(ChemotherapyAdvisor) – Combining an approved liposomal formulation of doxorubicin (Doxil®) with an experimental liposomal formulation of topotecan (Topophore C™) produced “therapeutically superior” results in two models of recurrent ovarian cancer, a study reported in Clinical Cancer Research online January 9.
Nilesh A. Patankar, PhD, of the University of British Columbia, Vancouver, Canada, and Merrimack Pharmaceuticals, Cambridge, MA, and colleagues, designed a proof-of-concept study to support use of the combination of the liposomal formulations of doxorubicin and topotecan to treat ovarian cancer.
The investigators exposed ES-2, OVCAR-3, and SKOV-3 ovarian cancer cell lines to liposomal formulations of the drugs both alone and in combination at different time frames (ie, 1, 4, 8, 24, 48, and 72 hours).
“Based on drug doses capable of achieving 50% reduction in cell viability over 72 hours, doxorubicin/topotecan combinations were additive in SKOV3 but highly synergistic in ES-2 and OVCAR-3 cells,” the authors reported, with favorable drug-drug interactions increasing with increased drug exposure time.
The pharmacokinetic profile of liposomal topotecan remained unaffected when coadministered with liposomal doxorubicin.
In vivo assessments of antitumor efficacy were completed in two of the models, ES-2 and SKOV-3, using female mice. In the ES-2 model, liposomal doxorubicin at the maximum tolerated dose (MTD) of 7.5mg/kg combined with free topotecan at an MTD of 15mg/kg “did not enhance median survival time over that achieved with topotecan alone,” Dr. Patankar noted.
In contrast, median survival time was increased to 52 days with the combination of liposomal topotecan MTD 2.5mg/kg and liposomal doxorubicin 7.5mg/kg vs 18 days for untreated animals or those treated with liposomal topotecan alone at an MTD of 5mg/kg (40 days).
In the SKOV-3 model, the combination showed better therapeutic efficacy when compared with the individual drugs.
“Our results showed that an approved liposomal formulation of doxorubicin when used in combination with a liposomal topotecan formulation achieved significantly better treatment outcomes against models of ovarian cancer,” the authors wrote.
“This combination also achieved improved therapeutic effects at lower drug doses that are better tolerated and hence will be ideally suited for use in the context of emerging targeted therapies that will ultimately lead to a time when refractory ovarian cancer is treated with curative intent and not merely as a palliative care.”