Clinical significance of increased gelatinolytic activity in the rectal mucosa during external beam radiation therapy of prostate cancer.
OBJECTIVE
Rectal toxicity (proctitis) is a dose-limiting factor in pelvic radiation therapy. Mucosal atrophy, i.e., net extracellular matrix degradation, is a prominent feature of radiation proctitis, but the underlying mechanisms are not known. We prospectively examined changes in matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinase A and B) in the rectal mucosa during radiation therapy of prostate cancer, as well as the relationships of these changes with symptomatic, structural, and cellular evidence of radiation proctitis.


METHODS
Seventeen patients scheduled for external beam radiation therapy for prostate cancer were prospectively enrolled. Symptoms of gastrointestinal toxicity were recorded, and endoscopy with biopsy of the rectal mucosa was performed before radiation therapy, as well as 2 and 6 weeks into the treatment course. Radiation proctitis was assessed by endoscopic scoring, quantitative histology, and quantitative immunohistochemistry. MMP-2 and MMP-9 were localized immunohistochemically, and activities were determined by gelatin zymography.


RESULTS
Symptoms, endoscopic scores, histologic injury, and mucosal macrophages and neutrophils increased from baseline to 2 weeks. Symptoms increased further from 2 weeks to 6 weeks, whereas endoscopic and cellular evidence of proctitis did not. Compared to pretreatment values, there was increased total gelatinolytic activity of MMP-2 and MMP-9 at 2 weeks (p = 0.02 and p = 0.004, respectively) and 6 weeks (p = 0.006 and p = 0.001, respectively). Active MMP-2 was increased at both time points (p = 0.0001 and p = 0.002). Increased MMP-9 and MMP-2 at 6 weeks was associated with radiation-induced diarrhea (p = 0.007 and p = 0.02, respectively) and with mucosal neutrophil infiltration (rho = 0.62).


CONCLUSIONS
Pelvic radiation therapy causes increased MMP-2 and MMP-9 activity in the rectal mucosa. These changes correlate with radiation-induced diarrhea and granulocyte infiltration and may contribute to abnormal connective tissue remodeling in radiation proctitis.
Hovdenak
Nils
N
Department of Oncology, Bergen University Hospital, Bergen, Norway.
Wang
Junru
J
Sung
Ching-Ching
CC
Kelly
Thomas
T
Fajardo
Luis F
LF
Hauer-Jensen
Martin
M
D000368:Aged; D004724:Endoscopy; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D012007:Rectum / Q000473:pathology* / Q000528:radiation effects; D013997:Time Factors
D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9