin-induced Akt activation in Caov-3 cells, but not in A2780 cells. In the presence of Topotecan, Cisplatin-induced growth inhibition and apoptosis were significantly enhanced in Caov-3 cells. Topotecan inhibited not only Cisplatin-induced Akt activation but also VEGF and HIF-1α expression. Moreover, treatment with Topotecan increased the efficacy of Cisplatin-induced growth inhibition in the intraabdominal dissemination and production of ascites in athymic nude mice inoculated with Caov-3 cells. CONCLUSION: We herein demonstrated that Topotecan inhibits Akt kinase activity and VEGF transcriptional activation after Cisplatin treatment in platinum-resistant ovarian cancers. We clarified how Topotecan enhanced the clinical activity in the platinum-resistant ovarian cancer. These results provide a rationale for using Topotecan in clinical regimens aimed at molecular targeting agents in platinum-resistant ovarian cancers.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cisplatin/pharmacology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Topotecan/pharmacology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/administration & dosage , Drug Synergism , Enzyme Activation/drug effects , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Ovarian Neoplasms/enzymology , Proto-Oncogene Proteins c-akt/metabolism , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/pharmacology , Topotecan/administration & dosage , Vascular Endothelial Growth Factor A/metabolism , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To report a case of a methotrexate (MTX)-resistant heterotopic interstitial pregnancy in which dactinomycin was necessary as a second-line chemotherapy. DESIGN: Case report. SETTING: Medical college-affiliated hospital. PATIENT(S): A 39-year-old woman with vaginal bleeding after the transfer of two thawed 8-cell embryos. INTERVENTION(S): MTX 50 mg/m(2) was given to the patient to treat a concomitant pregnancy in which an interstitial pregnancy and an intrauterine blighted ovum were identified. However, the patient's hCG level rose despite two MTX administrations. As a result, dactinomycin was then administered as a second-line chemotherapy. The patient's serum hCG level declined to a normal range after two administrations of dactinomycin. CONCLUSION(S): Dactinomycin could be an alternative in cases for which MTX is not effective and persistently high hCG levels exist.
