Cytosine arabinoside induced changes in natural killer and antibody dependent cellular cytotoxicity functions in multiple sclerosis patients.

Five multiple sclerosis patients were treated weekly with cytosine arabinoside (araC) on an escalating dose schedule. The dose was initiated at 50 mg/M2 and then increased once each week by 50 mg/M2 (unless toxicity caused delay). Dosage decisions were based on whether or not the antibody-dependent cellular-cytotoxicity (ADCC) or natural killer (NK) cytotoxicity levels had been reduced to a level more than 2 standard deviations below the control range. Cytosine arabinoside treatment was discontinued in 2 of 5 subjects at doses of 500 mg/M2 due to toxicity. The 3 remaining patients demonstrated sustained reductions in the percentage of FcR+ cells in their peripheral blood. The maximum percentage reductions from the baseline values ranged from 50% to 76%. Concomitant reductions in the NK activity at the same doses ranged from 65% to 83%. ADCC activity in all 3 patients, however, was relatively resistant to suppression. The nadirs for the ADCC activity were only 16% to 44% below the baseline minimum. AraC was shown to reduce the proportion of FcR+ cells and NK cytotoxic activity in preference to ADCC activity.

Suppression of natural killer cell cytotoxicity in the peripheral blood of patients receiving interferon therapy.

Lymphoblast interferon (IFN-alpha) was administered to patients with advanced stages of cancer in a phase I drug toxicity trial. IFN-alpha was given i.m. twice daily at 12-h intervals over a 7-day course of therapy in dosages ranging from 1.5 to 100 X 10(6) U/day. A total of 28 patients was studied, including 9 with breast carcinoma, 11 with other solid tumors, and 8 with lymphoid malignancies. Immune cell parameters were determined for each patient before, during, and up to 20 days after therapy. Leukopenia was evident after 1-2 days of IFN-alpha administration, became maximal after 6-7 days of therapy, and then returned to baseline values by day 13 post-therapy. Circulating natural killer (NK) cell activity was found to increase significantly by 2 h after the initial IFN injection, especially in patients receiving the higher dosages. However, most subjects demonstrated a return to baseline NK levels at 24 h despite the continued presence of elevated serum concentrations of IFN. By day 7 of therapy, NK-cell function was markedly depressed. Following cessation of IFN, NK levels rapidly returned to pretherapy baseline values. Changes in K-cell cytotoxic function (ADCC) tended to parallel those of NK-cell function. Although NK/K-cell function was affected by IFN therapy, no change in the percentage of circulating Fc receptor-bearing cells was found. This indicates that the cytotoxic cells were probably present in the circulation, but were not able to express their lytic function.

Effector cells in natural cytotoxicity against human bladder cancer cell lines.

Human peripheral blood mononuclear cells obtained by ficoll-hypaque sedimentation were depleted of Fc-receptor-bearing (FcR+) cells. Cytotoxicity (direct killing of target cells by effector cells), tested in a 40 h assay, was significantly decreased against a variety of target cells. Tests in which no FcR+ cells could be detected were also positive for "natural killing" (NK) against a spectrum of target cells from normal donors. NK in this system was mediated by more than one subpopulation of lymphocytes. Monocytes probably did not play a significant role. Decreasing the FcR+ cells in peripheral blood mononuclear cells in patients with bladder cancer and in controls did not reveal specific antitumor activity.