Dose rate-dependent marrow toxicity of TBI in dogs and marrow sparing effect at high dose rate by dose fractionation

Abstract

We evaluated the marrow toxicity of 200 and 300 cGy total-body irradiation (TBI) delivered at 10 and 60 cGy/min, respectively, in dogs not rescued by marrow transplant. Additionally, we compared toxicities after 300 cGy fractionated TBI (100 cGy fractions) to that after single-dose TBI at 10 and 60 cGy/min. Marrow toxicities were assessed on the basis of peripheral blood cell count changes and mortality from radiation-induced pancytopenia. TBI doses studied were just below the dose at which all dogs die despite optimal support. Specifically, 18 dogs were given single doses of 200 cGy TBI, delivered at either 10 (n=13) or 60 (n=5) cGy/min. Thirty-one dogs received 300 cGy TBI at 10 cGy/min, delivered as either single doses (n=21) or three fractions of 100 cGy each (n=10). Seventeen dogs were given 300 cGy TBI at 60 cGy/min, administered either as single doses (n=5) or three fractions of 100 cGy each (n=10). Within the limitations of the experimental design, three conclusions were drawn: 1) with 200 and 300 cGy single-dose TBI, an increase of dose rate from 10 to 60 cGy/min, respectively, caused significant increases in marrow toxicity; 2) at 60 cGy/min, dose fractionation resulted in a significant decrease in marrow toxicities, whereas such a protective effect was not seen at 10 cGy/min; and 3) with fractionated TBI, no significant differences in marrow toxicity were seen between dogs irradiated at 60 and 10 cGy/min. The reduced effectiveness of TBI when a dose of 300 cGy was divided into three fractions of 100 cGy or when dose rate was reduced from 60 cGy/min to 10 cGy/min was consistent with models of radiation toxicity that allow for repair of sublethal injury in DNA.

Comparing High and Low Total Body Irradiation Dose Rates for Minimum-Intensity Conditioning of Dogs for Dog Leukocyte Antigen–Identical Bone Marrow Grafts

“…In a similar study, it was reported that platelet and granulocyte toxicity was reduced in dogs given 300 cGy TBI at a 10 cGy/minute when compared to a rate of 60 cGy/minute [17]. A possible explanation for the differences is that the previous studies were done with uninterrupted irradiation delivered from two opposing 60 cobalt sources, while irradiation from a linear accelerator in the current study required, by necessity, an interruption midway through the procedure in order to re-position the dog for exposure from the opposing side.…”

A feasibility study of low‐dose total body irradiation for relapsed canine lymphoma

“…A comparison of canine marrow toxicity from fractionated versus single‐dose TBI at a rate of 10 cGy min −1 of 3 showed that there was no difference in the toxicity of the patients 24 . Another study showed a strong indication that platelet count decreased more with 60 cGy minute −1 dose rate than 10 cGy minute −1 dose rate as a single dose, although survival was not statistically different 25 . In our study, a single treatment at a lower dose rate was chosen to minimize side‐effects, cost of therapy, anaesthesia and dogs' time away from home.…”

Antibody-Based Screen for Ionizing Radiation-Dependent Changes in the Mammalian Proteome for Use in Biodosimetry

“…As an initial test to determine whether radiation-responsive proteins identified after ex vivo radiation could also be detected after in vivo radiation, we used a large animal model, the dog. The canine model of radiation exposure and hematopoiesis is highly predictive of clinical outcomes in humans (25–28). Hence, although ultimately any new diagnostic will need to be validated in humans, the dog is an attractive large animal model for pilot testing and initial characterization of new diagnostics for detailed biodosimetry, since it will be ethically unfeasible to obtain data from human in vivo exposures over a wide range of doses and times (we are limited for human studies to rare accidental and well-characterized exposures or to therapeutically determined doses and times).…”