Effect of radiation dose rate and cyclophosphamide on pulmonary toxicity after total body irradiation in a mouse model.
OBJECTIVE
Interstitial pneumonitis (IP) is still a major complication after total body irradiation (TBI) and bone marrow transplantation (BMT). It is difficult to determine the exact role of radiation in this multifactorial complication, especially because most of the experimental work on lung damage was done using localized lung irradiation and not TBI. We have thus tested the effect of radiation dose rate and combining cyclophosphamide (CTX) with single fraction TBI on lung damage in a mouse model for BMT.


METHODS
TBI was given as a single fraction at a high dose rate (HDR, 0.71 Gy/min) or a low dose rate (LDR, 0.08 Gy/min). CTX (250 mg/kg) was given 24 h before TBI. Bone marrow transplantation (BMT) was performed 4-6 h after the last treatment. Lung damage was assessed using ventilation rate (VR) and lethality between 28 and 180 days (LD(50/28-180)).


RESULTS
The LD50 for lung damage, +/- standard error (SE), increased from 12.0 (+/- 0.2) Gy using single fraction HDR to 15.8 (+/- 0.6) Gy using LDR. Adding CTX shifted the dose-response curves towards lower doses. The LD50 values for the combined treatment were 53 (+/- 0.2) and 3.5 (+/- 0.2) Gy for HDR and LDR, respectively. This indicates that the combined effect of CTX and LDR was more toxic than that of combined CTX and HDR. Lung damage evaluated by VR demonstrated two waves of VR increase. The first wave of VR increase occurred after 6 weeks using TBI only and after 3 weeks in the combined CTX-TBI treatment, irrespective of total dose or dose rate. The second wave of VR elevation resembled the IP that follows localized thoracic irradiation in its time of occurrence.


CONCLUSIONS
Lung damage following TBI could be spared using LDR. However, CTX markedly enhances TBI-induced lung damage. The combination of CTX and LDR is more toxic to the lungs than combining CTX and HDR.
Department of Oncology and Danish Cancer Society, Aarhus University Hospital.
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Safwat
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Nielsen
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El-Badawy
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J
Overgaard
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000379:methods; D003520:Cyclophosphamide / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000528:radiation effects*; D008297:Male; D051379:Mice; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000528:radiation effects*; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000209:etiology*; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide