Reduced receptor expression for platelet-derived growth factor and epidermal growth factor in dividing mouse lung epithelial cells.

The roles of growth factors in mouse lung neoplasia were investigated by examining receptors for platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) in epithelial cell lines. Whereas nontumorigenic lung cells expressed mRNA and protein for PDGF receptor (PDGFR)-alpha, PDGFR-beta, and EGF receptor (EGFR), five of six neoplastic lines did not. Because this exceptional tumorigenic cell line grows slowly, we hypothesized that receptor levels increased with cell stasis. To test this hypothesis, serum concentrations were manipulated, and log-phase and post-confluent cells were compared. Consistent with our hypothesis, PDGFR-alpha and EGFR contents, but not PDGFR-beta contents, increased at stasis. Ki-ras mutation initiates lung tumorigenesis in mice, but activation of Ki-ras did not affect receptor expression. This was determined both by transfecting nontumorigenic cells with activated Ki-ras and neoplastic cells with a Ki-ras antisense construct and by diminishing Ki-ras activation by using a farnesyltransferase inhibitor. Stasis-associated upregulation of growth-factor receptor expression suggests a function in lung cell differentiation that is abrogated during neoplastic growth.

Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung tumor formation by FGN-1 (sulindac sulfone).

The sulfone derivative of the non-steroidal anti-inflammatory drug (NSAID), sulindac, has been reported to inhibit mammary and colon tumor formation in rodent models of chemically-induced carcinogenesis. Unlike its parent compound, this metabolite lacks cyclo-oxygenase inhibitory activity. A tumor induction protocol, consisting of NNK administration in the drinking water over several weeks to model chronic human exposure, was used to test whether the sulfone (called FGN-1) could inhibit the formation of primary lung tumors in mice. A total of 150 female, AIN76A-fed, A/J mice received 9 mg of NNK each. Concentrations of FGN-1 that had been previously determined not to affect body weight gain were added to the food at levels of 0, 250, 500 and 750 mg/kg of diet (30 mice/group) starting 2 weeks before NNK administration and continuing for 22 weeks. At that time pleural surface tumors were counted. Tumor incidence decreased significantly from 96 % in the control diet and 93% in the 250 FGN-1 mg/kg diet to 63 and 67% in the 500 and 750 mg FGN-1/kg diet groups, respectively (P < 0.001 by chi-square analysis). Lung tumor multiplicity decreased from 18.1+/-3 tumors/ mouse (mean+/-SEM, control diet) to 12.3+/-3 (250), 5.3+/-1 (500) and 2.1+/-1 (750) (P < 0.0005 by post hoc ANOVA). In previous studies using this carcinogenesis protocol, the maximum tolerated dose of sulindac inhibited lung tumor multiplicity by no more than 50% with no effect on incidence. This dose-dependent reduction in tumorigenesis by a non-toxic dose of FGN-1 indicates a strong chemopreventive activity against experimental induction of lung carcinogenesis. The greater potency of the sulfone over sulindac and its lack of toxic side effects because of its inability to affect cyclo-oxygenase activity suggests that clinical testing in individuals at high risk for lung cancer should be considered.

Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene.

Chronic butylated hydroxytoluene (BHT) treatment after a single administration of a carcinogen increases lung tumor multiplicity in some inbred strains of mice. We report that BALB/cOla and BALB/cByJ mice given a low dose (10 microg/g of body weight) of 3-methylcholanthrene (MCA) develop no lung tumors unless this is followed by chronic BHT exposure. Slightly higher MCA doses (15 and 25 microg/g) induce low lung tumor multiplicities (0.6 and 1.9 tumors/mouse, respectively) that are increased 12-26-fold by chronic BHT administration. This low-dose MCA/BHT model in BALB mice will facilitate the identification of genes regulating susceptibility to lung tumor promotion and pulmonary chemopreventative agents that act at a postinitiation site.