Therapeutic heating of malignant tissue holds promise as an adjunctive modality in cancer treatment. To this end, a thorough knowledge of hyperthermic effects on cell cycle is crucial, both in the context of normal tissue to be spared from lethal effects, and for synergy of hyperthermia with other treatments which fare optimally at various stages of the cell cycle. Established cell lines, with many of the characteristics of neoplastic tissue, have been utilized to study the effects of hyperthermia on cell cycle progression. At best, such populations resemble only the most malignant and undifferentiated types of neoplasm. In addition, these experiments have usually focused on cell death as an endpoint. However, it must be stressed that in developing hyperthermia as an adjunctive therapeutic modality in oncology, it is necessary to establish the greatest possible ratio between lethal effects on malignant versus normal tissue. The usefulness of hyperthermia in cancer treatment may ultimately reside in its sublethal effects. We propose an entirely new approach to study the effects of sublethal hyperthermia on cell cycle kinetics. As opposed to using an established cell line, we will study the effects of heating on virus-transformed erythroid cells which continue to respond to the physiologic regulator of erythropoiesis, erythropoietin. This system will permit not only the analysis of hyperthermic effects on proliferating cells, as has been accomplished in the past, but also the study of hyperthermic perturbations on hormone-regulated differentiation within a homogeneous cell population. We will use flow cytometry to analyze DNA content, erythroid differentiation antigen density (recognized by monoclonal antibodies), and cell size over the course of proliferation and differentiation of Friend virus complex-induced erythroleukemia, as regulated by erythropoietin. Then we will study time-temperature effects on these parameters, principally in the sublethal range of cell heating. We will collect data on control and heat-perturbed cells in a correlated manner so that we can construct a mathematical model, in the form of continuity equations, to describe cellular responses in a multidimensional parameter space. This approach will foster an understanding of cell heating effects in terms of a continuous biological process, and may be applicable in the prediction of hyperthermic effects on renewing cell populations during the course of cancer treatment.
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