Abstract
The use of combinations of chemopreventive agents is a promising strategy for increasing efficacy while lowering toxicity to prevent cancer, including lung cancer. To test whether this strategy of using combinations would enhance efficacy, combinations containing SAHA and atorvastatin were evaluated for their ability to prevent mouse lung tumors. Lung tumors were induced in female strain A/J mice (8-9 week-old) by administering i.p. an injection of 16 mg/kg vinyl carbamate once a week for three weeks. Two weeks after the last injection of vinyl carbamate, some of the mice started to receive in their diet, either 500mg/kg SAHA, 18, 60 or 180 mg/kg atorvastatin, combinations containing SAHA and one of the three dose levels of atorvastatin, or the Control Diet. Mice were sacrificed either at 21 or 32 weeks after the first dose of vinyl carbamate. At week 21, SAHA, the low (18 mg/kg diet) and high (180 mg/kg) concentrations of atorvastatin, and the three combinations containing SAHA and atorvastatin decreased the multiplicity of lung tumors/mouse, while at Week 32, lung tumor multiplicity was reduced by only SAHA (31.5 ± 1.6 lung tumors/mouse) and the combinations containing SAHA with either 60 or 180 mg/kg concentration of atorvastatin (21.9 ± 1.7 and 24.7 ± 1.9 lung tumors/mouse, respectively) compared to the yield in the Control Group of 42.7 ± 1.6 lung tumors/mouse. At both sacrifices, the combinations containing SAHA and the middle and high concentrations of atorvastatin demonstrated greater efficacy in decreasing tumor multiplicity than either SAHA or atorvastatin administered alone (p-value ≤ 0.05). At Week 21, both the size of the lung tumors and the multiplicity of adenocarcinomas were decreased by SAHA, 180 mg/kg atorvastatin and all three combinations, while at Week 32 only the combinations containing SAHA with either 60 or 180 mg/kg atorvastatin (0.160 ± 0.094 and 0.041 ± 0.041 lung adenocarcinomas/mouse, respectively) decreased the size of the lung tumors and the multiplicity of adenocarcinomas (1.44 ± 0.25 lung adenocarcinomas/mouse, p-value ≤ 0.05). Although, the ability of the two chemopreventive agents and the combinations to decrease the occurrence of lung tumors, to slow the growth of the tumors, and to slow their progression to carcinomas decreased with time, the efficacy of the combinations was still significant at the Week 32 sacrifice. Hence, the combinations of SAHA and atorvastatin demonstrated greater and more prolonged efficacy in preventing and slowing the progression of mouse lung tumors supporting the concept of using combinations of chemopreventive agents for cancer prevention. Supported in part by N01-CN-35116 from NCI.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):B51.
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