Abstract
BackgroundAdvanced ovarian cancer is characterized by peritoneal metastasis and the accumulation of ascites. Peritoneal metastasis of ovarian cancer is a major cause of the negative treatment outcome, as these metastases are resistant to most chemotherapy regimens. The aim of this study was to clarify aggressive pathology of peritoneal metastasis and examine the therapeutic efficacy of a liposomal agent in the model.MethodsA human cancer cell line ES-2 of ovarian clear cell carcinoma, known as a chemotherapy-resistant cancer, was cultured in nonadherent plate to form spheroid and single cell suspension was transplanted into mouse peritoneal cavity. The epidermal growth factor receptor (EGFR) pathways in the cellular aggregates were analyzed both spheroid and ascites. The pharmacokinetics and therapeutic efficacy of CPT-11 (45 mg/kg) and IHL-305 (45 mg/kg), an irinotecan-encapsulated liposome, were examined by intravenous administration.ResultsEstablished peritoneal metastasis model showed an accumulation of ascites. The activation of EGFR and Akt was demonstrated in cellular aggregates both in the spheroid and ascites. In ascites samples, the area under the curve of SN-38, the activated form of CPT-11, was 3.8 times higher from IHL-305-treated mice than from CPT-11-treated mice. IHL-305 prolonged the survival time and decreased the accumulation of ascites and tumor metastasis. The median survival time were 22, 37 and 54 days in the control, CPT-11-treated, and IHL-305-treated mice, respectively.ConclusionsEGFR/Akt pathway contributes to the aggressive progression in ES-2 peritoneal metastasis model and effective delivery into ascites of IHL-305 was thought to useful treatment for ovarian cancer with peritoneal metastasis.
Highlights
Advanced ovarian cancer is characterized by peritoneal metastasis and the accumulation of ascites
Establishment of ES-2 peritoneal metastasis mouse model Various numbers of ES-2 human ovarian cancer cells were inoculated into the peritoneal cavities of mice, and the survival and performance statuses after inoculation were observed
Survival of mice with peritoneal metastasis treated with Irinotecan hydrochloride (CPT-11), IHL-305 We demonstrated that CPT-11 and IHL-305 suppressed the accumulation of ascites and the formation of metastases as surrogate endpoints and examined the survival time of the mice as the primary endpoint
Summary
Advanced ovarian cancer is characterized by peritoneal metastasis and the accumulation of ascites. Peritoneal metastasis of ovarian cancer is a major cause of the negative treatment outcome, as these metastases are resistant to most chemotherapy regimens. For the treatment of ovarian cancer with peritoneal metastasis, the intraperitoneal administration of cisplatin or paclitaxel has been examined in clinical trials. Though some of these trials were successful [3,5,6,7], other trials did not succeed because of chemical peritonitis and the enhancement of adverse effects [8]. None of the intraperitoneal or intravenous chemotherapy regimens have been confirmed as effective against ovarian cancer with peritoneal metastasis. A novel therapy for the treatment of ovarian cancer with peritoneal metastasis is needed
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