Sequential oral 9-nitrocamptothecin and etoposide: a pharmacodynamic- and pharmacokinetic-based phase I trial.
OBJECTIVE
Resistance to topoisomerase (topo) I inhibitors has been related to down-regulation of nuclear target enzyme, whereas sensitization to topo II inhibitors may result from induction of topo II by topo I inhibitors. Here, we evaluated a sequence-specific administration of a topo I inhibitor followed by a topo II inhibitor.


METHODS
Twenty-five patients with advanced or metastatic malignancies were treated with increasing doses (0.75, 1.0, 1.25, 1.5, 1.75, or 2.0 mg/m(2)) of 9-nitrocamptothecin (9-NC) on days 1 to 3, followed by etoposide (100 or 150 mg/d) on days 4 and 5. At the maximally tolerated dose, 20 additional patients were enrolled. The median age was 60 years (range, 40-84 years). Endpoints included pharmacokinetic analyses of 9-NC and etoposide, and treatment-induced modulations of topo I and II expression in peripheral blood mononuclear cells.


RESULTS
Neutropenia, thrombocytopenia, nausea, vomiting, diarrhea, and fatigue were dose-limiting toxicities and occurred in six patients. Despite a median number of four prior regimens (range 1-12), 2 (4%) patients had an objective response and 13 (29%) patients had stable disease. In contrast to the expected modulation in topo I and IIalpha levels, we observed a decrease in topo IIalpha levels, whereas topo I levels were not significantly altered by 9-NC treatment.


CONCLUSIONS
Sequence-specific administration of 9-NC and etoposide is tolerable and active. However, peripheral blood mononuclear cells may not be a predictive biological surrogate for drug-induced modulation of topo levels in tumor tissues and should be further explored in larger studies.
Simon
George R
GR
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, SRB-2, Tampa, 33612-9416, USA.
Lush
Richard M
RM
Gump
Jana
J
Tetteh
Leticia
L
Williams
Charles
C
Cantor
Alan
A
Antonia
Scott
S
Garrett
Christopher
C
Rocha-Lima
Caio
C
Fishman
Mayer
M
Sullivan
Daniel M
DM
Munster
Pamela N
PN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000097:blood / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000097:blood / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
D005047:Etoposide; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C079905:rubitecan; D002166:Camptothecin