The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide.
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 medulloblastoma's 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.
Bacolod
M D
MD
Department of Surgery, Duke University Medical Center, Durham,NC 27710, USA. mdb2005@med.cornell.edu
Lin
S M
SM
Johnson
S P
SP
Bullock
N S
NS
Colvin
M
M
Bigner
D D
DD
Friedman
H S
HS
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000445:Aldehyde Oxidoreductases / Q000235:genetics; D000449:Aldehyde Reductase / Q000235:genetics; D000074408:Aldo-Keto Reductases; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003627:Data Interpretation, Statistical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype
C093853:4-hydroxyperoxycyclophosphamide; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D018906:Antineoplastic Agents, Alkylating; C073119:TAP1 protein, human; D003520:Cyclophosphamide; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D000445:Aldehyde Oxidoreductases; D000080924:Aldehyde Dehydrogenase 1 Family; C524846:ALDH1B1 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial