Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications.

The balance between production and activation of MMPs and their inhibition by TIMPs is a crucial aspect of cancer invasion and metastasis. On the basis of the concept that MMPs synthesized in tissues seep into the bloodstream, we have examined MMP levels in the plasma of patients with cancer. In colorectal, breast, prostate, and bladder cancer, most patients with aggressive disease have increased plasma levels of gelatinase B. In patients with advanced colorectal cancer, high levels of either gelatinase B or TIMP complex were associated with shortened survival. We propose that these assays may be clinically useful in characterizing metastatic potential in selected kinds of cancer. In rheumatoid arthritis and systemic lupus erythematosus (SLE), serum and plasma levels of stromelysin-1 were approximately 3-5-fold increased. Fluctuating serum stromelysin-1 levels in SLE did not correspond with change in disease activity. In SLE, stromelysin-1 may be a component of the chronic tissue repair process rather than being responsible for inciting tissue damage. On the basis of these observations, we conclude that measurement of plasma/serum MMP and TIMP levels may provide important data for selecting and following patients considered for treatment with drugs that interfere with MMP activity.

Preclinical and clinical evaluation of 5-fluorouracil biochemical modulation with folinic acid and hydroxyurea for patients with colorectal carcinoma.

BACKGROUND: Approximately 140,000 new cases of colorectal carcinoma will be diagnosed in 1995 in the United States, and more than one-third of these patients will die from progressive disease. Despite the modest improvement in response rate with chemotherapy, little improvement in patient survival has been noted. Consequently, the evaluation of new agents, modalities, and combinations is needed. METHODS: Two cell lines, HCT 116 and COLO 320 HSR, were treated with various concentrations of 5-fluorouracil (5-FU), folinic acid (FA), and hydroxyurea (HU). Subsequently, 41 patients with advanced, measurable metastatic colorectal carcinoma were enrolled in the study. Patients were treated with oral doses of HU (500 mg) every 8 hours on Days 1 and 2, 5-FU (400-500 mg/m2) intravenously Day 2 and FA (100 mg/m2) intravenously on Day 2 of every week for 6 consecutive weeks, followed by a 2-week rest period. All patients were evaluable for toxicity, and 40 were evaluable for response. RESULTS: In both cell lines, the combination of 5-FU/FA/HU consistently produced the best cytotoxic effect. Clinically, the maximum tolerated dose of 5-FU was established at a level of 500 mg/m2 (450 mg/m2 for patients older than 70 years of age). Ten patients experienced Grade 3 or 4 toxicity, consisting mainly of diarrhea. Eleven of 40 evaluable patients responded (three complete responses, eight partial responses), with a median survival of 12+ months and time to progression of 8.5+ months. CONCLUSION: The biochemical modulation of 5-FU with FA and HU were significantly effective in treating patients with metastatic colorectal carcinoma. Overall, this regimen was well tolerated with only moderate toxicity. Further studies incorporating intravenous HU as well as a randomized Phase III study of 5-FU/FA/HU versus 5-FU/FA are recommended.

Plasma assay of gelatinase B: tissue inhibitor of metalloproteinase complexes in cancer.

BACKGROUND: Matrix metalloproteinases (MMPs), especially gelatinase A and gelatinase B (GLB), are believed to be important components of the metastatic process. Tissue Inhibitors of Metalloproteinases (TIMPs) form complexes with MMPs and inhibit cancer dissemination. After local secretion, MMPs and their complexes with TIMPs leach into the blood stream where their concentration can be measured, thereby serving as surrogate markers of disease. Elevated plasma gelatinase B levels have been detected in gastrointestinal cancer and breast cancer. The goal of this study was to determine whether plasma GLB:TIMP complexes also are increased in cancer and whether these tests have potential use as prognostic tumor markers. METHODS: An enzyme-linked immunosorbent assay (ELISA) was developed to measure the plasma concentration of GLB:TIMP complexes in patients with cancer. Correlation between ELISA results and clinical outcome was sought. RESULTS: Plasma GLB:TIMP complexes were significantly increased in patients with gastrointestinal cancer and gynecologic cancer, but not in patients with breast cancer. When results from plasma GLB:TIMP complexes and plasma GLB assays were combined (GLB/complexes), abnormal levels of one or both assays were found in 36% and 65% of patients with gastrointestinal and gynecologic cancer, respectively. In Stage IV gastrointestinal cancer, patient survival was shorter (P < 0.001) in the group with increased plasma GLB/complexes than for those with normal plasma levels (4 months vs. 20 months, respectively). CONCLUSIONS: The assay of plasma gelatinase B and GLB:TIMP complexes may be clinically useful in predicting survival in subsets of patients with cancer. The possibility of using these assays in early stage cancer to predict metastasis should be studied.

Chlorpromazine-induced immunopathy: progressive increase in serum IgM.

Long-term chlorpromazine therapy has been associated with the asymptomatic development of a high incidence of antinuclear antibodies, coagulation inhibitors, and increased serum levels of IgM. The purpose of this study has been to characterize the natural history of this chlorpromazine-induced (CPZ) immunopathy. To this end we carried out a prospective study of schizophrenic patients with the immunopathy to compare the effect of continuing CPZ versus switching to haloperidol therapy. Although no marked differences were noted between the 2 groups at the end of 5 years, 6 of 29 patients who continued to receive CPZ, as compared to none of 14 patients on haloperidol, had progressive elevations of serum IgM. In spite of a high incidence of antinuclear antibodies, none of the patients developed a lupus-like syndrome. One patient, however, who had been maintained on CPZ for more than 15 years, developed Waldenström macroglobulinemia, as characterized by an IgM monoclonal gammopathy and a lymphocyte immunoglobulin heavy and kappa light chain gene rearrangement. Another CPZ-treated patient developed immune thrombocytopenia. Based on the potential serious sequelae of prolonged stimulation of the immune system by CPZ, we recommend that patients who develop an increase in serum IgM while on CPZ be switched to other types of anti-psychotic medications.