In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia.
The in vitro efficacies of three new drugs--clofarabine (CLOF), nelarabine (NEL) and flavopiridol (FP) - were assessed in a panel of acute lymphoblastic leukaemia (ALL) cell lines. The 50% inhibitory concentration (IC50) for CLOF across all lines was 188-fold lower than that of NEL. B-lineage, but not T-lineage lines, were >7-fold more sensitive to CLOF than cytosine arabinoside (ARAC). NEL IC50 was 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells were eightfold more sensitive to NEL than B-lineage but there was considerable overlap. FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. Potential cross-resistance of CLOF, NEL and FP was observed with many front-line ALL therapeutics but not methotrexate or thiopurines. Methotrexate sensitivity was inversely related to that of NEL and FP. Whilst NEL was particularly effective in T-ALL, a subset of patients with B-lineage ALL might also be sensitive. CLOF appeared to be marginally more effective in B-lineage than T-ALL and has a distinct resistance profile that may prove useful in combination with other compounds. FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.
Beesley
Alex H
AH
Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research, and Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
Palmer
Misty-Lee
ML
Ford
Jette
J
Weller
Renae E
RE
Cummings
Aaron J
AJ
Freitas
Joseph R
JR
Firth
Martin J
MJ
Perera
Kanchana U
KU
de Klerk
Nicholas H
NH
Kees
Ursula R
UR
D000227:Adenine Nucleotides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000473:pathology; D002648:Child; D000077866:Clofarabine; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; C104457:nelarabine; D000077866:Clofarabine