In vitro cytotoxicity of nelarabine, clofarabine and flavopiridol in paediatric acute lymphoblastic leukaemia

• Published in: British journal of haematology Vol. 137; no. 2; pp. 109 - 116
• Main Authors: Beesley, Alex H., Palmer, Misty‐Lee, Ford, Jette, Weller, Renae E., Cummings, Aaron J., Freitas, Joseph R., Firth, Martin J., Perera, Kanchana U., De Klerk, Nicholas H., Kees, Ursula R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2007; Blackwell
• Subjects: acute lymphoblastic leukaemia; Adenine Nucleotides - pharmacology; Antineoplastic Agents - pharmacology; Arabinonucleosides - pharmacology; Biological and medical sciences; Burkitt Lymphoma - pathology; Child; clofarabine; Dose-Response Relationship, Drug; drug resistance; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flavonoids - pharmacology; flavopiridol; Hematologic and hematopoietic diseases; Humans; Inhibitory Concentration 50; Leukemia-Lymphoma, Adult T-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; nelarabine; Piperidines - pharmacology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Tumor Cells, Cultured; Human; Antineoplastic agent; Purine derivatives; Purine nucleoside; Treatment resistance; Hematology; Acute leukemia; Cytotoxicity; Malignant hemopathy; Clofarabine; Lymphoid neoplasm; Flavonoid; In vitro; Nelarabine; Polyphenol; Flavopiridol; Antimetabolic; acute lymphoblastic leukaemia; Phenols; Nucleoside analog; Acute lymphocytic leukemia; drug resistance; Child
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2007.06527.x

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.