Chemoprevention of murine lung cancer by gefitinib in combination with prostacyclin synthase overexpression.
BACKGROUND
We hypothesized that the combination of the EGFR tyrosine kinase inhibitor (TKI) gefitinib with the powerful chemopreventive manipulation of lung-specific transgenic prostacyclin synthase (PGIS) overexpression on tumorigenesis in FVB/N mice would result in augmented chemoprevention.


METHODS
Wildtype and littermate PGIS overexpressors (OE) were given urethane, 1 mg/kg i.p. followed by thrice weekly i.p. injections of gefitinib, 50 mg/kg or 100 mg/kg, or vehicle. Pulmonary adenomas were enumerated and measured.


RESULTS
Gefitinib at either 50 mg/kg or 100 mg/kg administered i.p. three times weekly was effective in inhibiting EGF induced EGFR tyrosine phosphorylation and downstream signaling. The PGIS overexpressors showed significant decreases in tumor multiplicity consistent with prior studies. Gefitinib had no effect on tumor multiplicity or volume in wildtype mice. Among the PGIS overexpressors, a significant reduction in tumor multiplicity was shown in the 50 mg/kg, but not the 100 mg/kg, gefitinib treatment group vs. vehicle control animals (1.13+/-0.29 vs. 2.29+/-0.32 tumors/mouse, p=0.015). We examined the phosphorylation status in selected downstream effectors of EGFR (Erk, Akt, Src, PTEN). The major difference in the 50 mg/kg vs. 100 mg/kg group was an increase in p-Src in the PGIS OE mice receiving the higher dose.


CONCLUSIONS
We conclude that gefitinib alone has no chemopreventive efficacy in this model; it augmented the effect of PGIS overexpression at 50 mg/kg but not 100 mg/kg. Increased p-Src is correlated with loss of efficacy at the higher dose, suggesting the potential for combined EGFR and Src inhibition strategies in chemoprevention.
Keith
Robert L
RL
Veterans Administration Medical Center, Division of Pulmonary Sciences and Critical Care Medicine, Denver, CO 80220, United States.
Karoor
Vijaya
V
Mozer
Anthony B
AB
Hudish
Tyler M
TM
Le
Mysan
M
Miller
York E
YE
D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D015820:Cadherins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D066246:ErbB Receptors; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D015232:Dinoprostone; D000077156:Gefitinib