Abstract B54: Prevention of mouse lung tumors by combinations of budesonide and Targretin or SAHA

Abstract

Abstract Individual chemopreventive drugs have been shown to prevent and slow the growth and progression of mouse lung tumors. Combinations of these chemopreventive agents have been proposed as a strategy for increasing efficacy, while lowering drug toxicity. In addition, non-invasive procedures such as MRI have been suggested as a means to determine the ability of drugs to inhibit the growth of tumors and avoid using serial sacrifices. Three drugs representing different mechanisms of action (budesonide, a nonsteroidal anti-inflammatory; Targretin, a selective activator of RXR; and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor) were used singly and in combination to inhibit development of mouse lung tumors. Lung tumors were induced in female Strain A/J mice by i.p. administration of 100 mg/kg 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNK) once a week for four consecutive weeks. Two weeks after the fourth dose of NNK, the mice started to receive a diet (AIN-76A) containing either1.6 mg/kg budesonide, 160 mg/kg Targretin, 500 mg/kg SAHA, or combinations of budesonide plus either Targretin or SAHA. At Week 21, the multiplicity of lung tumors in control mice (28.13 ± 1.62) was significantly reduced to 10.50 ± 0.74, 15.96 ± 0.90, and 12.42 ± 1.57 by budesonide, Targretin, and SAHA, respectively. The combinations containing budesonide plus Targretin or SAHA demonstrated significantly more inhibition of total tumors than either agent acting alone, resulting in 7.25 ± 0.87 and 5.00 ±1.16 tumors/mouse, respectively. The multiplicity of carcinomas was also significantly reduced by budesonide, Targretin, and SAHA from 5.10 ± 0.83 in control mice to 0.88 ± 0.21, 1.12 ± 0.27, and 0.37 ± 0.15, respectively, whereas the combinations demonstrated a greater efficacy than either agent acting alone, yielding 0.10 ± 0.07, and 0.12 ± 0.12 for the combinations containing Targretin or SAHA, respectively. Mice administered budesonide, Targretin or the control diet were monitored by MRI at Weeks 21, 26 and 31 after the first dose of NNK and groups sacrificed at Weeks 21 and 31 after MRI for tumor counts. The two drugs (budesonide and Targretin) significantly reduced the size and number of tumors when monitored by MRI. At week 21, it was demonstrated by MRI that Targretin and budesonide significantly reduced the multiplicity of total lung tumors by 32% and 64%, respectively, from controls. In conclusion, relative to their individual effects, combinations containing budesonide and either Targretin or SAHA demonstrated greater efficacy in inhibiting both the occurrence of mouse lung tumors and their progression to carcinomas. Supported in part by NCI grant 5R21CA135335. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B54.