The main reasons for the failure of most chemopreventive agents during clinical trials are poor in vivo bioavailability and dose-limiting side effects. One potential approach to surmount these problems in
lung cancer chemoprevention trials could be direct delivery of agents into the pulmonary tissue. In this study, we assessed the efficacy of intranasally delivered bio-response
diindolylmethane (BRD) against
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung
tumorigenesis in mice. Mice treated with NNK (two doses of 50mg/kg at an interval of a week, intraperitoneal) developed 16.3±2.9 lung
tumors per mouse. Post-
carcinogen administration of BRD, via intranasal instillation, for 24 weeks, twice a week, at a dose of 2mg per mouse (0.6mg pure
diindolylmethane per mouse) reduced the lung
tumor multiplicity to 4.6±2.2
tumors per mouse (72% reduction). Likewise, large
tumors (>1mm) were almost completely abolished and multiplicities of
tumors with a size of 0.5-1mm were reduced by 74%.
Tumor volume was also reduced by 82%. Further studies using an in vitro model of lung
tumorigenesis showed that BRD exhibited pronounced antiproliferative and apoptotic effects in premalignant and malignant bronchial cells but only minimal effects in parental immortalized cells through, at least in part, suppression of the
phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. These results showed the potent lung
tumor inhibitory activities of low doses of BRD given via intranasal instillation and, therefore, intranasal delivery of BRD holds a great promise for
lung cancer chemoprevention in subjects at high risk to develop
lung cancer.