Assessment of the protective effect of amifostine on radiation-induced pulmonary toxicity.
The objective of this study was to assess the radioprotective effects of amifostine in the rat model of radiation-induced lung injury using fractionated doses of radiation, to determine whether amifostine given before irradiation protects tumor from radiation cytotoxicity, and to determine whether changes in plasma levels of transforming growth factor (TGF)-beta correlate with radioprotective effect of amifostine. R3230 AC mammary adenocarcinoma was transplanted on the right posterior chest wall of female Fisher-344 rats. Both tumor-bearing and non-tumor-bearing animals were irradiated to the tumor or right lung using 4 MV photons and fractionated dose of 35 Gy/5 fractions/5 days. Animals with tumors and those without were randomized into 4 groups, respectively (8 to 10 rats per group), to receive (1) radiation alone; (2) radiation + amifostine; (3) amifostine alone; (4) sham radiation. Amifostine (150 mg/kg) was given intraperitoneally 30 minutes before each fraction of irradiation. The tumor size was measured twice a week. Breathing rate was assessed every 2 weeks. TGF-beta levels in plasma were assessed monthly after treatment. Six months after irradiation, animals were euthanized and lung tissue was processed for hydroxyproline content analysis. A significant increase in breathing frequency started 9 weeks after irradiation in animals that received radiation only. In the radiation + amifostine group, there was both a delay and a significantly lower peak in breathing frequency (P < .001). Hydroxyproline content was higher in the radiation-alone group than in rats given amifostine prior to radiation (P < .05). The TGF-beta levels in plasma showed an increase from 1 to 3 months after radiation, peaking at 2 months in the rats with (2.80 +/- 0.23) or without (5.32 +/- 1.21) amifostine compared to sham irradiation. TGF-beta levels were significantly lower at 1 to 3 months in rats receiving amifostine plus radiation versus those receiving radiation alone. Tumor growth delay and regrowth rate after radiation were not different between radiation-alone and radiation + amifostine groups. This study confirms the protective effect of amifostine in reducing radiation-induced pulmonary toxicity. No tumor protection was demonstrated after fractionated radiotherapy. The reduction in pulmonary injury with amifostine in paralleling lower plasma levels of TGF-beta, suggesting that monitoring plasma levels of this cytokine may reflect the efficacy of an intervention aimed at preventing radiation-induced lung injury.
Vujaskovic
Zeljko
Z
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA. vujas@radonc.duke.edu
Feng
Qin Fu
QF
Rabbani
Zahid N
ZN
Samulski
Thaddeus V
TV
Anscher
Mitchell S
MS
Brizel
David M
DM
D000230:Adenocarcinoma; D004999:Amifostine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D019583:Dose Fractionation, Radiation; D005260:Female; D006909:Hydroxyproline / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000473:pathology / Q000532:radiotherapy; D009368:Neoplasm Transplantation; D017564:Radiation Pneumonitis / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D012119:Respiration / Q000187:drug effects / Q000528:radiation effects; D012129:Respiratory Function Tests; D016212:Transforming Growth Factor beta / Q000097:blood
D011837:Radiation-Protective Agents; D016212:Transforming Growth Factor beta; D004999:Amifostine; D006909:Hydroxyproline