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Clin Cancer Res. 2013 Feb 15;19(4):865-77. doi: 10.1158/1078-0432.CCR-12-2459. Epub 2013 Jan 9.

Topotecan and doxorubicin combination to treat recurrent ovarian cancer: the influence of drug exposure time and delivery systems to achieve optimum therapeutic activity.

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1
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. npatankar@gmail.com

Abstract

PURPOSE:

To provide proof-of-concept data to support use of Doxil-liposomal topotecan (Topophore C) combinations to treat ovarian cancer.

EXPERIMENTAL DESIGN:

ES-2, OVCAR-3, and SKOV-3 ovarian cancer cell lines were treated with doxorubicin-topotecan combinations by exposing the cells to drugs from 1 to 72 hours. Pharmacokinetic analysis was conducted following administration of liposomal formulations of these drugs alone and in combination. Efficacy assessments were completed in ES-2 and SKOV-3 ovarian cancer models.

RESULTS:

On the basis of drug doses capable of achieving 50% reduction in cell viability over 72 hours, doxorubicin-topotecan combinations were additive in SKOV-3 but highly synergistic in ES-2 and OVCAR-3 cells. Favorable drug-drug interactions increased with increased drug exposure time. Topophore C pharmacokinetic remained unaffected when co-administered with Doxil. In the ES-2 model, Doxil at maximum tolerated dose (MTD 7.5 mg/kg) in combination with free topotecan (MTD 15 mg/kg) did not enhance median survival time (MST) over that achieved with topotecan alone. In contrast, MST was increased to 52 days with combination of Topophore C (MTD 2.5 mg/kg) and Doxil (7.5 mg/kg) compared with untreated animals (MST 18 days) or those treated with Topophore C alone (MTD 5 mg/kg, MST 40 days). In the SKOV-3 model, combination treatments showed better therapeutic efficacy than the individual drugs.

CONCLUSIONS:

Topotecan-doxorubicin combinations produced additive or synergistic effects which were best achieved when the tumor cells were exposed to drugs over extended time. Doxil-Topophore C combinations are therapeutically superior as judged in two ovarian cancer models. Clin Cancer Res; 19(4); 865-77. ©2012 AACR.

PMID:
23303216
DOI:
10.1158/1078-0432.CCR-12-2459
[Indexed for MEDLINE]
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