EFFECT OF RADIATION-DOSE RATE AND CYCLOPHOSPHAMIDE ON PULMONARY TOXICITY AFTER TOTAL-BODY IRRADIATION IN A MOUSE MODEL

Purpose: Interstitial pneumonitis (IF) is still a major complication a fter total body irradiation (TBI) and bone marrow transplantation (BMT ). It is difficult to determine the exact role of radiation in this mu ltifactorial 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 combin ing cyclophosphamide (CTX) with single fraction TBI on lung damage in a mouse model for BMT. Methods and Materials: TBI was given as a singl e 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 24h before TBI. Bone marr ow transplantation (BMT) was performed 4-6 h after the last treatment. Lung damage was assessed using ventilation rate (VR) and lethality be tween 28 and 180 days (LD(50/28-180)). Results: The LD(50) for lung da mage, +/- standard error (SE), increased from 12.0 (+/- 0.2) Gy using single fraction HDR to 15.8 (+/- 0.6) Gy using LDR. Adding CTX shift t he dose-response curves towards lower doses. The LD,, values for the c ombined treatment were 5.3 (+/- 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 eval uated by VR demonstrated two waves of VR increase. The first wave of V R increase occurred after 6 weeks using TBI only and after 3 weeks in the combined CTX-TBI treatment, irrespective of total dose or dose rat e. The second wave of VR elevation resembled the IP that follows local ized 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 m ore toxic to the lungs than combining CTX and HDR.