Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: pharmacokinetic and pharmacodynamic evaluation.
Topotecan is a topoisomerase (Topo) I inhibitor used in ovarian carcinoma chemotherapy. Topo I inhibitors are thought to be more cytotoxic using protracted schedules of administration. We tested this hypothesis on a preclinical model: human ovarian carcinoma OVCAR-3 implanted i.p. Nude mice 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 toxicity was maximal when the total dose was delivered within 5 and 10 days of treatment. However, the efficacy was the greatest (all of the mice cured) in the 20-day schedule using 0.625 mg/kg/day, hence, making this latter schedule the most efficient without any major toxicity. A pharmacokinetic study was conducted to identify parameters related to the efficacy and toxicity 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 toxicity. 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.
Guichard
S
S
Groupe de Pharmacologie clinique et expérimentale (EA 3035), Institut Claudius Regaud, rue de Pont St Pierre, 31052 Toulouse Cedex, France. guichard@icr.fnclcc.fr
Montazeri
A
A
Chatelut
E
E
Hennebelle
I
I
Bugat
R
R
Canal
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004264:DNA Topoisomerases, Type I