Cellular Aspects of Tumor Therapy

A question which must often be considered when attempts are made to apply laboratory findings to medical problems is: Are the end-points used in the research problem directly applicable to the practical problem, and to what extent? Fortunately, research in the field of cellular radiobiology often can be directly applied to problems in radiation therapy because a criterion of effect commonly used by the cellular radiobiologist, i.e., inhibition of proliferative ability, is also the end-point of concern to the therapist. Although a considerable literature exists on the lethal effects of radiation on microorganisms, it has been only during the last few years that new tissue culture technics have afforded similar quantitative studies with mammalian cells. The early experiments of Rous and Jones (1), followed by the improvements of Puck et al. (2), permit, in essence, evaluation of the proliferative capacity of single cells as determined by ability to grow into visible colonies. One of the principal problems in radiobiology is the question: Where and what, on a cellular level, are the sites of action of lethal irradiation. The proposal that these sites reside in the chromosomes (3) suggested to us that sublethal damage accumulated by surviving cells might be heritable. Investigation of this possibility led to the finding that none of the damage (within the resolution of our techniques) is inherited by the progeny of surviving cells (4). A surviving cell, therefore, can completely repair the sublethal events which it has experienced at the time of exposure. Our studies also showed that the repair of sublethal damage was completed before the first division post-irradiation. In addition to the more basic aspects of our findings, which will be reported in detail elsewhere (5), the observation that mammalian cells which survive an acute exposure to x-rays rapidly undo their sublethal damage suggests an immediate application to radiation therapy. This stems from the fact that fractionated dosage schedules are commonly employed in which successive treatments are separated by at least a day. Our observations indicate that twenty-four hours is enough time for substantial if not complete recovery of surviving cells in culture. When the recovery effects we have observed in culture are used for a theoretical analysis of tumor therapy, as will be developed later in this paper, it is found that the total dose required to reach a given survival level is predicted to increase rapidly with the number of treatments. This is in general agreement with the variation of tumoricidal doses with number of treatments observed in practice (6, 7). This in turn suggests that the relationship between total dose for a given survival and total number of treatments, the “isosurvival” curve, is the same as the relationship between tumoricidal dose and total number of treatments, the “isoeffect” curve, thus reinforcing the view that radiotherapeutic effects can be evaluated on the basis of cell survival.