Are hypoxic cells critical for the outcome of fractionated radiotherapy in a slow-growing mouse tumor?

Purpose: To investigate the significance of hypoxic cells, reoxygenation and repopulation for the outcome of fractionated radiotherapy of a slow- growing subline of a murine fibrosarcoma and to compare the results with those previously obtained from the original fast-growing tumor. Materials and methods: A slow-growing subline, 457-O, was obtained among the tumors that recurred after a single irradiation to the third generation isotransplants of a mouse fibrosarcoma, FSa-II. The single cell suspensions were transplanted into the mouse foot and when the tumors reached an average diameter of 4 mm, they were subjected to one to 20 equal daily γ-ray doses given in air (A) or under hypoxic conditions (H). The TCD₅₀ (50% tumor control radiation dose) was calculated according to the tumor control frequency within 180 days. The linear-quadratic plus time model was fitted to these data by logistic regression analysis. Results: The volume doubling time of the 457-O tumors was ~2.2 times slower than that of the original FSa-II tumors. The TCD₅₀(H) (single dose) was 52.3 Gy and increased with an increasing number of fractions to a TCD₅₀(H) (20 doses) of 90.8 Gy. This increase of 38.5 Gy was much smaller than that of 149 Gy for the original FSa-II. The TCD₅₀(A) (single dose) and TCD₅₀(A) (20 doses) were 41.3 and 50.6 Gy, respectively. This small difference of 9.3 Gy contrasted with a significant increase of 52.9 Gy for the FSa-II. Discussion: These results suggested no repopulation of 457-O tumor clonogens during the course of up to 20 daily doses, while the original FSa-II tumor cells repopulated substantially. Hypoxic clonogens in the slow-growing tumor reoxygenated but some fractions remained critical. Conclusion: The present data together with those obtained from the fast- growing FSa-II suggested that hypoxic clonogens were critical for the outcome of fractionated radiotherapy. Repopulation was insignificant in this slow- growing tumor during five to 20 daily doses.