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In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets.
- Source :
-
Blood [Blood] 2005 Nov 15; Vol. 106 (10), pp. 3532-7. Date of Electronic Publication: 2005 Jul 28. - Publication Year :
- 2005
-
Abstract
- Although the prognosis of pediatric leukemias has improved considerably, many patients still have relapses. Tipifarnib, a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n = 25). AML samples were significantly more sensitive to tipifarnib compared to B-cell precursor ALL (BCP ALL) or N BM samples. Within AML, French-American-British (FAB) M5 samples were most sensitive to tipifarnib. T-cell ALL samples were significantly more sensitive than BCP ALL and N BM samples. In AML there was a marked correlation between tipifarnib resistance and daunorubicin or etoposide resistance, but not to cytarabine or 6-thioguanine. RAS mutations were present in 32% of AML and 18% of ALL samples, but there was no correlation between RAS mutational status and sensitivity to tipifarnib. Future studies are needed to identify biomarkers predictive of tipifarnib sensitivity. In addition, clinical studies, especially in T-cell ALL, seem warranted.
- Subjects :
- Adolescent
Antineoplastic Agents therapeutic use
Child
Child, Preschool
Drug Screening Assays, Antitumor
Farnesyltranstransferase antagonists & inhibitors
Farnesyltranstransferase metabolism
Female
Humans
Leukemia, Monocytic, Acute drug therapy
Leukemia, Monocytic, Acute genetics
Male
Mutation
Oncogene Protein p21(ras) genetics
Oncogene Protein p21(ras) metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Quinolones therapeutic use
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Biomarkers, Tumor metabolism
Drug Resistance, Neoplasm drug effects
Leukemia, Monocytic, Acute enzymology
Precursor Cell Lymphoblastic Leukemia-Lymphoma enzymology
Quinolones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 106
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 16051737
- Full Text :
- https://doi.org/10.1182/blood-2005-04-1640