Synergy of karenitecin and mafosfamide in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines.
نویسندگان
چکیده
BACKGROUND A major barrier to treatment of leptomeningeal disease is the lack of proven combination chemotherapy regimens for intrathecal administration. The purpose of this study was to determine the cytotoxic effects of karenitecin and mafosfamide in vitro against leukemia, medulloblastoma, and neuroblastoma cell lines. PROCEDURE A modified methyl tetrazolium (MTT) assay was used to determine the sensitivity of the cells to karenitecin and mafosfamide. Cells were exposed to drug for 72 hr, after which the number of surviving cells was quantitated. For drug combination experiments, cells were exposed to medium alone (controls), single drugs alone (mafosfamide only, karenitecin only) or to different concentrations of the combination of the two drugs (karenitecin + mafosfamide), for a total of 36 concentration pairs per plate. The universal response surface approach (URSA) was used to analyze the cytotoxic effects of the combination of karenitecin and mafosfamide. RESULTS The IC(50)s of karenitecin and mafosfamide for the various cell lines were similar. For both drugs nearly complete inhibition of cell growth was demonstrated at higher concentrations in all cell lines. In the neuroblastoma cell lines (SK-N-DZ; SK-N-SH) and the DAOY medulloblastoma cell line, the combination of karenitecin and mafosfamide were synergistic. In the D283 medulloblastoma and both the leukemia cell lines (JM1 and Molt-4), the drug interaction was additive. Antagonism was not seen in any cell line. CONCLUSIONS Karenitecin and mafosfamide are additive or synergistic in vitro against tumor types that disseminate to the leptomeninges. These results provide guidance for the choice of potential combination intrathecal regimens.
منابع مشابه
Effects of Trichostatin A on the Histone Deacetylases (HDACs), Intrinsic Apoptotic Pathway, p21/Waf1/Cip1, and p53 in Human Neuroblastoma, Glioblastoma, Hepatocellular Carcinoma, and Colon Cancer Cell Lines
Background: The aberrant and altered patterns of gene expression play an important role in the biology of cancer and tumorigenesis. DNA methylation and histone deacetylation are the most studied epigenetic mechanisms. Histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA) and trichostatin A (TSA) are a group of anticancer compounds for the treatment of solid and hematological canc...
متن کاملVariable 5-methylcytosine levels in human tumor cell lines and fresh pediatric tumor explants.
DNA methylation was measured in human tumor cell lines and freshly explanted pediatric tumors by [3H]uridine labeling followed by DNA hydrolysis and high-performance liquid chromatography. The percentage of cytosine residues modified to 5-methylcytosine in 4 cell lines derived from pediatric tumors was increased or similar to the levels of 3.45% found in two strains of diploid human fibroblasts...
متن کاملSynergistic Anti-Cancer Effects of Second-Generation Proteasome Inhibitor Carfilzomib with Doxorubicin and Dexamethasone Via p53-Mediated Apoptosis in Pre-B Acute Lymphoblastic Leukemia Cells
Background: The ubiquitin-proteasome system (UPS) plays a crucial role in regulating the levels and functions of a large number of proteins in the cell, which are important for cancer cell growth and survival. The proteasome is highly activated in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is the most common malignancy in children. The attempt to inhibit proteasome as a ther...
متن کاملMS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors.
The antitumor efficacy of the synthetic benzamide derivative MS-27-275 (MS-275), an inhibitor of histone deacetylation [T. Suzuki et al., J. Med. Chem., 42: 3001-3003, 1999], was evaluated in a series of pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma (EWS), retinoblastoma, medulloblastoma, undifferentiated sarcoma (US), osteosarcoma, and malignant r...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Pediatric blood & cancer
دوره 50 4 شماره
صفحات -
تاریخ انتشار 2008