Initial experiences with serum alkaline DNase activity in monitoring the effects of therapy for carcinoma of the uterine cervix.

The objective was to evaluate if variations in serum alkaline DNase activity (SADA) can predict the effects of therapy in women with early stages of primary cervical carcinoma. 29 out of 33 patients had no evidence of disease after therapy. Only 5 out of the 29 women showed increased SADA levels after therapy compared with the pretreatment SADA value. Of the 4 women with evidence of disease after therapy, 3 had unchanged or decreased SADA levels. We conclude that serum alkaline DNase activity seems to have little to offer in predicting the effects of treatment in stage I and stage II cervical carcinoma.

Prognostic significance of pretreatment serum levels of squamous cell carcinoma antigen and CA 125 in cervical carcinoma.

Serum levels of squamous cell carcinoma antigen SCC, carcinoembryonic antigen CA 125, and tissue polypeptide antigen were determined in 142 patients with primary cervical carcinoma, 60 patients with precancerous lesions and in 129 healthy women. With regard to elevated tumour marker levels, specificity ranged from 94.6% to 97.7%. Sensitivity was highest (44.4%) for SCC. A stage relation was found for all tumour markers except for carcinoembryonic antigen. In stage Ib, SCC levels increased according to tumour volume. SCC, CA 125 or both markers were elevated in 7 of 8 patients with pelvic lymph node metastases compared with only 17 of 58 patients with negative nodes (P = 0.005). In a multivariate analysis, pretreatment serum levels of SCC and CA 125 were found to be significantly related to patient survival, in addition to stage. In cervical SCC, the risk of a fatal outcome increased 16 times with SCC levels > or = 4.5 ng/ml, compared with SCC levels < or = 1.3 ng/ml. We conclude that pretreatment serum levels of SCC may be of value as an adjunct to clinical staging. In addition, serum determinations of SCC and CA 125 seem to be useful in predicting the risk of pelvic lymph node metastases and as prognostic risk factors for disease outcome.

Cyclic guanosine 3',5'-monophosphate mediates 3-morpholinosydnonimine-induced inhibition of human natural killer cells.

Nitric oxide (NO) donors were used to investigate the effect of NO on and the role of cyclic GMP in the regulation of human natural killer (NK) cell function. NO-producing drugs, molsidomine and its metabolite 3-morpholinesydnonimine (SIN-1), inhibited NK cell-mediated cytotoxicity significantly at 0.04-5 mM. At 1 mM, SIN-1 completely inhibited NK cell activity while molsidomine decreased NK cell-mediated cytolysis by 35% of the control value. These data suggest that NO from exogenous NO-donors may down-regulate NK cell cytotoxic function. The stimulatory effect of interferon-gamma (IFN-gamma) on human NK cell-mediated killing could not overtake the NK cell inhibition induced by the NO releasing drugs, indicating different modes of action for IFN-gamma and SIN-1. The results in the present study also showed that SIN-1 (1 mM) stimulated cyclic GMP production 37-fold in NK cells. In the presence of 0.5 mM IBMX, a phosphodiesterase inhibitor, the increase in cyclic GMP was even more pronounced, demonstrating a relation between cyclic GMP stimulation and NK cell inhibition by SIN-1. Further evidence for mediation via cyclic GMP was provided by the finding that methylene blue (20 microM), an inhibitor of soluble guanylate cyclase, decreased both the inhibition of SIN-1-induced NK cell cytotoxicity as well as cyclic GMP formation. Moreover, membrane-penetrating cyclic GMP and its analogues inhibited NK cell-mediated cytolysis significantly. Molsidomine was without effect on cyclic GMP levels. Our data indicate that cyclic GMP may play a role in human NK cell regulation and suggest that the inhibitory effect of cGMP may be elicited by NO.

Influences of diet and surgical trauma on serum alkaline DNase activity levels.

Changes in serum alkaline DNase activities might predict the therapeutic response in various malignant diseases. A decrease in serum alkaline DNase activity within days from the onset of therapy has been related to tumour necrosis and may be a possible sign of clinical response to effective treatment. To study if changes in serum alkaline DNase activity could be induced by non-tumour related tissue destruction, sera were collected on several occasions perioperatively in 18 patients undergoing surgery for benign gynaecological disease. Thirty apparently healthy women served as the control group. A significant decrease (P less than 0.001) in serum alkaline DNase activity was observed after an overnight fast in both groups of women. In contrast to the control women, the operated patients showed a significant decrease (P less than 0.001) in serum alkaline DNase activity throughout the operative period and 1 week postoperatively. We conclude that serum alkaline DNase activity is influenced by dietary factors as well as surgical trauma. These factors may limit the clinical usefulness of SADA in patients with cancer.

Nitric oxide synthase pathway may mediate human natural killer cell cytotoxicity.

The present study provides evidence that the human natural killer (NK) cell effector mechanism causing target cytolysis has a requirement for L-arginine. In a deficient medium (DM) containing only salts, buffer system and glucose, NK cell-mediated cytotoxicity was found to decrease by 70% as compared to that obtained in a complete medium (CM). However, adding L-arginine to such DM could restore the activity of NK cells to the normal level. Many other components of CM, such as serum, glutamine and vitamins did not improve NK cell-mediated killing in DM. When all amino acids except L-arginine were added to DM only a partial recovery of NK cell functional cytolysis was seen. L-arginine enhanced the NK cell activity in a dose-dependent manner. Additionally, the inhibitor of both inducible and constitutive nitric oxide synthase, N-monomethyl-L-arginine (L-NMMA) inhibited NK cytolytic activity in DM supplemented with L-arginine indicating participation of nitric oxide (NO). The results also show that the stimulatory effect of L-arginine on human NK cell-mediated cytotoxicity was accompanied by an increase in NO formation as determined by accumulation of nitrite and citrulline. L-NMMA gave a dose-dependent reduction in NO generation as well. The nitrite and citrulline production dose-dependently correlated with not only the concentration of L-arginine in the cultivation medium, but also the enhanced NK cell-mediated cytolysis. Taken together, these findings could define a L-arginine/NO-linked effector mechanism in human NK cells. Nitrite and citrulline were not formed when NK cell-mediated target cell killing took place in a L-arginine-free DM supplemented with additives. Thus, it appears as if human NK cells may cause target cell killing via both NO-dependent and -independent processes.

Immunosuppressive properties of plasma and lymphocytes from the human retroplacental blood.

The retroplacental compartment in which maternal blood is in direct and continuous contact with trophoblasts derived from the fetus seems to be the place where maternal and fetal cells regulate each others' activities. To assess the role of the retroplacental compartment in the immune regulation of pregnancy, 10 healthy pregnant women were selected for evaluation of the immune activity of their lymphocytes and plasma from the retroplacental blood. The results showed that the proliferation and cytotoxic capacity of these lymphocytes, but not of maternal peripheral lymphocytes, against fetal cells were significantly inhibited in undirect mixed lymphocyte culture and direct cell-mediated cytotoxic assay, respectively. The plasma from retroplacental blood showed significant immunosuppressive properties and depressed the proliferation of maternal peripheral lymphocytes stimulated by fetal HLA as well as the cytotoxic activity of these cells against the fetal lymphocytes. The present data suggest that the retroplacental compartment seems to be an immunosuppressive barrier, protecting the fetus from maternal rejection.