Multiple mechanisms of N-(phosphonoacetyl)-L-aspartate drug resistance in SV40-infected precrisis human fibroblasts.
Normal and SV40-infected human fibroblasts were grown in the presence of the drug N-(phosphonoacetyl)-L-aspartate (PALA) and examined for evidence of genetic instability. Both cell populations were precrisis and showed a normal, diploid karyotype at early passage. In contrast to the normal IMR-90 cells, which showed growth arrest and did not form colonies in PALA, the SV40-infected IMR-90 cells formed colonies at a very high frequency and continued to cycle in the drug. The drug-resistant colonies senesced after continued growth in culture, indicating that this change in ability to amplify preceded immortalization. This is the first observation of mortal human cells overcoming the drug-induced growth arrest. Although all previously isolated PALA-resistant colonies demonstrated CAD gene amplification as the mechanism of the drug-resistant phenotype, these SV40-infected human cells also showed alternative mechanisms, including increases in gene copy number by aneuploidy and formation of an isochromosome 2p.
Schaefer
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Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill 27599.
Livanos
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White
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Tlsty
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TD
D000782:Aneuploidy; D000970:Antineoplastic Agents / Q000633:toxicity*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002472:Cell Transformation, Viral; D002869:Chromosome Aberrations; D002889:Chromosomes, Human, Pair 2; D002999:Clone Cells; D004351:Drug Resistance / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D013539:Simian virus 40 / Q000235:genetics*
D000970:Antineoplastic Agents; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid