Intraperitoneal topoisomerase-I inhibitors. Preliminary findings with 9-aminocamptothecin.
The i.p. administration of topoisomerase I (Topo I) inhibitors has a pharmacologic advantage over intravenous application, including preservation of the biologically active lactone form. In our ongoing study, patients have received 9-amino-20(S)-camptothecin (9-AC) i.p. on days 1, 3, 5, 8, 10, and 12, repeated every 4 weeks. The daily dose has been escalated to level IV of 1.5 mg/m2 (9.0 mg/m2 per course), median of 3 cycles, range 1-4, with a reversible Grade 3 neutropenia in one patient. Responses included one CR (resolution of a pleural effusion), two patients without progressive disease (PD), two not evaluable, and two patients too early for evaluation. The area under the curve (AUC)i.p./AUCpl ratio (pharmacologic advantage) ranged from 7.6 to 16.5 on average, and, using nonlinear modeling, the pharmacologic decay data were fit to one- or two-compartmental models. Overall, a 9-AC i.p. application is well tolerated and anticipated to be an active regimen against i.p. malignancies, particularly those known to be sensitive to systemic Topo-I inhibitors.
Muggia
F
F
Department of Medicine-Division of Oncology, Department of Radiology, New York University School of Medicine, New York, New York 10016, USA.
Liebes
L
L
Potmesil
M
M
Hamilton
A
A
Hochster
H
H
Hornreich
G
G
Sorich
J
J
Downey
A
A
Wasserstrom
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C080125:9-aminocamptothecin; D002166:Camptothecin