No abstract

A B S T R A C T Recent studies indicate that oxygen radicals such as superoxide or singlet oxygen may be important in the functional activity of human granulocytes. We have examined the possible importance of these radicals in the functional capacity of human blood monocytes. Monocytes, like granulocytes, generate chemiluminescence during phagocytosis. Chemiluminescence is impaired 50-90% by superoxide dismutase, an enzyme which enhances the dismutation of superoxide to hydrogen peroxide. These results indicate that superoxide is related to the chemiluminescence generated by monocytes. Superoxide dismutase in a concentration which impaired chemiluminescence also impaired the staphylococcal killing by monocytes. Hexose monophosphate shunt activity and hydrogen peroxide production by granulocytes and monocytes were also evaluated. The oxidation of [1-14C]glucose was used as a measure of hexose monophosphate shunt activity and the oxidation of ["4C]formate as an estimation of hydrogen peroxide production. The oxidation of both substrates by monocytes was increased during phagocytosis but, in contrast to results in granulocytes, was not further increased by the addition of superoxide dismutase.These data indicate that superoxide may be important in bactericidal activity of human monocytes. Our results also suggest that the metabolism of oxygen radicals in monocytes and granulocytes may be different.

A randomized trial was conducted by the Southwest Oncology Group (SWOG) in advanced carcinoma of the stomach and pancreas. Patients were assigned to receive monthly 5-fluorouracil 96-hour continuous infusions with either bolus mitomycin-C or oral methyl-CCNU. Mitomycin-C and methyl-CCNU were administered every eight weeks. The 5 FU-mitomycin combination produced a 14% and 22% response rate in disseminated stomach and pancreatic carcinoma, respectively. The combination of infusion 5 FU and methyl-CCNU achieved responses in 9% and 5% of stomach and pancreatic tumors, respectively. There was no significant difference in survival between limbs for either tumor. Median survival in gastric carcinoma on the 5 FU-mitomycin regimen was 25 weeks vs. 18 weeks on the 5 FU-METHYL-CCNU arm. In pancreatic carcinoma median survival on the mitomycin limb was 19 weeks as compared to 17 weeks on the methyl-CCNU program. Leukopenia was greater for the first course on the mitomycin limb. Regression analysis demonstrated that performance status was the most important pretreatment characteristic for predicting survival in both tumors. Neither 5 FU infusion combination appears to significantly alter the dismal prognosis of advanced upper gastrointestinal neoplasms.

Intracellular and extracellular superoxide (O2.-) generation by human monocytes and macrophages was quantitated by the nitroblue tetrazolium (NBT) reduction method. Human monocytes reduced 4.4 +/- 0.9 nmoles/10(6) cells/15 minutes with an increase to 12.4 +/- 1.3 during phagocytosis of zymosan. Based on inhibition by superoxide dismutase, superoxide generation of these cells was 1.8 +/- 0.9 nmoles in the resting state and 16.8 +/- 2.8 nmoles with zymosan phagocytosis. Human macrophages obtained by thoracentesis had comparable levels of NBT reduction and O2.-generation. Monocytes from a patient with chronic granulomatous disease demonstrated no increment in O2.-production during phagocytosis. Thus, human monocytes and macrophages appear capable of generating substantial amounts of O2.-during phagocytosis which may play an important role in bactericidal and other cell functions.

These results suggest that gemcitabine plus docetaxel or irinotecan is well tolerated in patients with chemotherapy-naïve advanced NSCLC. The survival data with the combination gemcitabine-docetaxel are promising. Gemcitabine-docetaxel combination therapy may be particularly useful for patients who have experienced toxicities with a platinum regimen or in patients who may be more susceptible to platinum-related toxicity.