The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide.

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 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.

• Authors: M D Bacolod, S M Lin, S P Johnson, N S Bullock, M Colvin, D D Bigner, H S Friedman
• Journal: Current cancer drug targets (Curr Cancer Drug Targets) Vol. 8 Issue 3 Pg. 172-9 (May 2008) ISSN: 1873-5576 [Electronic] Netherlands
• PMID: 18473730 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 4-hydroxyperoxycyclophosphamide
• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents, Alkylating
• TAP1 protein, human
• Cyclophosphamide
• AKR1B10 protein, human
• Aldo-Keto Reductases
• Aldehyde Reductase
• Aldehyde Oxidoreductases
• Aldehyde Dehydrogenase 1 Family
• ALDH1B1 protein, human
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP-Binding Cassette Transporters (genetics)
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase 1 Family
• Aldehyde Dehydrogenase, Mitochondrial
• Aldehyde Oxidoreductases (genetics)
• Aldehyde Reductase (genetics)
• Aldo-Keto Reductases
• Antineoplastic Agents, Alkylating (therapeutic use)
• Cell Line, Tumor
• Cerebellar Neoplasms (drug therapy, enzymology, genetics)
• Cyclophosphamide (analogs & derivatives, therapeutic use)
• Data Interpretation, Statistical
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Genotype
• Humans
• Medulloblastoma (drug therapy, enzymology, genetics)
• Oligonucleotide Array Sequence Analysis
• Phenotype