In vitro activity of the novel cytotoxic agent CHS 828 in childhood acute leukemia.
CHS 828, a pyridyl cyanoguanidine, is a new drug candidate now in phase I/II trials, that has shown promising anticancer activity in experimental tumor models and primary cultures of cancer cells from patients. In this study the fluorometric microculture cytotoxicity assay was used for evaluation of CHS 828 in primary cell cultures from children with acute leukemia. The activity of and interaction with the standard drugs, doxorubicin, melphalan, etoposide and cytosine arabinoside (Ara-C), were also assessed. Samples from 65 patients, 42 with acute lymphocytic leukemia (ALL) and 23 with acute myelocytic leukemia (AML) were tested with 72-h continuous drug exposure. There was 50% cell kill at very low CHS 828 concentrations; median IC50 was 0.01 microM in ALL and 0.03 in AML samples (NS) with large interindividual variability in both groups. ALL samples were significantly more sensitive than AML samples to melphalan, doxorubicin and etoposide, but not to Ara-C. In AML samples, combinations between CHS 828 and each of the four standard drugs resulted in significantly lower cell survival than either drug alone. This was also observed in ALL samples, except for Ara-C. Using the additive interaction model, CHS 828 showed a synergistic effect with melphalan in 67%, doxorubicin in 47%, etoposide in 38% and Ara-C in 14% of AML samples. In most ALL samples subadditive effects were found. Further exploration of CHS 828 in childhood leukemia is warranted, especially in AML.
Department of Women's and Children's Health, University Hospital, Uppsala, Sweden. Britt-Marie.Frost@kbh.uu.se
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BM
Frost
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Lönnerholm
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Nygren
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R
Larsson
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Lindhagen
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003486:Cyanides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007938:Leukemia / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000473:pathology; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D012727:Sex Characteristics; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003486:Cyanides; D006146:Guanidines; D007202:Indicators and Reagents; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine