Homeopathic mistletoe adverse reaction mimics nodal involvement in 18F-FDG PET/CT performed for evaluation of response to chemotherapy in lymphoma.

Some patients use complementary medicine. We present a patient with Hodgkin's lymphoma, scanned with 18F-FDG PET/CT for evaluation of response after chemotherapy, who was self-administering mistletoe as a homeopathic medicine product. The careful review of the images of the entire scan and patient collaboration in anamnesis were crucial to avoid a false positive result. A review of the published scientific data on the effects of mistletoe is also presented.

Dose-finding design using mixed-effect proportional odds model for longitudinal graded toxicity data in phase I oncology clinical trials.

Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. This dose is typically defined as the dose associated with a certain probability of severe toxicity during the first cycle of treatment, although toxicity is repeatedly measured over cycles on an ordinal scale. We propose a new adaptive dose-finding design using longitudinal measurements of ordinal toxic adverse events, with proportional odds mixed-effect models. Likelihood-based inference is implemented. The optimal dose is then the dose producing a target rate of severe toxicity per cycle. This model can also be used to identify cumulative or late toxicities. The performances of this approach were compared with those of the continual reassessment method in a simulation study. Operating characteristics were evaluated in terms of correct identification of the target dose, distribution of the doses allocated and power to detect trends in the risk of toxicities over time. This approach was also used to reanalyse data from a phase I oncology trial. Use of a proportional odds mixed-effect model appears to be feasible in phase I dose-finding trials, increases the ability of selecting the correct dose and provides a tool to detect cumulative effects.

Phase I trial of r viscumin (INN: aviscumine) given subcutaneously in patients with advanced cancer: a study of the European Organisation for Research and Treatment of Cancer (EORTC protocol number 13001).

Safety of aviscumine by subcutaneous route was assessed in patients with advanced cancer refractory to chemotherapy. Patients with progressive disease received escalating doses twice weekly. Treatment of the accrued 26 patients (10 colorectal cancer (CRC), 6 soft tissue sarcoma (STS), 5 melanoma (MM), 5 others) was well tolerated without substance-related grade 3 or 4 toxicities. Grade 1/2 toxicities were predominantly injection site reactions. Aviscumine lacked dose-limiting toxicity (DLT) up to a maximal dose of 10 ng/kg. An increase of interleukin-1 beta and interferon-gamma from baseline was seen in the patient's plasma between the 1st and 11th injection. Highest release of both cytokines was in the dose range of 4-5.9 ng/kg. Interferon-gamma was not detected after doses higher than 6 ng/kg. Eight patients (5 CRC, 1 MM, 1 STS, 1 RCC) had disease stabilisation for 79-250 days (median122 days) associated with an increase of interleukin (IL)-1 beta and interferon (IFN)-gamma. Aviscumine was well tolerated and appeared to possess clinical activity at a biologically active dose between 4 and 6 ng/kg.

Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model.

This study investigates the effects of mistletoe lectin-I (ML-I) on melanoma growth and spread in vivo. The human melanoma cell line MV3 was xenografted into severe combined immunodeficient mice and vehicle solution or purified ML-I was administered at 30, 150 and 500 ng per kg body weight (20 mice per group) daily. After 19 days, mice were killed, primary tumours (PTs) and lungs were dissected out, and tumour weights, number of lung metastases (LMs), number of tumour-infiltrating dendritic cells (DCs), and apoptosis rates in the melanoma cells and in the DCs were assessed. A 35% reduction of PT weight (P=0.03) and a 55% decrease in number of LMs (P=0.016) were evident for low-dose ML-I (30 ng kg(-1)) treatment but not for higher doses. Mistletoe lectin-I increased apoptosis rates in the melanoma cells of PTs at all doses, while no induction of apoptosis was noted in the LMs. Low-dose ML-I significantly increased the number of DCs infiltrating the PTs (P<0.0001) and protected DCs against apoptosis, while higher doses induced apoptosis in the DCs (P<0.01). Our results demonstrate that low-dose ML-I reduced melanoma growth and number of metastases in vivo, primarily due to immunomodulatory effects.

The proteasome inhibitor bortezomib augments anti-proliferative effects of mistletoe lectin-I and the PPAR-gamma agonist rosiglitazone in human melanoma cells.

BACKGROUND: The NFkappaB signalling pathway plays an important role in chemoresistance and decreased apoptosis. One indirect way to inhibit the NFkappaB pathway is to slow down the proteasomal degradation of its inhibitor IkappaB, thus preventing NFkappaB from translocation into the nucleus. Hence, the effect of the proteasome inhibitor bortezomib (Velcade) on the cell proliferation of the MV3, FemX-1 and G361 human melanoma cell lines and its action in combination with the PPAR-gamma agonist rosiglitazone or the mistletoe lectin ML-I, both having anti-proliferative effects on melanoma cells in single agent use, was investigated. MATERIALS AND METHODS: Proliferation of melanoma cells under the different treatment regimes over a broad concentration range (0.0001-100 microg/ml) was assessed by means of the XTT cell proliferation assay. RESULTS: At a concentration of 0.1 microg/ml bortezomib significantly reduced the proliferation rate of all melanoma cells to 1-13% of the control, which was mediated through increased apoptosis and inhibition of NFkappaB expression. Furthermore, the combination of bortezomib and rosiglitazone was the most potent and increased the effectiveness against melanoma cell growth by 63-71% (compared to single use of rosiglitazone) and by 27-39% (compared to single use of bortezomib), respectively. CONCLUSION: This combination strategy might be a promising approach for future melanoma therapy.

Using the continual reassessment method: lessons learned from an EORTC phase I dose finding study.

Many clinicians often do not feel comfortable with the Continual Reassessment Method (CRM). This article reviews its implementation, showing the characteristics, advantages and limitations of this method in Phase I studies as an alternative to the classical 'Fibonacci' escalation schema. A two center, dose escalation phase I study of rViscumin was carried out. Thirty-seven patients were included at 14 different dose-levels (10 to 6400 ng/kg). The complete clinical results are presented elsewhere. A 2-step CRM design enables one to speed-up the study and most importantly to obtain an accurate estimate of the maximum tolerated dose (MTD). Different management issues related to a multicenter study are illustrated and we show how the method can go wrong when severe toxicity, or dose limiting toxicity (DLT), is not considered by the clinician as being sufficient to limit dose escalation (here a grade 3 asthenia related to the drug). This would have affected any dose finding methods. We believe that CRM is a good alternative to the standard method from both a statistical and a practical point of view but further methodological research is necessary to address the issues related to the composite nature of the endpoint.

Quality of life is improved in breast cancer patients by Standardised Mistletoe Extract PS76A2 during chemotherapy and follow-up: a randomised, placebo-controlled, double-blind, multicentre clinical trial.

The objective of this randomised, multicentre, double-blind clinical trial was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to mistletoe lectins, on quality of life (QoL) in breast cancer patients. A total of 352 patients were randomly allocated to 2 groups receiving PS76A2 (15 ng mistletoe lectin/0.5 ml) or matching placebo twice weekly for 4 to 6 cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy followed by 2 months follow-up. The primary efficacy end-point was the change from baseline of 3 FACT-G subscales (physical, emotional and functional well-being) during the fourth CMF cycle. Secondary measures included GLQ-8 (8 linear analogue self-assessment scales), Spitzer's uniscale and haematological variables. The main variables of safety analysis were adverse events, including injection site reactions and clinical laboratory tests. The results showed that physical, emotional and functional well-being improved upon PS76A2, but deteriorated following placebo. The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G, which was analysed as O'Brien's rank sum of its 3 subscales: The total score increased by 4.40 +/- 11.28, indicating a higher QoL after PS76A2, but decreased by 5.11 +/- 11.77 with placebo (p<0.0001). The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 (sum of item nos. 1, 5, 6, 7, 8) and GLQ-3 (sum of item nos. 2, 3, 4). GLQ-5 characterises typical aspects of QoL, while GLQ-3 consists of 3 side-effects of CMF (feeling sick, numbness or pins and needles, loss of hair). GLQ-5 decreased by 42.9 +/- 125.0 upon PS76A2, indicating an improvement in QoL, but increased by 60.3 +/- 94.0 upon placebo (p<0.0001). GLQ-3 deteriorated in both groups (PS76A2: 13.9 +/- 52.4; placebo: 34.5 +/- 57.0), but the differences in favour of PS76A2 were, nevertheless, statistically significant (p=0.0007). The total score GLQ-8 improved by 28.9 +/- 154.6 after PS76A2 and deteriorated by 94.8 +/- 141.1 after placebo (p<0.0001). Spitzer's uniscale improved by 12.2 +/- 30.7 upon PS76A2 and deteriorated by 10.8 +/- 26.1 with placebo (p<0.0001). After follow-up without chemotherapy, a significant treatment difference in favour of PS76A2 was determined by means of FACT-G, GLQ-8 and Spitzer's uniscale. PS76A2 was well tolerated in this trial, with the exception of slight local reactions in 17.6% of the PS76A2 group. In conclusion, PS76A2 (15 ng mistletoe lectin/0.5 ml twice weekly) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up.

Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts.

BACKGROUND: In single case observations, tumour remissions after intratumoral injections of mistletoe extracts have been described. MATERIALS AND METHODS: We investigated the antitumour activity of intratumorally (i.t.)-injected lectin-rich mistletoe extract at different dosages and i.t.-injected mistletoe lectin I in comparison to intravenous (i.v.) Gemcitabine and i.t. treatment with placebo in a human pancreatic cancer xenograft. RESULTS: In a preliminary dose-response experiment, the most marked tumour inhibition was induced when mistletoe extract was given at 8 mg/kg body weight (BW) and mistletoe lectin I at 5.3 microg/kg BW. In a second experiment, bi-weekly i.t. injections of mistletoe extract over 8 weeks resulted in a very high antitumour activity with an optimal T/C value (=median relative tumour volume of the test group vs. the control) of 0.4% combined with 3/8 partial and 3/8 complete remissions. Gemcitabine was less active with 2/8 partial and 1/8 complete remissions and an optimal TIC of 4.6%. CONCLUSION: I.t.-injected lectin-rich mistletoe extract should be further evaluated in patients with inoperable locally advanced pancreatic cancer.

Weekly 24 h infusion of aviscumine (rViscumin): a phase I study in patients with solid tumours.

Aviscumine is a ribosome-inactivating protein with potent antitumour activity in vitro and in vivo and is an Escherichia coli-derived recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a prolonged infusion of aviscumine in cancer patients. Aviscumine was given once weekly as a 24 h central intravenous infusion in patients with advanced, refractory progressive solid malignant tumours. Fourteen fully eligible patients (11 male, 3 female) with a median age 58 yrs (range 41-77) were enrolled. They had histologically verified disease, were 18 yrs old, had an ECOG PS 2 and adequate bone marrow, liver and renal function. DLT was defined as any non-haematological grade 3-4 toxicity (Common Toxicity Criteria [CTC] version 2.0), neutrophil count <500/ microl for 7 days, febrile neutropenia or thrombocytopenia grade 4. The MTD was defined as the dose level below the dose at which 2 patients per dose level experienced a DLT during the first treatment cycle. Colorectal cancer, soft tissue sarcoma and pancreatic cancer were the most common tumour types. Dose levels of aviscumine ranged from 4 to 6 microg/kg. The median number of cycles was 2.8 (range, 2-8). Common side effects in cycle 1 were fatigue, fever, nocturia, urticaria, erythema and pruritus. DLTs occurred in 2/3 patients on the 6 microg/kg dose level and consisted of increases in ASAT grade 3, ALAT grade 3, gammaGT grade 3/4, hypokalemia grade 3 and fatigue grade 3. No DLTs were observed on dose levels 4 and 5 microg/kg. The best response (RECIST) was stable disease in 4 pts, lasting for 4-8 cycles. Pharmacokinetics indicated that potentially active plasma levels of the compound were maintained during the entire infusion. We conclude that the recommended dose for weekly 24 h infusions of Aviscumine should be 5 microg/kg.

Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group.

BACKGROUND: Aviscumine is an Escherichia coli-derived recombinant type II ribosome-inactivating protein with potent antitumor activity in vitro and in vivo. It is the recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the intravenous (i.v.) administration of aviscumine in cancer patients. Translational research included the evaluation of pharmacokinetics and monitoring of plasma cytokine and anti-aviscumine antibody induction after administration of the drug. PATIENTS AND METHODS: Aviscumine was given twice weekly as a 1 h central i.v. infusion in patients with advanced, refractory progressive, solid malignant tumors who had not been previously exposed to natural mistletoe preparations. They had histologically or cytologically verified disease, were > or =18 years old, had an Eastern Cooperative Oncology Group performance status < or =2 and adequate bone marrow, liver and renal function. DLT was defined as any non-hematological grade 3-4 toxicity (National Cancer Institute Common Toxicity Criteria version 2.0), neutrophil count <500/microl for > or =7 days, febrile neutropenia or thrombocytopenia grade 4. The MTD was defined as the dose at which >20% of patients experienced DLT during the first treatment cycle. The Continual Reassessment Method was used to determine the number of patients required per dose level. RESULTS: Forty-one fully eligible patients (19 male, 22 female) with a median age of 56 years (range 37-74) were enrolled. Colorectal, ovarian, renal cell and breast cancer were the most common tumor types. Dose levels of aviscumine ranged from 10 to 6400 ng/kg. The median number of cycles was two (range one to eight). Common clinical toxicities in cycle 1 were fatigue, fever, nausea, vomiting and allergic reactions. Fatigue grade 3 was dose limiting in one of six patients at 4000 ng/kg and reversible grade 3 liver toxicity (elevation in alkaline phosphatase, transaminases and/or gamma-glutamyltransferase) occurred in one of 10 patients at 4800 ng/kg and in two of five patients at 6400 ng/kg. The best response (RECIST criteria) was stable disease in 11 patients, lasting for two to eight cycles. The pharmacokinetic evaluation revealed a short alpha half-life of 13 min and linear kinetics on dose levels > or =1600 ng/kg. Aviscumine stimulated the immune system with a release of cytokines such as interleukin (IL)-1beta, IL-6 and interferon-gamma, and induced immunoglobulin (Ig) G- and/or IgM-anti-aviscumine antibodies of uncertain clinical relevance. CONCLUSIONS: The recommended dose for further clinical trials is 5600 ng/kg twice weekly. Based on the short half-life of the recombinant protein observed in this trial, the exploration of prolonged infusion schedules of aviscumine is warranted.

The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial.

Patients with breast cancer receiving adjuvant chemotherapy frequently suffer from a restricted quality of life (QoL) due to the side-effects of chemotherapy and the consequences of coping with the diagnosis. Therefore, the objective of this clinical study was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to the galactoside-specific mistletoe lectin, on QoL by performing a placebo-controlled trial. Overall, 272 patients with breast cancer receiving adjuvant CMF chemotherapy (cyclophosphamide-methotrexate-fluorouracil) were enrolled and randomised to groups receiving placebo or PS76A2 at concentrations of 10, 30 or 70 ng mistletoe lectin (ML) per ml. The patients received 0.5 ml study medication twice weekly subcutaneously for 15 consecutive weeks (4 CMF cycles). Primary variables were the self-assessment QoL scores GLQ-8 (Global Life Quality) and Spitzer's uniscale. As a result, statistically significant effects on QoL were obtained with the medium dose (15 ng ML/0.5 ml). The treatment difference between the medium dose and placebo with regard to the GLQ-8 sum was 60.8 mm (95% confidence interval: 19.3 to 102.0 mm). The treatment effect for Spitzer's uniscale between the medium dose and placebo was 16.4 mm (95% confidence interval: 6.3 to 26.6 mm). The results on QoL were supported by an increase of T helper lymphocytes (CD4+) and the CD4+/CD8+ ratio (p<0.05). Overall, PS76A2 was well tolerated. Local reactions at the injection sites occurred dose-dependently, but were mild at the low and medium dose levels.

Use of alternative medicine by patients with cancer in a rural area of Switzerland.

BACKGROUND: Many cancer patients use alternative therapies in addition to conventional treatment. In a survey among such patients, we assessed the prevalence of and the motivation for alternative therapy use in a rural area of Switzerland. METHODS: From 1st February to 30th November 2001, we interviewed 108 patients treated in the oncology outpatient clinic of the Langenthal District General Hospital, Switzerland, using a structured questionnaire. 77% of the patients were female. 49% of the patients (i.e., 64% of the female patients) suffered from breast cancer. RESULTS: 42 (39%) of all patients had used an alternative therapy in addition to conventional treatment at least once. Mistletoe preparations were by far the most popular with a prevalence of 74%. Homeopathy (24%) and cancer diets (12%) were used less often. 79% of the patients seeking help from alternative treatment informed their treating oncologist and/or medical practitioner accordingly. 57% of the doctors encouraged their patients to continue the alternative treatment, none discouraged the patient to do so. The main reasons for the use of alternative therapy were: the desire to feel more hopeful (83%); "to do as much as possible myself to cure the disease" (83%); and to harness mental energy (62%). Only 19% of the patients hoped to be cured of cancer by alternative therapy. CONCLUSIONS: The motivation to seek help from alternative treatment is not based on a distrust of conventional care. Maintaining hope and taking an active role in self-care are the main stimuli for using alternative medicine.

The effect of formulation variables on the stability of nebulized aviscumine.

The pulmonary drug delivery of proteins present an alternative to parenteral and oral administration. Nebulization of aqueous protein solutions is an ideal method for pulmonary application of therapeutic proteins considering the difficulties of their formulation as MDIs or DPIs. This research presents the effect of variable excipients on the stability of freeze-dried aviscumine after reconstitution and nebulization. Formulations containing different lyoprotectants have been lyophilized and reconstituted with isotonic salt solution. The loss of aviscumine activity in the nebulizer reservoir and after nebulization with a PariBoy air-jet nebulizer, a Multisonic ultrasonic nebulizer and a Systam ultrasonic nebulizer was determined by a binding assay. The effect of variable lyoprotectants such as 8% (w/v) Dextran T1, HES130, HES450, HP-beta-CD and 6% (w/v) HES450 plus 2% (w/v) mannitol on the stability of aviscumine to air-jet and ultrasonic nebulization has been evaluated. Only 50% of aviscumine activity was retained after 20 min nebulization, where 8% (w/v) HES450 was shown to be the best stabilizer. Stabilization of aviscumine by the addition of variable surfactants as 0.01 and 0.1% (w/v) Poloxamer 188, 0.03 and 0.1% (w/v) PEG 8000, 0.03 and 0.1% (w/v) Solutol HS15 and 0.03 and 0.1% (w/v) octanoyl-N-methyl-glucamide to the reconstitution solution has also been studied. By the addition of 0.03% (w/v) octanoyl-N-methyl-glucamide, 70% of the activity was retained after 20 min nebulization.

Effect of excipients on the stability and aerosol performance of nebulized aviscumine.

Pulmonary delivery is an attractive alternative route to deliver protein drugs that are currently delivered by injection. Inhalation therapy via nebulizers is a well accepted way for pulmonary application of proteins considering the formulation difficulties of MDIs or DPIs. This research presents the effect of variable excipients on the stability and aerosol performance of freeze-dried aviscumine after reconstitution and nebulization. Aviscumine formulations containing 100 mmol/L Tris buffer, 0.1% (w/v) Polysorbate 80, 0.01% (w/v) Na(2)-EDTA and 8% (w/v) Hydroxyethyl starch have been lyophilized and reconstituted with a buffered isotonic solution pH 8. The aviscumine activity was determined by a binding assay directly after reconstitution and after nebulization with a PariBoy air-jet nebulizer, a Multisonic and a Systam ultrasonic nebulizer. The stabilization of aviscumine by the addition of variable buffer salts to the reconstitution medium, such as 50, 100, and 200 mmol/L Tris buffer, 20 and 100 mmol/L phosphate buffer, and 20 and 100 mmol/L Tricine buffer, was studied. About 50% of aviscumine activity was lost after 20 min nebulization time without any additives. Nevertheless, higher buffer concentrations confer greater stability. About 70% of the aviscumine activity could be retained by the addition 0.03% octanoyl-N-methylglucamide and 100 mmol/L Tricine to the reconstitution medium.

Food safety and risk assessment: naturally occurring potential toxicants and anti-nutritive compounds in plant foods.

The centralisation and globalisation of the world food supply presents opportunities for massive epidemics of food borne illness. Food processing generally decreases exposure to naturally occurring toxicants. A significant number of deaths are caused in both developed and developing countries from the consumption of naturally occurring toxicants and this exceeds the numbers attributable to artificial food contaminants and pollutants. The risk posed by naturally occurring toxicants is greater in developing countries where food choice and facilities for food processing are limited. The main risk in developed countries is from food important from areas where food safety controls are inadequate. Toxins derived from marine algae present a specific threat to health especially as seafood is being traded from areas where poisoning by algal toxins is known to occur. A systematic approach to food safety using HACCP methodology and identity preservation of the food are crucial in the prevention of food related illness. There is also a need for international agreed standards for tolerable levels of naturally occurring toxicants in foodstuffs but these should derived not be set unreasonably low as this would threaten food security in developing countries. The occurrence of a number of fatalities in developing countries among people consuming herbal teas and dietary supplements underscores the need to assess the safety of these products before they are placed on the market.

[Blood and tissue eosinophilia, mistletoe lectin antibodies and quality of life in a breast cancer patient undergoing intratumoral and subcutaneous mistletoe therapy]. / Blut- und Gewebseosinophilie, Mistellektin-Antikörper und Lebensqualität bei einer Mammakarzinom-Patientin unter intratumoraler und subkutaner Misteltherapie.

BACKGROUND: Mistletoe therapy (MT) is a method of complementary medicine whose efficacy is controversially discussed. Until now there is a lack of data of high-dose intratumoral application. PATIENT AND METHODS: We are presenting a 3-year follow-up of an 80-year-old woman with metastasized breast cancer (c(2)T3/N1/M1) receiving combined intra- and peritumoral and subcutaneous MT with ABNOBAviscum(r) and concomitant pamitron acid. At time of admission the patient had bone metastases (thoracic vertebra 11 fracture), a lymphangiosis carcinomatosa, bilateral pleural effusions, and a reduced quality of life (QoL). RESULTS: Under MT we induced an eosinophilia and an elevation of eosinophil cationic protein (ECP). Simultaneously, we ascertained a reduction of 50% of Ca 15-3 and a sustained partial tumor remission. After 5 months the mistletoe-lectin-1 antibodies IgG-1 and -3 were maximally increased and we perceived a second Ca 15-3 reduction. After 3 months we observed a benefit in QoL. During the following 5 months the patient gained about 10 kg in weight. In the second year slow tumor progress was observed. After 19 months the patient had pneumonia which caused an MT pause. Subsequently, a combined intratumoral mistletoe and letrozol therapy brought a partial remission. The patient lived without chemo and radiation therapy more than 3 years with good QoL and died after 41 months, after a sepsis and a following stroke without signs of tumor progress. CONCLUSION: In metastasized breast cancer a palliative high-dose local MT can make a contribution to a tumor reduction and a benefit in QoL.

In vivo-induction of antibodies to mistletoe lectin-1 and viscotoxin by exposure to aqueous mistletoe extracts: a randomised double-blinded placebo controlled phase I study in healthy individuals.

BACKGROUND: Several studies have been performed in tumour patients to analyse the immunological response to mistletoe extracts. Considering the fact that these extracts are given subcutaneously in most instances, the kind of application resembles a typical immunization schedule. We therefore wanted to see how those extracts act on immunocompetent cells of healthy individuals hoping that this kind of provocation test may give new informations about a more specific application of these extracts in certain diseases. SUBJECTS/METHODS: 47 healthy individuals were exposed for twelve weeks either to Iscador Quercus special (IQ) known to be rich in mistletoe lectin (ML)-1 (n = 16), to Iscador Pini (IP) being poor in ML-1 but enriched in viscotoxins (n = 15), or to placebo (physiological saline) (n = 16) in a randomised, double-blinded placebo-controlled study. Humoral immunoreactivity was analysed by measuring antibodies towards the two compounds ML-1 and viscotoxin VA2 (VA2). Sera were collected in intervals of four weeks up to week 12 and again three months after last exposure. RESULTS: None of the subjects had antibodies to ML-1 or VA2 before exposure. In week 12, anti-ML-1 antibodies of the IgG-type were found in all 16 IQ-treated individuals but only 6 of the 15 probands exposed to IP. In contrast, anti-VA2 IgG-antibodies could be detected in all individuals of both groups. The antibodies were preferentially of the IgG1 and IgG3 type while antibodies of the IgA and IgM type were produced only in a few probands. Antibodies of the IgE-type occurred only in the IQ-exposed individuals and were directed against ML-1 but not VA2. None of the probands receiving placebo developed antibodies to ML-1 or VA2. Severe side effects were not observed in any of the probands. CONCLUSIONS: These data obtained in healthy individuals clearly indicate that IQ and IP-extracts can induce antigen-specific humoral responses. They may, therefore, provide, a solid basic for the evaluation of the humoral immune response in disease states.

Dietary mistletoe lectin supplementation and reduced growth of a murine non-Hodgkin lymphoma.

The growth of a murine non-Hodgkin lymphoma (NHL) tumour has been shown to be reduced by incorporating mistletoe lectin (ML-1) into the diet. The morphological characteristics of NHL tumours in mice fed ML-1-supplemented diets were different from those in LA (control)-fed mice. The degree of mitotic activity was lower and nuclear area reduced. The degree of lymphocyte infiltration was increased in tumours from ML-1 fed mice and this was accompanied by a high incidence of apoptotic bodies. Visual observation of NHL tumours from individuals fed ML-1 diet showed a poorly developed blood supply in contrast to control-fed mice. A major reduction in number of blood capillaries in NHL tumours was confirmed by microscopic evaluation of tumour sections. The results suggested an anti-angiogenic response in ML-1-fed mice. The feeding of ML-1 compared to control diet thus provided several identifiable changes in the morphology of NHL tumours which were consistent with the observed reduction in tumour weight. There was no longer histological evidence of viable tumour in 25% mice fed the ML-1 diet for 11 days. Morphological studies of the small bowel indicated (a) that the lectin induces hyperplasia, and (b) that the lectin binds avidly to lymphoid tissue of Peyer's patches. There was evidence of limited endocytosis of the lectin. An experiment where ML-3 was added to the diet of mice three days after inoculation of tumour cells showed that the lectin was able to slow down further growth of an established tumour. The results show that ML lectins induce powerful anti-cancer effects when provided by the oral route.

Effects of a lectin- and a viscotoxin-rich mistletoe preparation on clinical and hematologic parameters: a placebo-controlled evaluation in healthy subjects.

BACKGROUND AND OBJECTIVES: Mistletoe preparations, which are widely used among patients with cancer in Germany, have immunomodulating properties in vitro and in vivo. The aim of this evaluation was to determine and compare the effects of a lectin-rich (Iscador Qu [IQ] special, Weleda Company, Schwäbisch, Gmünd, Germany.) and a lectin-poor but viscotoxin-rich (Iscador Pini [IP] Weleda Company) mistletoe preparation on clinical and hematologic parameters in healthy subjects. DESIGN: In a double-blinded study, 48 volunteers were randomized to one of three groups: 16 received IQ or IP in increasing doses or placebo twice per week subcutaneously for 12 weeks. The differential blood count and the acute phase markers haptoglobin and C-reactive protein were examined weekly and the symptoms were scored using standardized questionnaires. RESULTS: IQ resulted in significant eosinophilia (315 +/- 109) beginning at week 5 (until week 12) compared to IP (183 +/- 120) or placebo (200 +/- 179). Furthermore, the acute phase marker haptoglobin was significantly increased in the IQ group during week 4. Dose-dependent local reactions (LRs) at the injection site occurred in all subjects who received mistletoe preparations but were stronger in the IQ-treated subjects than in the IP-treated group. The LRs observed in the IQ-treated group were characterized by stronger itching and longer latency than LRs in the IP-treated group (p < 0.05). Severe side-effects did not occur in any of the probands. CONCLUSIONS: IQ but not IP can induce eosinophilia in healthy individuals, and this may be related to its content of mistletoe lectins. In contrast, exposure to the viscotoxin-enriched extract IP did not result in specific changes of hematologic parameters. Furthermore, intensity and time course of local reactions seemed to depend on the concentration of mistletoe lectins in those extracts.

Combined cytotoxic action of Viscum album agglutinin-1 and anticancer agents against human A549 lung cancer cells.

BACKGROUND: Viscum album agglutinin-1 (VAA-1) is assumed to be the biologically most active ingredient of misteltoe extracts that are often used as adjuvant cancer therapy. To develop new approaches for lung cancer treatment, we evaluated the antineoplastic activity of VAA-1 alone and in combination with other chemotherapeutic drugs, including doxorubicin, cisplatin and taxol in the human lung carcinoma cell line A549. MATERIALS AND METHODS: Cytotoxicity was determined by 5-bromo-2'-deoxyuridine (BrdU) ELISA-assays and drug interaction assessed by the isobologram method. Analysis of cell cycle distribution was obtained using flow cytometry. RESULTS: For all drug combinations tested the outcome was additive with the combination of VAA-1 and cycloheximide showing strong synergistic effects. Moreover, VAA-1 induced G1-phase accumulation mechanisms without causing apoptosis. CONCLUSION: Our findings suggest that the simultaneous administration of VAA-1 with all anticancer agents tested is advantageous since cytotoxic effects are enhanced. These data may provide new clinicalperspectives in future mistletoe therapy.