Although the ras genes have long been established as proto-oncogenes, the dominant role of activated ras in cell transformation has been questioned. Previous studies have shown frequent loss of the wildtype Kras2 allele in both mouse and human lung adenocarcinomas. To address the possible tumor suppressor role of wildtype Kras2 in lung tumorigenesis, we have carried out a lung tumor bioassay in heterozygous Kras2-deficient mice. Mice with a heterozygous Kras2 deficiency were highly susceptible to the chemical induction of lung tumors when compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells and a mouse lung tumor cell line containing an activated Kras2 allele. Allelic loss of wildtype Kras2 was found in 67% to 100% of chemically induced mouse lung adenocarcinomas that harbor a mutant Kras2 allele. Finally, an inverse correlation between the level of wildtype Kras2 expression and extracellular signal-regulated kinase (ERK) activity was observed in these cells. These data strongly suggest that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression.
Female B6C3F1 mice were exposed to graded doses of nickel sulfate to determine a threshold response for myelotoxicity and immunotoxicity, and to identify which of the populations of lymphoreticular cells were most sensitive to the toxic effects of nickel. Animals were given free access to the chemical in the drinking water at 0, 1, 5, or 10 g/l for 180 d. Water consumption, blood and tissue nickel concentrations, body and organ weights, histopathology, immune responses, bone marrow cellularity and proliferation, and cellular enzyme activities were evaluated. There was no mortality. Mice in the 5-g/l and 10-g/l dose groups drank less water than controls; the responses measured in the 10-g/l group may have been due to a combination of dehydration and chemical toxicity. Decreases in body and organ weights were confined to mice in the 10-g/l dose group, except for the dose-related reductions in thymus weights. Blood nickel was measured at 4, 8, 16, and 23 wk of exposure. The mean blood nickel values showed increases between 4 and 8 wk that were proportional to time and dose; thereafter there was no substantial increase in blood nickel in any of the dose groups, except for an increase in the mean blood concentration in the 10-g/l group at 23 wk. The kidney was the major organ of nickel accumulation. The primary toxic effects of nickel sulfate were expressed in the myeloid system. There were dose-related decreases in bone marrow cellularity, and in granulocyte-macrophage and pluripotent stem-cell proliferative responses. In unfractionated bone marrow cells glucose-6-phosphate dehydrogenase enzyme activity from the hexose monophosphate shunt was more sensitive to nickel sulfate than were representative glycolytic or Krebs cycle enzymes, with 25-35% maximum inhibition at 5 g/l and 10 g/l. Aliquots of bone marrow cells were separated into enriched bands of lymphocytes, granulocyte-macrophages, and erythrocytes; enzyme inhibition that occurred in unfractionated bone marrow cell aliquots was only expressed after cell separation in the enriched granulocyte-macrophage cell population, suggesting that these committed stem cells were a primary target of nickel sulfate toxicity. There was one example of systemic immunotoxicity, reduction in the lymphoproliferative response to lipopolysaccharide, and it was regarded as secondary to the primary effect of nickel sulfate on the myeloid system, since this was the only significant change among a panel of seven immune parameters that were evaluated.
A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg of 3'-azido-3'-deoxythymidine (AZT)/kg bw/day, through a 18 to 19-day gestation [National Toxicology Program, NIH Pub. No. 04-4458, 2004]. The incidences of alveolar/bronchiolar adenomas and carcinomas, in the 200 and 300 mg/kg male treatment groups, were significantly greater than that of the controls. In the present study, we evaluated the benign and malignant lung neoplasms from this bioassay for point mutations, in the K-ras and p53 cancer genes that are often mutated in human lung tumors. K-ras and p53 mutations were detected by cycle sequencing of polymerase chain reaction-amplified DNA, isolated from formalin-fixed, paraffin-embedded neoplasms. K-ras mutations were detected in 25 of 38 (66%) of the AZT-induced lung tumors, and the predominant mutations were codon 12 G-->T transversions. p53 mutations were detected in 32 of 38 (84%) of the AZT-induced lung tumors, with the predominant mutations being exon 8, codon 285 A-->T transversions, and exon 6, codon 198 T-->A transversions. No K-ras or p53 mutations were detected in five tumors, examined from control mice. The patterns of mutations identified in the lung tumors suggest that incorporation of AZT or its metabolites into DNA, oxidative stress, and genomic instability may be the contributing factors to the mutation profile and development of lung cancer in these mice.
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