In vitro cytotoxicity of docetaxel in childhood acute leukemias.
OBJECTIVE
In seeking to identify novel effective antileukemic agents, we assessed the in vitro activity of the taxoid docetaxel (Taxotere; Rhone-Poulenc Rorer, Antony, France) in primary leukemic cells supported in culture by bone marrow-derived stromal layers.


METHODS
Bone marrow samples from children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were cultured on allogeneic bone marrow-derived stromal layers and exposed to various concentrations of docetaxel. After 7 days of culture, the number of viable leukemic cells were counted by flow cytometry and compared with that in parallel cultures without drugs.


RESULTS
In 20 samples tested (15 B-lineage ALL, one T-lineage ALL, and four AML), the median cytotoxicity was 78% after a 7-day culture in the presence of 100 ng/mL docetaxel (range, 54% to 95%). The effects were dose-dependent and extended to all five ALL samples with the t(9;22)(q34;q11) (Philadelphia chromosome) or 11q23 abnormalities, karyotypes associated with an unfavorable outcome. Studies with continuously growing cell lines demonstrated that docetaxel exerted its cytotoxic effect by inducing apoptosis, and was consistently more effective than paclitaxel (Taxol; Bristol-Myers Squibb, Wallingford, CT) (mean 50% cell kill [LC50], 6.93 v 12.86 ng/mL in six leukemic cell lines). The antileukemic activities of docetaxel and vincristine were synergistic. While the mean (+/- SD) cytotoxicity of vincristine (0.1 ng/mL) was 11.2% +/- 7.3% and that of docetaxel (10 ng/mL) was 19.3% +/- 17.5% in CEM-C7 cells after 24 hours, combining the two agents increased the cytotoxicity to 62.5% +/- 20.7% (P = .003).


CONCLUSIONS
Docetaxel, at concentrations achievable in vivo, is cytotoxic to ALL and AML cells. These results provide a rationale for clinical trials of docetaxel in patients with acute leukemia.
Consolini
R
R
Department of Hematology-Oncology, St Jude Children's Research Hospital, University of Tennessee College of Medicine, Memphis 38105, USA.
Pui
C H
CH
Behm
F G
FG
Raimondi
S C
SC
Campana
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D000208:Acute Disease; D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D014750:Vincristine; D017239:Paclitaxel