Repopulation between radiation fractions in human melanoma xenografts.

Rate of tumor repopulation between radiation fractions was studied using two human melanoma xenograft lines (E.F. and V.N.). Tumors were given five radiation fractions under hypoxic conditions in vivo and clonogenic cells survival was measured in vitro after the last radiation fraction. Dose-response curves were established for interfraction times of 12, 24, 36, and 48 hr by varying dose per fraction from 4.2 to 11.2 Gy. Assuming an oxygen enhancement ratio of 2.8, these doses corresponded to doses of 1.5 to 4.0 Gy under aerobic conditions, that is, clinically relevant doses per fraction were used. The dose-response curves were nearly parallel and were shifted to the right with increasing interfraction time, demonstrating significant repopulation between the radiation fractions. Iso-effect analyses showed that additional radiation doses of 2.0 +/- 0.6 Gy/day (E.F.) and 2.2 +/- 0.6 Gy/day (V.N.), corresponding to doses of 0.7 +/- 0.2 Gy/day (E.F.) and 0.8 +/- 0.2 Gy/day under aerobic conditions, would be required to compensate for the repopulation. These doses were equivalent to the surviving clonogenic cells showing doubling times of 40-50 hr (E.F.) and 30-40 hr (V.N.) during the treatment period. The radioresponsiveness of the two melanoma xenograft lines was also measured. Tumors in air-breathing mice were given from 5 to 15 daily fractions of 2.0 Gy and cell survival curves were established in vitro. Theoretical survival curves, calculated from SF2 in vitro and rate of repopulation during fractionated irradiation in vivo, agreed fairly well with the measured survival curves. This suggested that the radioresponsiveness of the melanoma xenograft lines was governed by two main parameters: (a) cellular radiation sensitivity and repair capacity and (b) rate of repopulation between radiation fractions.