Increased plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in lung and breast cancer are altered during chest radiotherapy.
OBJECTIVE
Does the release of plasma matrix metalloproteinase-9 (MMP-9) by radiation-activated airway epithelial cells and infiltrating inflammatory cells play a role in the radiation damage or repair process in the lungs? We evaluated lung damage by ionizing radiation using plasma levels of MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and MMP-3 as biologic markers of tissue damage, and also their relationship to changes in pulmonary epithelial permeability, clinical signs and symptoms, and lung structural changes.


METHODS
Seven serial studies were conducted in each of 8 patients undergoing chest radiotherapy (RT) for lung or breast cancer, beginning before the first treatment (baseline) and then biweekly to approximately 100 days during and after RT. Chest radiographs were monitored for each patient. Sandwich enzyme-linked immunoassays (ELISA) were used to measure plasma MMP-3, MMP-9, and TIMP-1 levels. Lung permeability was evaluated by measuring the rate of epithelial clearance of approximately 150 microCi ( approximately 5.6 MBq) inhaled (99m)Tc diethylenetriamine pentaacetate aerosol (DTPA).


RESULTS
Lung and breast cancer resulted in very high plasma levels of MMP-9 (126-893 ng/mL) and TIMP-1 (496-8985 ng/mL) in all subjects studied before initiation of RT. This compares with plasma MMP-9 and TIMP-1 values in healthy volunteers of 29 +/- 11 ng/mL and 436 +/- 86 ng/mL, respectively. RT was followed by a sharp decrease in plasma MMP-9 within the first 2 weeks, but without a corresponding change in TIMP-1. In contrast, plasma MMP-3 levels, which are generally increased with inflammation, were elevated in only 1 of 5 subjects.


CONCLUSIONS
Lung and breast cancer are associated with high plasma levels of MMP-9 and TIMP-1. These high baseline plasma levels of MMP-9 were reduced in the first 2 weeks of RT in 7 of 8 subjects, and TIMP-1 plasma levels remained high in all subjects. The decrease in plasma MMP-9 after initiation of chest RT appears to reflect a suppressive effect on cancer-induced cellular responses rather than a primary role for MMP-9 in radiation-induced lung damage. Likewise, the lack of a rise in plasma MMP-3 levels does not support a role for MMP-3 in tissue injury or repair in the lung. It remains to be determined whether plasma MMP-9 measurements will serve as a useful parameter in predicting cancer relapse.
Susskind
Herbert
H
Clinical Research Center, Brookhaven National Laboratory, Upton, NY 11973, USA. Hssusski@optonline.net
Hymowitz
Michelle H
MH
Lau
Yat Hong
YH
Atkins
Harold L
HL
Hurewitz
Adam N
AN
Valentine
Edward S
ES
Meek
Allen G
AG
Zucker
Stanley
S
D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000201:enzymology* / Q000532:radiotherapy*; D002463:Cell Membrane Permeability / Q000528:radiation effects; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism / Q000528:radiation effects; D008175:Lung Neoplasms / Q000097:blood / Q000201:enzymology* / Q000532:radiotherapy*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D011832:Radiation Injuries / Q000097:blood / Q000000981:diagnostic imaging / Q000201:enzymology; D011859:Radiography; D011877:Radionuclide Imaging; D011878:Radiotherapy / Q000009:adverse effects; D016284:Technetium Tc 99m Pentetate / Q000493:pharmacokinetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
D019715:Tissue Inhibitor of Metalloproteinase-1; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D016284:Technetium Tc 99m Pentetate