Topotecan is a topoisomerase (Topo) I inhibitor used in @entity43 chemotherapy. Topo I inhibitors are thought to be more cytotoxic using protracted schedules of administration. We tested this hypothesis on a preclinical model: @entity1 @entity43 OVCAR-3 implanted i.p. @entity19 were treated i.p. with a total dose of topotecan of 12.5 mg/kg delivered in 1, 5, 10, 20, 40, or 80 daily injections. The @entity137 was maximal when the total dose was delivered within 5 and 10 days of treatment. However, the efficacy was the greatest (all of the @entity19 cured) in the 20-day schedule using 0.625 mg/kg/day, hence, making this latter schedule the most efficient without any major @entity137 . A pharmacokinetic study was conducted to identify parameters related to the efficacy and @entity137 of topotecan in our model. The use of a population pharmacokinetic approach allowed us to define a therapeutic window: maintaining plasma concentrations above 0.2 microM for >10 h was necessary for an optimal antitumor effect and avoiding plasma concentrations >0.7 microM allowed a manageable @entity137 . Finally, Topo I activity was monitored in ascites from animals treated with different topotecan administration schedules. The optimal schedule defined above allowed for sustained inhibition of Topo I activity associated with a greater antitumor activity. These in vivo data constitute a rationale for clinical studies testing this type of administration.

Schedule-dependent activity of topotecan in OVCAR-3 XXXX xenograft: pharmacokinetic and pharmacodynamic evaluation.

@entity43 :: ('MESH:D010051', 'Disease') :: ['ovarian carcinoma'] @entity1 :: ('9606', 'Species') :: ['human'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity19 :: ('10090', 'Species') :: ['mice', 'Nude mice']
@entity43 :: (MESH:D010051,Disease) :: ['ovarian carcinoma']
