Influence of adjacent low-dose fields on tolerance to high doses of protons in rat cervical spinal cord

The dose-response relationship for a relatively short length (4 mm) of rat spinal cord has been shown to be significantly modified by adjacent low-dose fields. In an additional series of experiments, we have now established the dose-volume dependence of this effect.

Wistar rats were irradiated on the cervical spinal cord with single doses of unmodulated protons (150 MeV) to obtain sharp lateral penumbras, by use of the shoot-through technique, which employs the plateau of the depth-dose profile rather than the Bragg peak. Three types of inhomogeneous dose distributions were administered: Twenty millimeters of cervical spinal cord were irradiated with variable subthreshold (= bath) doses (4 and 18 Gy). At the center of the 20-mm segment, a short segment of 2 mm or 8 mm (= shower) was irradiated with variable single doses. These inhomogeneous dose distributions are referred to as symmetrical bath-and-shower experiments. An asymmetrical dose distribution was arranged by irradiation of 12 mm (= bath) of spinal cord with a dose of 4 Gy. The caudal 2 mm (= shower) of the 12-mm bath was additionally irradiated with variable single doses. This arrangement of inhomogeneous dose distribution is referred to as asymmetrical bath-and-shower experiment. The endpoint for estimation of the dose-response relationships was paralysis of the fore limbs or hind limbs and confirmation by histology.

The 2-mm bath-and-shower experiments with a 4-Gy bath dose showed a large shift of the dose-response curves compared with the 2-mm single field, which give lower ED50 values of 61.2 Gy and 68.6 Gy for the symmetrical and asymmetrical arrangement, respectively, compared with an ED50 of 87.8 Gy after irradiation of a 2-mm field only. If the bath dose is increased to 18 Gy, the ED50 value is decreased further to 30.9 Gy. For an 8-mm field, addition of a 4-Gy bath dose did not modify the ED50 obtained for an 8-mm field only (23.2 and 23.1 Gy).

The spinal cord tolerance of relatively small volumes (shower) is strongly affected by low-dose irradiation (= bath) of adjacent tissue. The results of all bath-and-shower experiments show the effect of a low bath dose to be highest for a field of 2 mm, less for 4 mm, and absent for 8 mm. Adding a 4-Gy bath to only 1 side of a 2-mm field still showed a large effect. Because glial progenitor cells are known to migrate over at least 2 to 3 mm, this observation indicates that interference with stem cell migration is not the most likely mechanism of a bath effect.