Abstract LB-464: Phenylbutyl isoselenocyanate (ISC-4) and phenylbutyl isothiocyanate (PBITC) inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced lung tumorigenesis in A/J mouse
Authors: Gimbor Melissa A. , Sk Ugir Hossain , Aliaga Cesar , Amin Shantu , Sharma Arun K. 
Published: July 2012

Lung cancer is the leading cause of cancer deaths in both men and women with 90% of cases attributed to tobacco smoking. Evidence has shown that there is a 20–30 year latency period from tobacco exposure to invasive disease making chemopreventive approaches desirable. Our lab has previously shown the organoselenium compound ISC-4, an analog of naturally occurring established chemopreventive isothiocyanates, potently inhibits Phase I CYP450 enzymes at the protein level and induces Phase II enzyme activity via a transcriptional mechanism. In A/J mice treated with the tobacco procarcinogen NNK, dietary ISC-4 was able to reduce the number of O6-methyl guanine DNA adducts, which are critical for NNK induced carcinogenesis, in liver and lung. Based on these results we used an A/J mouse model of lung cancer to test the chemopreventive effects of ISC-4 against NNK induced lung tumorigenesis. As a positive control we included a group of high dose PBITC, the sulfur analog of ISC-4, which had never been tested in a chronic feeding model but shown to be very effective in pre-initiation assays at inhibiting NNK tumorigenesis. Based on bioavailability and MTD studies, A/J mice were fed ISC-4 in the AIN-76 diet at 0.19 μmol/g, 0.38 mol/g, and 0.57 μmol/g diet. PBITC, which is tolerated at higher dose, was given at 0.38 μmol/g and 3.0 mol/g diet. Mice (n=30/group) were fed control or experimental diet for two weeks and then injected with a single dose of 10 μmol NNK (IP). They were continued on diet for 22 weeks and then sacrificed. Lung tumors were counted and blood and tissues were collected for toxicity analyses. Mice treated with NNK plus dietary ISC-4 at 0.19 μmol/g, 0.38 μmol/g, and 0.57 μmol/g resulted in tumor multiplicity of 4.14 ± 0.35, 1.90 ± 0.28, and 2.13 ± 0.33 tumors/lung, respectively, compared to 13.9 ± 0.83 tumors/lung for mice treated with NNK on control diet, a reduction of 72–90% (p &lt; 0.0001). Mice treated with 0.38 μmol/g and 3.0 μmol/g diet PBITC resulted in tumor multiplicity of 2.93 ± 0.40 and 0.80 ± 0.20 tumors/lung, respectively, a reduction of 82 and 98% (p &lt; 0.0001). None of the treatment groups showed a decrease in body weight. Mice in all the groups, except 0.38 μmol/g PBITC and NNK control diet group, gained ∼10–20% less weight as compared to untreated control AIN-76 group. Blood analysis showed normal toxicity values for all groups except for the highest dose of ISC-4. HE staining of the liver and kidney samples showed no signs of toxicity except for two mice in the high dose of PBITC. In conclusion, both ISC-4 and PBITC showed great promise as chemopreventive agents for inhibition of NNK induced lung tumors. These results show that PBITC has a larger chemopreventive index, but at equimolar doses ISC-4 was more effective at tumor inhibition than PBITC (p=0.04).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-464. doi:10.1158/1538-7445.AM2011-LB-464