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INDUCTION OF DNA ADDUCTS, TUMORS, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A/J MOUSE LUNG BY IP. ADMINISTRATION OF DIBENZ[A,H]ANTHRACENE
Nelson, G B., M J. Mass, B C. Roop, AND J A. Ross. INDUCTION OF DNA ADDUCTS, TUMORS, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A/J MOUSE LUNG BY IP. ADMINISTRATION OF DIBENZ[A,H]ANTHRACENE. Presented at American Association for Cancer Research, San Francisco, CA, 04/6-10/2002.
Induction of DNA adducts, tumors, and Ki-ras oncogene mutations in strain AlJ mouse lung by ip. administration of dibenz[a,h]anthracene
Previous studies of polycyclic aromatic hydrocarbon (P AH) induced lung tumors in the strain NJ mouse model system have demonstrated quantitative and qualitative relationships between DNA adducts, lung tumors, and mutations in Ki-ras in the tumors. Dibenz[a,h]anthracene (DB[a,h]A), although tumorigenic, failed to induce detectable mutations in Ki-ras. To verify this observation, DB[a,h]A was administered at 10 mg/kg body weight ip. to male strain NJ mice. DNA adducts were measured by 32p-postlabeling I, 2, 3, 5, 7, 10, 21, and 28 days after treatment. Lung tumors were evaluated 240 days after DB[a,h]A administration. Tumor DNA was isolated, and Ki-ras codons 12 and 61 were amplified by PCR and sequenced to detect the presence of activating mutations. This dose ofDB[a,h]A was tumorigenic at 240 days, yielding a mean of 11.2 tumors/lung. Covalent DNA adducts were induced at early time points in the lung DNA, reaching maximal levels 7 days after administration of DB[a,h]A. In contrast to the previous study, mutations were observed in codon 12 of Ki-ras in 58% (22/38) of a sample of tumors analyzed. Of those tumors showing codon 12 mutations, the most frequently observed mutations were GGT to TGT (9/22) and GGT to G.rT (9/22) transversions, with GGT to CGT transversions (2/22) and GGT to GAT transitions (2/22) also being observed. A single codon 61 mutation, CAA to CGA, was also seen. These results are similar to those for other PAHs that form bay-region diolepoxides in the A/J mouse lung model system.
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