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Schedule-dependent
activity of temozolomide plus CPT-11 against a human central nervous system
tumor-derived xenograft
Patel VJ, Elion GB, Houghton PJ, Keir S, Pegg AE, Johnson SP, Dolan
ME, Bigner DD, Friedman HS
Department of Surgery, Pathology [Duke University Medical
Center, Durham, North Carolina 27710, USA
Temozolomide, an imidazole tetrazinone, and CPT-11, a camptothecin
derivative, have previously been shown to have anti-central nervous system tumor
activity in laboratory and clinical studies.
The current experiments were designed to evaluate the activity of temozolomide
plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c.
in athymic nude mice.
The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on
day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14.
The combination of these two agents produced greater than additive activity
against D-54 MG.
This enhanced activity was maintained when the initial administration of CPT-11
was delayed to day 3 or day 5.
However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the
single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days
later, the enhancement of activity was substantially reduced.
These results demonstrate that the combination of temozolomide plus CPT-11
displays a schedule-dependent enhancement of antitumor activity, suggest a
mechanistic explanation for the enhanced activity, and provide the rationale for
a Phase I trial of this regimen.
PMID: 11051270 [PubMed - indexed for MEDLINE]
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