A new molecular approach for predicting lung cancer
Initial Award Abstract
Human lung is the most sensitive and specific target organ for environmental pollutants including environmental tobacco smoke (ETS) i.e. involuntary or passive smoking. Cigarette smoking is considered to be the major cause of lung cancer. According to the most recent estimates, tobacco smoking contributed to the death of 400,000 people in the United States in 1990, accounting for 19% of all deaths. Since only 5-7% of long-term smokers are estimated to develop lung cancer, it appears that genetic and other host factors might play a role in individual susceptibility to this disease. Although the presence of over 4, 000 chemical in cigarette smoke makes the precise identification of carcinogenic chemicals difficult, polycyclic aromatic hydrocarbons and N-nitrosamines are believed to be the major cancer causing chemicals present in the smoke. Polycyclic aromatic hydrocarbons are converted to the ultimate carcinogenic derivatives by a group of enzymes called cytochrome P450 monooxygenases (CYPs). Higher expression of one of the CYPs called CYP1A1 has been implicated with the initiation of lung cancer.
The non-invasive human biological material available to assess the activity of this enzyme (CYP1A1) include blood, urine, hair and nails. Hence there is a need for more readily obtainable research material that can give measurable and reproducible results. Several studies have indicated that the expression of this enzyme in lymphocytes does not reflect a true measure of the enzyme activity present in the lung. Therefore we propose that we shall measure the expression of this enzyme using hair follicles of two strains of mice which are “Ah responsive” (i.e., they produce CYP1A1 in response to polycyclic aromatic hydrocarbons) and “Ah nonresponsive” (do not induce CYP1A1 in response to polycyclic aromatic hydrocarbons).
Therefore we shall develop a system in which we can use hair follicles of mice and show that these hair follicles reflect the expression of CYP1A1 in the lung. These investigations, if successful, can eventually be applied to humans and may form the basis of a non-invasive test to predict individuals’ susceptibility to polycyclic aromatic hydrocarbon-induced lung cancer. |