The effects of altered fractionation schedules on the survival of human cell lines differing in their proliferative activity and repair capacity.

Plateau phase cultures of human cell lines were used as model systems to study the relative influences of proliferation and repair on the effectiveness of altered fractionation schedules. A human normal diploid fibroblast cell line (AG1522) which has a high capacity to repair potentially lethal radiation damage (PLD) and very little proliferative activity when grown to confluence was compared to human tumor cell lines which maintain significant cell-cycle activity in plateau phase. The human fibrosarcoma cell line, HT1080, used in the present study exhibited a much greater rate of turnover than the normal fibroblasts as determined from tritiated thymidine incorporation (5 day labeling index of 66% vs 20%) and no PLD repair, as determined by delayed plating experiments, in plateau phase. Twenty Gy were delivered to both cell lines over 5 days in 3 regimens: one 4 Gy fraction/day, two 2 Gy fractions/day with a 2 hr interval between doses, and two 2 Gy fractions/day with a 6 hr interval between doses. Although the normal fibroblasts demonstrated the greatest sparing between acute single doses and one 4 Gy fraction/day, there was little additional benefit (increased survival) from the increased dose fractionation. In contrast, the twice daily fractionation schedules resulted in significant differential sparing of the fibrosarcoma cells compared to the normal fibroblasts. With the 6 hr interval between doses, the survival advantages of the cell line with the slow turnover rate and high PLD repair capacity were completely lost. Split-dose experiments indicated slightly less sublethal damage repair in the fibrosarcoma cell line, but for both cell lines recovery was complete in 2 hr. DNA distributions were measured by flow cytometry and long term labeling index measurements performed in parallel with the multifraction radiation survival studies. These data indicated the occurrence of some accumulation in G2 but also suggested no further cell division during treatment in the cell line with the most proliferative activity (fibrosarcoma). The concave upward shape of the tumor cell survival curves suggested that a resistant subpopulation (e.g. S-phase cells) may be dominating the survival response in the schedules with two 2 Gy fractions/day. Thus, it appears that the halting of cell division combined with the heterogenous nature of the tumor target cell population in terms of inherent (cell-age dependent) radiosensitivity led to a greater sparing with increased fractionation than observed in the homogenous normal cell population. These results are exactly the opposite of what has generally been observed so far with early vs late effects tissues and in rodent cell systems in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)