Chemoprevention of murine lung cancer by gefitinib in combination with prostacyclin synthase overexpression

RL Keith, V Karoor, AB Mozer, TM Hudish, M Le… - Lung Cancer, 2010 - Elsevier
RL Keith, V Karoor, AB Mozer, TM Hudish, M Le, YE Miller
Lung Cancer, 2010Elsevier
INTRODUCTION: 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. MATERIALS AND METHODS: Wildtype and
littermate PGIS overexpressors (OE) were given urethane, 1mg/kg ip followed by thrice
weekly ip injections of gefitinib, 50mg/kg or 100mg/kg, or vehicle. Pulmonary adenomas …
INTRODUCTION
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.
MATERIALS AND METHODS
Wildtype and littermate PGIS overexpressors (OE) were given urethane, 1mg/kg i.p. followed by thrice weekly i.p. injections of gefitinib, 50mg/kg or 100mg/kg, or vehicle. Pulmonary adenomas were enumerated and measured.
RESULTS
Gefitinib at either 50mg/kg or 100mg/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 50mg/kg, but not the 100mg/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 50mg/kg vs. 100mg/kg group was an increase in p-Src in the PGIS OE mice receiving the higher dose.
CONCLUSION
We conclude that gefitinib alone has no chemopreventive efficacy in this model; it augmented the effect of PGIS overexpression at 50mg/kg but not 100mg/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.
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