Acquisition of resistance to 6-azauridine through DNA amplification in neoplastic but not normal osteoblasts.
In this communication, we have characterized the resistance to AZUrd in tumorigenic mouse C3H-OS osteosarcoma cells and non-tumorigenic MC3T3-E1 osteoblast cells. DNA and RNA blot analysis showed a 30-fold increase in UMP synthase specific DNA and a 10-fold increase in mRNA, respectively, in resistant versus non-resistant C3H-OS cells. No corresponding increases in either UMP synthetase DNA or mRNA were evident in resistant MC3T3-E1 osteoblasts. Karyotype analysis of MC3T3-E1 and C3H-OS cells revealed translocations in the resistant cells. Regardless of drug-sensitive or resistant phenotype, the normal and neoplastic cells exhibited aneuploidy which was significantly more pronounced in the non-resistant tumor cells. Additionally, the number of chromosomes decreased in all resistant cells whether normal or neoplastic. We conclude that genomic instability in neoplastic cells is a prerequisite for the generation of drug resistant variants via the process of gene amplification.
Daniel
D L
DL
Biology Department, Bucknell University, Lewisburg, PA 17837.
Tonzetich
J
J
Chernin
M I
MI
McMaster
J H
JH
Novak
J F
JF
D000818:Animals; D001380:Azauridine / Q000494:pharmacology*; D002478:Cells, Cultured; D004351:Drug Resistance; D005784:Gene Amplification; D051379:Mice; D008809:Mice, Inbred C3H; D009097:Multienzyme Complexes / Q000235:genetics; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics*
D009097:Multienzyme Complexes; C027157:uridine 5'-monophosphate synthase; D001380:Azauridine; D009962:Orotate Phosphoribosyltransferase; D009964:Orotidine-5'-Phosphate Decarboxylase