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Topotecan and Doxorubicin Combination to Treat Recurrent Ovarian Cancer: The Influence of Drug Exposure Time and Delivery Systems to Achieve Optimum Therapeutic Activity
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.
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