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In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia
Author(s) -
Beesley Alex H.,
Palmer MistyLee,
Ford Jette,
Weller Renae E.,
Cummings Aaron J.,
Freitas Joseph R.,
Firth Martin J.,
Perera Kanchana U.,
De Klerk Nicholas H.,
Kees Ursula R.
Publication year - 2007
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2007.06527.x
Subject(s) - clofarabine , cytotoxicity , medicine , cancer research , lymphoblastic leukemia , in vitro , oncology , leukemia , chemistry , cytarabine , biochemistry
Summary 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.