Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study.
OBJECTIVE
To establish a successful treatment of subcutaneous fibrosis developing after high doses of gamma rays, suitable for use in clinical practice.


METHODS
We used an animal model of acute localized gamma irradiation simulating accidental overexposure in humans. Three groups of 5 Large White pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of necrosis developed within a few weeks which had healed after 26 weeks to leave a block of subcutaneous fibrosis involving skin and skeletal muscle. One experimental group of 5 pigs was dosed orally for 26 weeks starting 26 weeks after irradiation with 1600 mg/120 kg body weight of pentoxifylline (PTX) included in the reconstituted food during its fabrication, and another group of 5 was dosed orally for the same period with a daily dose of 1600 mg/120 kg body weight of PTX combined with 2000 IU/120 kg body weight of alpha-tocopherol. Five irradiated control pigs were given normal food only. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Depth of scar tissue was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 26 weeks after treatment started. The density, length, width, and depth of the block of fibrotic scar tissue, and the areas and volume of its projected cutaneous surface, were compared before treatment, 6 and 13 weeks thereafter, and at 26 weeks.


RESULTS
The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. No modifications were observed in the block of fibrotic scar tissue of pigs dosed with PTX alone. However, significant softening and shrinking of this block were noted in the pigs dosed with PTX + alpha-tocopherol 13 weeks after treatment started and at autopsy, when mean regression was approximately 30% for length, approximately 50% for width and depth, and approximately 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar tissue. The 50% decrease in the linear dimensions of the scar tissue, were comparable to the results obtained in our previous clinical studies, and were highly significant compared to the clinical and autopsy results for the controls. Histologic examination of the residual scar tissue revealed tissue which was more homogenous and less cellular and inflammatory than in control and PTX-dosed pigs. The tissular and cellular immunolocalization of tumor necrosis factor alpha (TNFalpha) was similar in the residual fibrotic tissues of all three groups of pigs, whereas the immunostaining of transforming growth factor beta-1(TGFbeta-1) diminished much more in the residual fibrotic scar tissue of the PTX + alpha-tocopherol-dosed pigs than in the two other groups.


CONCLUSIONS
The present results showed a striking regression of the subcutaneous fibrotic scar tissue that develops as a consequence of high doses of gamma rays.
Lefaix
J L
JL
CEA - DSV - DRR- Laboratoire de Radiobiologie et d'Etude du Génome, CEA-Saclay, Gif sur Yvette, France.
Delanian
S
S
Vozenin
M C
MC
Leplat
J J
JJ
Tricaud
Y
Y
Martin
M
M
D004338:Drug Combinations; D005355:Fibrosis / Q000188:drug therapy; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D010431:Pentoxifylline / Q000627:therapeutic use*; D011832:Radiation Injuries / Q000188:drug therapy*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D012867:Skin / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014810:Vitamin E / Q000627:therapeutic use*
D004338:Drug Combinations; D011837:Radiation-Protective Agents; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D010431:Pentoxifylline