Actions of high energy protons on mammalian cells: The influences of linear energy transfer and of dose rate
Marcus, Theodor R.
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The interaction between high energy protons and living matter has been increasingly studies recently. The Relative Biological Efficiency (RBE) of cyclotron-generated protons is well known in the shank portion of the proton beam, but poorly at, and beyond, the Bragg peak, where the linear Energy Transfer (LET) rises rapidly. It seemed likely that this increase in LET at the Bragg peak would cause a concomitant increase in RBE. Experiments were therefore designed to determine Bragg peak-RBE. Bateman, Bond and Robertson recently postulated that the effects of a given dose of radiation vary as a function of the cube root of the dose rate, suggesting greater efficiency at higher rates. This hypothesis was tested. Mouse Ehrlich ascites cells were irradiated in vitro, at shank or at Bragg peak, injected into fresh hosts, collected 20 hours later, smeared, and stained with Feulgen's stain. The end point was the percentage of aberrations (bridges, deletions) at anaphase. Fourteen different dose rate-dose-shank/peak combinations were tested, and for each, at least 1,000 anaphase figures were scored. The dose-response curve was rectilinear, as expected, with a ten percent increase in effect for every 93 rad total dose. Dose rate effects were inconclusive. Up to a total dose of 192 rad, dose rate effects were non-significant in spite of a 100-fold difference in rates: but at a total dose of 360 rad, the higher rates (6,000 and 9,000 rad/min) caused a significantly larger percentage of anomalies than the low (60 and 80 rad/min) rates. At 12,000 rad/min, effectiveness fell below that of 60 rad/min, a so far inexplicable observation. The RBE for the Bragg peak, compared to shank (RBE shank = 1) ranged from 1.1 to 1.3, except at the anomalous, 12,000 rad/min level, where it was 1.6. To test the effectiveness of dose rate levels on growing tissues, HAS-1 hamster tumors in the cheek pouch, were exposed to shank protons at various doses and at dose rates differing by a factor of 100X. At each dose-dose rate setting, twenty hamster were irradiated; the tumors were measured at regular intervals, and growth curves were constructed. The tumors grew at regular, though changing, rates, characteristic of the total dose, irrespective of the dose rate. The initial, radiation-generated lag phase of development was increase one day for every 175 rad total dose. During the ensuing log phase, all tumors grew at the same, fast rate, irrespective of their treatment. HAS-1 cells, irradiated in vitro before implantation, showed no dose rate effects at levels ranging from 150 to 15,000 rad/min, and growth was less affected by total dose, both absolutely and in dose-to-dose comparisons, than when irradiation occurred after the cells had become established in the cheek pouch. The data indicate that, at dose rates up to 15,000 rad/min, the growth of the HAS-1 tumor is dose rate independent: for this system, at least, the Bateman-Bond-Robertson hypothesis dose not appear applicable. At high total dose levels, however, Ehrlich ascites cells may show dose rate dependence. RBE at Bragg peak was, in this system, and compared to shank, 1.2 to 1.4, indicating that Bragg peak protons are biologically more effective than shank protons.
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