title: Multiple mechanisms of N-phosphonacetyl-L-aspartate resistance in human cell lines: carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase gene amplification is frequent only when chromosome 2 is rearranged.
abstract: Rodent cells resistant to N-phosphonacetyl-L-aspartate (PALA) invariably contain amplified carbamyl-P synthetase/aspartate transcarbamylase/dihydro-orotase (CAD) genes, usually in widely spaced tandem arrays present as extensions of the same chromosome arm that carries a single copy of CAD in normal cells. In contrast, amplification of CAD is very infrequent in several human tumor cell lines. Cell lines with minimal chromosomal rearrangement and with unrearranged copies of chromosome 2 rarely develop intrachromosomal amplifications of CAD. These cells frequently become resistant to PALA through a mechanism that increases the aspartate transcarbamylase activity with no increase in CAD copy number, or they obtain one extra copy of CAD by forming an isochromosome 2p or by retaining an extra copy of chromosome 2. In cells with multiple chromosomal aberrations and rearranged copies of chromosome 2, amplification of CAD as tandem arrays from rearranged chromosomes is the most frequent mechanism of PALA resistance. All of these different mechanisms of PALA resistance are blocked in normal human fibroblasts.
authors.affiliation: Imperial Cancer Research Fund, London, United Kingdom.
authors.forename: K A
authors.initials: KA
authors.lastname: Smith
authors.forename: O B
authors.initials: OB
authors.lastname: Chernova
authors.forename: R P
authors.initials: RP
authors.lastname: Groves
authors.forename: M B
authors.initials: MB
authors.lastname: Stark
authors.forename: J L
authors.initials: JL
authors.lastname: Martínez
authors.forename: J N
authors.initials: JN
authors.lastname: Davidson
authors.forename: J M
authors.initials: JM
authors.lastname: Trent
authors.forename: T E
authors.initials: TE
authors.lastname: Patterson
authors.forename: A
authors.initials: A
authors.lastname: Agarwal
authors.forename: P
authors.initials: P
authors.lastname: Duncan
authors.forename: M L
authors.initials: ML
authors.lastname: Agarwal
authors.forename: G R
authors.initials: GR
authors.lastname: Stark
mesh_terms: D001221:Aspartate Carbamoyltransferase / Q000235:genetics* / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics*; D002460:Cell Line; D002503:Centromere / Q000235:genetics; D002869:Chromosome Aberrations / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D015342:DNA Probes; D004080:Dihydroorotase / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005784:Gene Amplification / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009097:Multienzyme Complexes / Q000235:genetics*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016615:Telomere / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C033626:CAD trifunctional enzyme; D015342:DNA Probes; D009097:Multienzyme Complexes; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D010746:Phosphonoacetic Acid