Measurements of relative biological effectiveness (RBE) have been made on the range-modulated 70 MeV proton beam at TRIUMF using a precise cell sorting survival assay. In this study, Chinese hamster V79-WNRE cells were suspended in medium containing liquid gelatin at 37 degrees C in irradiation tubes and the gel was allowed to solidify by cooling to 4 degrees C. Complete cell survival responses were measured at 11 positions with 2 mm spacing within a proton stopping peak width of approximately 2 cm. Survival responses after proton irradiation were compared with responses to 60Co gamma rays measured at the same time, and RBE values were determined as a function of both dose and depth. Above doses of 4 Gy, the average RBE for these cells throughout the modulated proton stopping distribution was 1.21 +/- 0.05, measured at a survival of 1%. However, we also observed that, within the spread-out Bragg peak, the RBE increased with increasing depth, from approximately 1.2 at the proximal part to > 1.3 at the distal part of the peak. At the distal edge of the stopping distribution, the RBE value increased significantly, to an extent that may be of concern when this region of the treatment volume is close to sensitive tissues. Below 4 Gy, the RBE value was also dependent on radiation dose, increasing significantly to values of approximately 1.37 and 1.56 at 2 and 1 Gy, respectively. Our results illustrate that the use of a single RBE value in different irradiation protocols can be an oversimplification, and argues for the use of "proton gray doses" rather than "gamma-ray equivalent grays."

A decreased oxygen enhancement ratio (OER) at lower radiation doses has been previously reported (B. Palcic, J. W. Brosing, and L. D. Skarsgard, Br. J. Cancer 46, 980-984 (1984]. The question remained whether or not this effect is due to a possible oxygen contamination at low doses, which was not the case at high doses. To ensure a sufficient degree of hypoxia prior to the start of irradiation, Chinese hamster cells (CHO) were made hypoxic by gas exchange combined with metabolic consumption of oxygen at 37 degrees C. At the same time oxygen levels in cell suspension were measured using a Clark electrode. It was found that under experimental conditions used in this laboratory for hypoxic irradiations, the oxygen levels before the start of irradiation are always below the levels which could give any significant enhancement to radiation inactivation by X rays. Full survival curves were determined in the dose range 0-30 Gy using the conventional survival assay and in the dose range 0-3 Gy using the low dose survival assay. The results confirmed the earlier finding that the OER decreases at low doses. It is therefore believed that the dose-dependent OER is a true radiobiological phenomenon and not an artifact of the experimental method used in the low dose survival assay.

It is well known that cells of human tumor cell lines display a wide range of sensitivity to radiation, at least a part of which can be attributed to different capacities to process and repair radiation damage correctly. We have examined the response to very low-dose radiation of cells of five human tumor cell lines that display varying sensitivity to radiation, using an improved assay for measurement of radiation survival. This assay improves on the precision of conventional techniques by accurately determining the numbers of cells at risk, and has allowed us to measure radiation survival to doses as low as 0.05 Gy. Because of the statistical limitations in measuring radiation survival at very low doses, extensive averaging of data was used to determine the survival response accurately. Our results show that the four most resistant cell lines exhibit a region of initial low-dose hypersensitivity. This hypersensitivity is followed by an increase in radioresistance over the dose range 0.3 to 0.7 Gy, beyond which the response is typical of that seen in most survival curves. Mathematical modeling of the responses suggests that this phenomenon is not due to a small subpopulation of sensitive cells (e.g. mitotic), but rather is a reflection of the induction of resistance in the whole cell population, or at least a significant proportion of the whole cell population. These results suggest that a dose-dependent alteration in the processing of DNA damage over the initial low-dose region of cell survival may contribute to radioresistance in some cell lines.

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