Омела белая Viscum album Mistletoe
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- NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors
- 1. Introduction
ВыводыВодный, ферментированный омелы не влияют на цитостатической и цитотоксическую активность несколько общих обычных химиотерапевтических препаратов при применении в концентрациях, характерных для клинического использования. Мы могли бы показать это в груди, простаты, поджелудочной железы и рака легких клеточных линий. Хотя эти in vitro данные не могут непосредственно быть экстраполированы на комплекса in vivo условия, они способствуют знания, касающиеся безопасности раковых больных, получающих омелы поддерживается химиотерапии. Наши in vitro результаты находятся в соответствии с клиническим опытом и испытания, которые Iscador может быть использован в сочетании с традиционными онкологические препараты без опасности (herb лекарственных взаимодействий. NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid TumorsPatrick J. Mansky, Dawn B. Wallerstedt, [...], and Brian P. Monahan Additional article information AbstractPurpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380  mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.
1. IntroductionEuropean mistletoe (Viscum album L.), a semiparasitic plant growing on various trees [1], has been used in folklore and as a medicinal plant for several thousand years. In the modern era, it was first introduced as a plant extract preparation for the treatment of malignant diseases by Steiner [2]. A number of studies have reported immunostimulatory effects of mistletoe extracts, on mononuclear cells [3], lymphocytes [4–6], macrophages [7], and NK cells [8, 9]. Mistletoe extracts contain a number of biologically active components, including mistletoe lectins (reviewed in [10–16]) and viscotoxins [17, 18]. Mistletoe extracts may also have antiangiogenic properties [1]. Mistletoe lectins stimulate secretion of a number of cytokines including IL-6, IL-12, IL-1, and TNF-α [19–21], may enhance cytotoxic NK-cell activity, and may induced apoptosis [22] and induction of FAS ligand [23]. Some of these findings have been supported by microarray gene expression profiling [24]. Mistletoe extract reduces leukopenia in chemotherapy-treated mice and stimulates neutropoiesis in mice after cyclophosphamide chemotherapy [25]. In a dose-dependent fashion, ML-1 may upregulate protein synthesis in neutrophils at low doses, while high doses resulted in neutrophil apoptosis via a caspase-dependent mechanism [26]. Mixed findings have been reported on mistletoe antibody formation. In vivo antibody formation has a protective effect against the toxicity of mistletoe lectins to normal somatic cells [27]. While ML antibodies were absent in patients without adverse effects [28], a potential role of ML-antibodies in the neutralization of mistletoe lectin activity in vivo has been debated [27, 29]. Collectively, the mounting preclinical data with mistletoe therapy suggests that rigorous clinical trials are needed.
In a phase I study in HIV-positive patients treated with Viscum album Quercus Frischsaft (QuFrF) [30], limited toxicities included flu-like symptoms, gingivitis, eosinophilia, and a slight rise in serum urea nitrogen and creatinine. Natural mistletoe lectins were detected in normal volunteers 2 weeks after single dose injection. Fever and flu-like symptoms were observed [31]. Thus, mistletoe preparations appear to be well tolerated, and antibody response appears to be robust. However, the clinical efficacy of mistletoe in oncology settings remains unclear. Notably, in a large retrospective study of mistletoe therapy in nonmetastatic breast cancer patients, fewer adverse events and longer survival were observed in the mistletoe therapy group compared to conventional therapy alone [32]. In a comparable retrospective study design in pancreatic cancer patients, similar clinical outcomes were observed with fewer adverse events and improved survival in patients treated with mistletoe [33]. Despite compelling preclinical data and these isolated reports of clinical benefit of mistletoe preparations, recent reviews of clinical trials still note methodological weaknesses of current published studies on mistletoe [34] as well as conflicting results on tumor response and survival prolongation on treatment using various mistletoe preparations [35–38]. A number of recently published studies confirm this mixed picture [39–42]. With converging preclinical evidence suggesting immunostimulatory and antiangiogenic properties of mistletoe, in addition to a dearth of well-designed clinical trials testing the safety and efficacy of mistletoe, the present study sought to administer mistletoe to advanced stage cancer patients, in combination with a standard, well-known chemotherapy regimen (GEM), hypothesizing that gemcitabine and mistletoe can be administered safely in combination to patients with advanced cancer. The study aims were to evaluate the following: (1) safety, toxicity, and maximum tolerated dose (MTD) of the mistletoe/GEM combination in patients with advanced solid cancers (ASC), (2) neutrophil count recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) GEM pharmacokinetics as an indicator of possible interactions of the mistletoe/GEM combination regimen.
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