Mistletoe extract reduces the surgical suppression of natural killer cell activity in cancer patients. a randomized phase III trial.

BACKGROUND: Major surgery suppresses natural killer (NK) cell cytotoxic activity which is potentially harmful for cancer patients by favouring haematogenic tumour cell dissemination. The influence of a perioperative infusion of a standardized mistletoe extract (Iscador) on immune functions was tested in a prospective, sequential, randomized clinical trial. PATIENTS AND METHODS: Colorectal cancer patients undergoing open tumour resection were randomly assigned to either mistletoe infusion or no additional therapy. We hypothesized that mistletoe infusion improves NK cell activity and increases expression of MHC class II antigen HLA-DR on monocytes 24 h and 7 days after surgery, respectively. For statistical analysis we used a sequential study design. The decision boundaries for the two triangular tests were calculated for altogether 62 patients. RESULTS: The sequential study design allowed stopping the recruitment prematurely. NK cell activity differed significantly between the therapy groups 24 h after surgery (p = 0.027). The absolute number of HLA-DR molecules on monocytes did not differ 7 days after surgery. NK cell activity of patients treated with mistletoe extract did not change significantly during the course of the study (-7.9% 24 h after surgery), whereas HLA-DR expression changed significantly (-38.5% at day 7 after surgery). For control patients both parameters decreased significantly after surgery (NK cell activity: -44.4% at 24 h; HLA-DR expression: -32.9% at day 7 after surgery). CONCLUSION: Perioperative infusion of mistletoe extracts can prevent a suppression of NK cell activity in cancer patients. The impact of this therapy on relapse and survival should be tested in further studies.

Cytotoxic activity and absence of tumor growth stimulation of standardized mistletoe extracts in human tumor models in vitro.

Mistletoe extracts are widely used in complementary and alternative cancer therapy in Europe. The extracts possess cytotoxic, as well as immunostimulatory effects. However, some investigators have suggested that low doses of mistletoe extracts could also induce tumor growth. The mistletoe extracts Helixor A, Helixor M and Helixor P were investigated for growth inhibitory and stimulatory effects in a panel of 38 human tumor cell lines in vitro. Mistletoe lectin I (ML-1), adriamycin and interleukin-6 (IL-6) were used as reference compounds. All three mistletoe preparations showed cytotoxic activity [T/C (Test/Control) < 30%]: Helixor P was the most potent, followed by Helixor M and Helixor A with IC50 (50% inhibitory concentration) values of 68.4, 114 and 133 microg/ml, respectively. The IC50 values of ML-1 and adriamycin were 0.026 and 0.069 microg/ml. None of the human tumor cell lines in the panel showed growth stimulation (T/C (Test/Control) > 125%) by the mistletoe extracts or ML-1, apart from two exceptions in the colon carcinoma cell line HCC-2998, in which Helixor M and ML-1 showed a marginal stimulation (TIC 128% and 131%, respectively) at one concentration only. Further investigations into the latter effect of Helixor M and ML-1 in the HCC-2998 line using five different proliferation assays, modified cell culture conditions and the identical production charge of mistletoe extract, as well as a new one, did not confirm the previous observation. It was concluded that the marginal stimulation found in the earlier experiments was a statistical coincidence. Helixor mistletoe preparations and ML-1 have cytotoxic activity and do not stimulate tumor cell proliferation in vitro which is in accordance with previous scientifically based observations on aqueous mistletoe extracts.