Joseph C. Siglin

Inhibition of lung tumor cell growth in vitro and mouse lung tumor formation by lovastatin

The HMG-CoA reductase inhibitor, lovastatin (LOV), has been reported to inhibit Ras farnesylation and the growth of Ras-transformed cells. Mouse lung tumors and human lung adenocarcinomas often have activating mutations in K-ras alleles. In the present study, we determined whether LOV inhibited the growth in vitro of mouse (C10, E9, LM1, LM2, and 82-132) and human (NCl-H125, H292, H441, H460, and H661) nor-transformed and neoplastically transformed lung epithelial cells and whether growth inhibition was related to cell transformation or K-ras activation. LOV inhibited the growth of mouse and human lung cells, but cell sensitivities were unrelated to neoplastic transformation or K-ras mutation. In addition, we evaluated whether LOV could inhibit the formation of lung adenomas induced by the tobacco-specific nitrosamine, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice. LOV was administered in the diet at 0, 40, 160, or 400 ppm ad libitum to male strain A/J mice beginning 1 week after lung tumor induction with NNK (10 mumol/mouse). Mice were euthanized 6 months later. Enumeration of lung tumors revealed that LOV did not affect tumor incidence or size, but significantly reduced tumor multiplicity in a dose-related manner. These data suggest that LOV can suppress the formation of NNK-induced lung tumors, possibly at an early promotional stage. This suppression does not appear to be related to either the presence of mutated K-ras or to changes in K-ras expression.

Variability of a mouse ear swelling test (MEST) in predicting weak and moderate contact sensitization

An investigation was conducted at two independent laboratories for the purpose of evaluating the ability of a mouse ear swelling test (MEST), previously developed and validated by S.C. Gad. B.J. Dunn, D. W. Dobbs, C. Reilly, and R.D. Walsh (1986, Toxicol. Appl. Pharmacol. 84, 93-114), to predict contact sensitization induced by weak to moderate contact sensitizers. Twenty-six coded chemicals, 23 with weak to strong potential to induce sensitization in animals and/or humans and 3 negative controls, were investigated. Each laboratory tested 18 materials: 10 chemicals were common to both labs and 16 chemicals were divided so that 8 were unique to each of the two labs. The methods and chemicals utilized were the same as those used and reported by Gad et al. (1986) and, therefore, data generated from this investigation were compared to results from their research. Contrary to results reported by Gad and co-workers, findings from the present study suggest that this MEST is a useful model for identifying strong contact sensitizers, but is not reliable for detecting weak to moderate allergens.