Successful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection.
OBJECTIVE
To investigate whether pravastatin mitigates delayed radiation-induced enteropathy in rats, by focusing on the effects of pravastatin on acute cell death and fibrosis according to connective tissue growth factor (CTGF) expression and collagen inhibition.


METHODS
Mitigation of delayed radiation-induced enteropathy was investigated in rats using pravastatin administered in drinking water (30 mg/kg/day) 3 days before and 14 days after irradiation. The ileum was irradiated locally after surgical exteriorization (X-rays, 19 Gy). Acute apoptosis, acute and late histologic alterations, and late CTGF and collagen deposition were monitored by semiquantitative immunohistochemistry and colorimetric staining (6 h, 3 days, 14 days, 15 weeks, and 26 weeks after irradiation). Pravastatin antitumor action was studied in HT-29, HeLa, and PC-3 cells by clonogenic cell survival assays and tumor growth delay experiments.


RESULTS
Pravastatin improved delayed radiation enteropathy in rats, whereas its benefit in acute and subacute injury remained limited (6 h, 3 days, and 14 days after irradiation). Delayed structural improvement was associated with decreased CTGF and collagen deposition but seemed unrelated to acute damage. Indeed, the early apoptotic index increased, and severe subacute structural damage occurred. Pravastatin elicited a differential effect, protecting normal intestine but not tumors from radiation injury.


CONCLUSIONS
Pravastatin provides effective protection against delayed radiation enteropathy without interfering with the primary antitumor action of radiotherapy, suggesting that clinical transfer is feasible.
Haydont
Valérie
V
UPRES EA 27-10, Radiosensibilité des tumeurs et tissus sains, Institut de Radioprotection et de Sûreté Nucléaire/Institut Gustave Roussy, Villejuif, France.
Gilliot
Olivier
O
Rivera
Sofia
S
Bourgier
Céline
C
François
Agnès
A
Aigueperse
Jocelyne
J
Bourhis
Jean
J
Vozenin-Brotons
Marie-Catherine
MC
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism / Q000528:radiation effects; D055513:Connective Tissue Growth Factor; D004353:Drug Evaluation, Preclinical; D005260:Female; D005355:Fibrosis; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007082:Ileum / Q000473:pathology / Q000528:radiation effects*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017035:Pravastatin / Q000627:therapeutic use*; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011837:Radiation-Protective Agents; D055513:Connective Tissue Growth Factor; D003094:Collagen; D017035:Pravastatin