Herbert Susskind

INCREASED PLASMA LEVELS OF MATRIX METALLOPROTEINASE-9 AND TISSUE INHIBITOR OF METALLOPROTEINASE-1 IN LUNG AND BREAST CANCER ARE ALTERED DURING CHEST RADIOTHERAPY

PURPOSE 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 AND MATERIALS 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. CONCLUSION 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.

Quantitative 123I IMP and 99mTc HMPAO imaging in the dog following cocaine administration

SPECT and associated imaging procedures were used in beagle dogs to (1) evaluate the uptake, distribution, and clearance properties of i.v.-injected 123I IMP (IMP) and 99mTc HMPAO (HMPAO) in the brain, lungs, liver, and kidneys; (2) quantify the acute effects (after 15 sec) of very low doses (0.5 or 1.0 mg/kg) cocaine on the kinetics and localization properties of IMP and HMPAO; and (3) evaluate comparative imaging properties of IMP and HMPAO for measuring regional cerebral blood flow (rCBF). Regional and global uptake and localization of IMP or HMPAO were evaluated in control studies using dynamic planar (0-30 min) and SPECT imaging (at 35 min). The regional distribution properties of IMP and HMPAO in the brain were estimated from regions of interest (ROIs) drawn around anatomic structures on MR slices and manually registered with corresponding SPECT slices. Cocaine significantly reduced the 30-min IMP uptake in the brain and lungs by approximately 15%, but only slightly changed HMPAO uptake in the brain and other organs. In the control studies, the respective uptakes of IMP in the brain and lungs were 9 and 39% greater (p < 0.01) than those of HMPAO. In control SPECT studies, the highest uptake of IMP was observed in the thalamus and progressively less activity was observed in the parietal lobe, frontal lobe, cerebellum, occipital lobe, and entire brain; activity in the olfactory bulb was lower than in all other regions. Cocaine reduced IMP uptake in the cerebellum (p < 0.01), occipital lobe (p < 0.01), and entire brain (p < 0.05). IMP uptake (cpm/pixel-mCi) in the different brain regions was 1.3 to 2.1 times greater than that of HMPAO (p < 0.001). HMPAO uptake was more homogeneous throughout the gray matter of the brain; no significant uptake differences were observed among flagged regions. Results indicate that single, acute doses of cocaine, 0.5 and 1.0 mg/kg, significantly altered the uptake and localization properties of IMP in the dogs brain, lungs, liver, and kidneys. Variations in regional uptake of IMP in the parietal, frontal, and occipital lobes, cerebellum, and thalamus were greater than with HMPAO.

Kinetics of Inhaled Krypton in Man

The total body retention of 79Kr and its clearance following a 10-min rebreathing period were measured in vivo in order to refine the dosimetry calculations. Radioactivity in the chest region and in the recirculating krypton-air mixture were measured continuously during rebreathing of the gas mixture and in the first 5 min of the gas washout period using a gamma camera and shielded NaI detector, respectively. Subjects were then counted in the Brookhaven whole-body counter at varying time intervals for up to 55 hr. The retention data of krypton for 16 subjects (12 males, 4 females) were resolved into a five-component exponential curve. The average half-times were 21.5 * 5.7 sec, 4.74 2 2.0 min, 0.33 2 0.11 hr, 2.41 * 0.95 hr, and 7.0 ? 1.7 hr. The half-time of the long-term component correlated highly with the percentage of total body fat. Internal dose calculations were performed using the MIRD techniques and were compared with previous estimations.

Does detoxification reverse the acute lung injury of crack smokers

The effect on chronic crack users of a 3 month detoxification programme on lung clearance of inhaled 99Tcm-diethylenetriamine pentaacetate (99Tcm-DTPA) aerosol, spirometry and gas exchange was determined in a controlled in-patient clinical treatment setting. Imaging studies were carried out in eight chronic crack users (four crack-only and four crack plus tobacco) before and after the successful completion of the detoxification programme to measure the clearance of inhaled 99Tcm-DTPA from the lungs, an index of lung epithelial permeability. 99Tcm-DTPA lung clearance, expressed in terms of the biological half-time, T1/2, was determined from the slopes of the least-squares fit regression lines of the respective time-activity plots. The mean (+/- S.D.) global T1/2 values of the crack-only (75 +/- 39 min) and crack plus tobacco users (22 +/- 10 min) were significantly shorter (P < 0.02 and P < 0.001, respectively) than from the lungs of the non-smoking controls (124 +/- 29 min). This was consistent with increased lung epithelial permeability secondary to crack-related lung injury. The mean global T1/2 value of the crack plus tobacco users was significantly shorter (P < 0.05) than that of the crack-only users. After detoxification, the abnormally rapid lung clearance became normal in two of the four crack-only users studied, improved in a third and remained unchanged in the fourth, a subject whose T1/2 value was already normal initially. However, lung clearance improved in only one of the four crack plus tobacco users studied. Faster 99Tcm-DTPA clearance was the only impairment found in seven of the eight crack users, the eighth having restrictive lung disease. Crack-related lung injury, reflected by abnormally rapid 99Tcm-DTPA lung clearance, may be at least partially reversible after a 3 month period of abstinence from crack.