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Current Cancer Drug Targets
ISSN (Print): 1568-0096
ISSN (Online): 1873-5576
VOLUME: 8
ISSUE: 3
DOI: 10.2174/156800908784293631      Price:  $58









The Gene Expression Profiles of Medulloblastoma Cell Lines Resistant to Preactivated Cyclophosphamide

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Author(s): M. D. Bacolod, S. M. Lin, S. P. Johnson, N. S. Bullock, M. Colvin, D. D. Bigner and H. S. Friedman
Pages 172-179 (8)
Abstract:
The total expression profiles of two medulloblastoma cell lines resistant to the preactivated form of cyclophosphamide (4-hydroperoxycyclophosphamide, 4-HC) were examined using the Affymetrix GeneChip U133A array. Our primary objective was to look for possible genes, other than the well-studied aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide (CP) resistance in medulloblastomas. We present here the lists of the most highly upregulated [30 for D341 MED (4-HCR); 20 for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR); 15 for D283 MED (4-HCR)] genes which may be involved in conferring CP-resistance to the two medullobalstoma cell lines. The lists of genes from the two sublines almost had no overlap, suggesting different mechanisms of CP-resistance. One of the most noteworthy upregulated gene is TAP1 [ 90-fold increase in D341 MED (4-HCR) relative to D341 MED ]. TAP1, a protein belonging to the ABC transporter family is normally involved in major histocompatibility class I (MHC I) antigen processing. This suggests the possible role of multidrug resistance (MDR), albeit atypical (which means it does not involve the usual MDR1 and MRP glycoproteins), in medulloblastomas CP-resistance. Apart from TAP1, a number of other genes involved in MHC1 processing were upregulated in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase in the expression of the aldo-keto reductase gene, AKR1B10, which may deactivate the reactive cyclophosphamide metabolite, aldophosphamide. For D283 MED (4-HCR), the most notable increase in expression is that of ALDH1B1, a member of the aldehyde dehydrogenase (ALDH) family of proteins.
Keywords:
Cyclophosphamide, drug resistance, medulloblastoma, brain tumor, oxazaphosphorine, aldehyde dehydrogenase, microarray, aldo-keto reductase
Affiliation:
Cornell University Weill Medical College, New York, NY 10021, USA.