Abstract
Ovarian cancer is known as the silent killer for being asymptomatic until late stages. Current first-line treatment consists of debulking surgery followed by i.v. chemotherapeutics administered intermittently, which leads to insufficient drug concentrations at tumor sites, accelerated tumor proliferation rates, and drug resistance, resulting in an overall median survival of only 2 to 4 years. For these reasons, more effective treatment strategies must be developed. We have investigated a localized, continuous chemotherapy approach in tumor models of human and murine ovarian cancers using the antineoplastic agent docetaxel. We show here that continuous docetaxel therapy is considerably more efficacious than intermittent therapy, resulting in a greater decrease in tumor burden and ascites fluid accumulation. Immunohistochemical analyses show that continuous chemotherapy abrogates tumor cell proliferation and angiogenesis to the tumor microenvironment, leading to greater tumor cell death than intermittent docetaxel therapy. Overall, our results show greater therapeutic advantages of continuous over intermittent chemotherapy in the treatment of ovarian cancer.
Highlights
Ovarian cancer is the leading cause of death from gynecologic malignancies, with the majority of patients not surviving beyond 5 years postdiagnosis [1]
To test whether continuous DTX provided by the injectable DTX-PoLigel formulation shows activity against ovarian cancer cells, human ovarian adenocarcinoma cells (SKOV3-luc) and mouse ovarian cancer cells (ID8) were exposed to four volumes of drug-free PoLigel or DTX-PoLigel at total DTX concentrations of 93, 186, 372, and 558 μmol/L, over 24, 48, and 72 hours, at which times cell viability was assessed by the MTT assay
Intermittent chemotherapy at the maximum tolerable doses (MTD), the approach currently used in the treatment of advanced ovarian cancer, has been highly unsuccessful
Summary
Ovarian cancer is the leading cause of death from gynecologic malignancies, with the majority of patients not surviving beyond 5 years postdiagnosis [1]. This leads to low drug concentrations at tumor sites and high levels in healthy tissues, resulting in dose-limiting toxicities [5, 6]. An alternative strategy is to maintain low drug levels in the systemic circulation through localized delivery, decreasing toxic side effects, and increasing local drug concentrations in the peritoneum, where ovarian cancer tumors and ascites reside. This can be achieved through i.p. administration. Based on clinical trials that have evaluated this treatment strategy, the Authors' Affiliations: Departments of 1Pharmaceutical Sciences and 2Medical Biophysics, University of Toronto, Ontario, Canada
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