) Carcinogenesis is widely held to be a multi-stage process involving a number of distinct events separated in time. It is difficult to visualize how a single brief exposure to a low dose of radiation could result in multiple mutations, and yet it is well established that a modest radiation dose can result in a whole spectrum of malignancies. A possibility that seems more likely is that radiation causes a single initial mutation resulting in genomic instability, followed by a cascade of events leading to a malignancy. There are many reports of genomic instability, but the endpoints studied are chromosomal aberrations or mutations. The applicant has succeeded in transforming immortalized human bronchial epithelial cells with a single low dose of high energy (1 GeV/nucleon) iron ions or with alpha particles so that, after in vitro culture for many generations, they become tumorigenic in nude mice. Between irradiation and the expression of tumorigenicity, a series of sequential changes take place: increased saturation density, loss of stimulus to terminal differentiation, loss of anchorage dependence, and accumulation of chromosomal changes. This would appear to be an ideal model of genomic instability with tumorigenesis as the endpoint. He proposes: (a) To investigate whether genomic instability induced by a low dose of high energy iron ions renders the cells more sensitive to transformation by a subsequent dose of low energy neutrons, high energy protons, or gamma-rays; (b) Establish cell lines from many (25) tumors resulting from exposure to high energy iron ions and look for repeatable patterns of chromosomal aberrations and/or chromosome loss; (c) Use a novel selectable reporter system to determine whether tumor cell lines induced by iron ions in bronchial epithelial cells have functional mismatch repair genes. This application has practical implications to space travel since somatic cells in astronauts may be occasionally traversed by a high energy iron ion and subsequently exposed to low energy neutrons and/or low LET radiations, such as gamma-rays or high energy protons.
