From Beans to Genes: Back to the Future

Developments in radiation biology have inevitably paralleled the evolution of systems and end points in the wider field of biology. I review the development of three areas that have interested me during the 35 years that I have been involved with radiation research. (1) The dose-rate effect. My first graduate student, Joel Beford, and I demonstrated the dependence of mammalian cell killing on the dose rate at which γ rays are delivered. These studies led to the recent development of pulsed low-dose-rate brachytherapy and the design of a new machine for clinical use. (2) Hypoxic radiosensitizers and bioreductive drugs. The hypothesis that the presence of foci of hypoxic cells in human tumors could limit their curability by γ rays led to the development of nitromidazales that preferentially sensitize hypoxic cells. Our contributions included the observation that misonidazole was also cytotoxic to hypoxic cells, that sensitization was increased by prolonged preincubation, and that the mechanism involved depletion of thiols. More recently we have collaborated with Ged Adams and Bob Sutherland in the development of a new generation of hypoxic cell cytotoxins. In particular, we have been concerned with the assessment of oncogenicity in relation to drug structure. (3) Oncogenic transformation in vitro. The use of in vitro assays for oncogenic transformation has represented a major interest for this laboratory largely due to collaborations first with Carmia Borek, and more recently with Richard Miller and Tom Hei. We published the first dose-response curves for γ rays, and more recently for a range of neutron energies and for charged particles of defined LET. Radiation-induced oncogenic transformation in C3H 10T1/2 cells has been shown to be due to a dominant acting transforming gene, which has been isolated and is in the process of being characterized and sequenced by Greg Freyer.