P53 MUTATION AND ABSENCE OF MDM2 AMPLIFICATION AND KI-RAS MUTATION IN4-HYDROXYAMINO QUINOLINE 1-OXIDE INDUCED TRANSPLANTABLE OSTEOSARCOMASIN RATS

Previously, we reported the establishment of two transplantable osteos arcomas, one induced by local application of a carcinogen, 4-hydroxyam ino quinoline 1-oxide(4-HAQO), and another which developed spontaneous ly in rats, and their subdivision into four lines with high and low me tastatic potential to the lung. In the present study, mutations of p53 and Ki-ras genes were investigated by PCR and SSCP followed by direct sequencing, and the amplification of the mdm2 gene was assessed by So uthern blot analysis. Mutations of p53 in exon 7 were detected in 4-HA QO-induced transplantable osteosarcomas, but not their spontaneous cou nterparts, irrespective of the metastatic potentials. Direct sequencin g revealed a CGC to CAC transition with an amino acid change of Arg to His, at codon 246. Neither Ki-ras mutations nor mdm2 amplification we re detected in airy of the transplantable tumors. The results suggest that while p53 mutations occurred during osteosarcoma development by 4 -HAQO without mdm2 amplification and Ki-ras mutation does not contribu te to osteosarcoma development in rats. (C) 1997 Elsevier Science Irel and Ltd.