Gene amplification and microsatellite instability induced in tumorigenic human bronchial epithelial cells by alpha particles and heavy ions.
Gene amplification and microsatellite alteration are useful markers of genomic instability in tumor and transformed cell lines. It has been suggested that genomic instability contributes to the progression of tumorigenesis by accumulating genetic changes. In this study, amplification of the carbamyl-P-synthetase, aspartate transcarbamylase, dihydro-orotase (CAD) gene in transformed and tumorigenic human bronchial epithelial (BEP2D) cells induced by either alpha particles or (56)Fe ions was assessed by measuring resistance to N-(phosphonacetyl)-l-aspartate (PALA). In addition, alterations of microsatellite loci located on chromosomes 3p and 18q were analyzed in a series of primary and secondary tumor cell lines generated in nude mice. The frequency of PALA-resistant colonies was 1-3 x 10(-3) in tumor cell lines, 5-8 x 10(-5) in transformed cells prior to inoculation into nude mice, and less than 10(-7) in control BEP2D cells. Microsatellite alterations were detected in all 11 tumor cell lines examined at the following loci: D18S34, D18S363, D18S877, D3S1038 and D3S1607. No significant difference in either PALA resistance or microsatellite instability was found in tumor cell lines that were induced by alpha particles compared to those induced by (56)Fe ions.
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Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Hei
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D000512:Alpha Particles; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001221:Aspartate Carbamoyltransferase / Q000235:genetics; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001980:Bronchi / Q000502:physiology / Q000528:radiation effects* / Q000648:ultrastructure; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000528:radiation effects; D002887:Chromosomes, Human, Pair 18 / Q000528:radiation effects; D002893:Chromosomes, Human, Pair 3 / Q000528:radiation effects; D004080:Dihydroorotase / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000502:physiology / Q000528:radiation effects / Q000648:ultrastructure; D005784:Gene Amplification / Q000528:radiation effects*; D020450:Heavy Ions; D006801:Humans; D007501:Iron; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D018895:Microsatellite Repeats; D009097:Multienzyme Complexes / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; C033626:CAD trifunctional enzyme; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D001224:Aspartic Acid; C013195:sparfosic acid; D007501:Iron; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D010746:Phosphonoacetic Acid