Омела белая Viscum album Mistletoe

Discussion

Since cancer patients receive besides anticancer agents numerous medications for supportive care and treatment of comorbid illnesses, consideration of metabolic interactions is important. Drug interactions could influence efficacy and toxicity of cytostatic drugs. For example cytotoxicity of taxanes which stabilize microtubule structures and thereby block the mitotic spindle apparatus is very susceptible to drugs that induce cell cycle arrest. Their effect can be potentiated or antagonized depending on the sequence of applied drugs [21].

Although mistletoe is frequently used in addition to conventional cancer therapeutics, there is only little information about possible interactions with chemotherapeutic drugs. Many anticancer drugs are metabolized by cytochrome P isoenzymes (CYPs) and the metabolism and pharmacokinetics of anticancer agents may be altered by herbal medicines. Thus, inhibition of CYPs could affect the intracellular concentration of drugs. Mistletoe was reported to be an inhibitor of CYP3A4 in vitro [22], however, the corresponding IC₅₀ values are physiologically irrelevant. The investigation of interferences of mistletoe with cytochrome P450 isoforms in human hepatocytes indicated no or only minor potential for herb-drug interactions [23], suggesting that clinically significant systemic interaction is unlikely.

The aim of our study was to investigate if clinically relevant doses of VAE interfere with standard chemotherapeutic agents in vitro by influencing their cytostatic and cytotoxic efficacy. We used the standard chemotherapeutic drugs doxorubicin for the treatment of breast cancer cell lines HCC1141 and HCC1937 [24], gemcitabine for the treatment of pancreatic carcinoma cell line PA-TU-8902 [25], mitoxantrone and docetaxel for the treatment of prostate cancer cell line DU145 [26] and cisplatin and docetaxel for the treatment of lung carcinoma cell line NCI-H460 [27]. According to typical usage in integrative oncological settings, Iscador M spec. (VAE-M) was used for the treatment of breast and Iscador Qu spec. (VAE-Qu) for the treatment of pancreatic, prostate and lung cancer cell lines [19,28,29].

Initially analyzing a sole VAE application we could demonstrate the well known anti-proliferative effects of higher doses of mistletoe extracts on cancer cell lines. The direct anti-proliferative and cytotoxic activity of mistletoe is based mainly on a dose dependent apoptotic effect of mistletoe lectins (ML) [30] which in case of ML I requires the internalization of its A chain that inactivates the 28 S ribosomal subunit leading to inhibition of protein synthesis and to induction of apoptosis via the intrinsic pathway [31-33]. Growth inhibition by mistletoe may also be the result of a cell cycle blockade in G0/G1 phase [34]. High concentrations of ML and viscotoxins cause cell lysis mainly through necrosis [35,36].

In the context of supportive therapy with chemotherapy protocols, where no direct induction of tumor-cell specific apoptosis by mistletoe is intended, patients usually are treated with VAE doses between 0.01 and 20 mg by 2 to 3 weekly subcutaneous injections. The concentrations of 0.1 and 1 μg/ml VAE are roughly corresponding to an injection of 5 mg Iscador when referring to the amount of circulating blood or body weight, respectively. Our results show that these lower, clinically typical VAE doses influenced neither proliferation nor apoptosis of the investigated cell lines.

VAE concentrations ≥10 μg/ml partially had an additive effect on chemotherapy induced cytostasis. Additive effects were previously shown in highly ML-sensitive Jurkat cells, where very low nontoxic concentrations of purified ML-I markedly enhanced etopside-induced apoptosis [33]. Siegle et al. demonstrated additive cytotoxic activity of Viscum album agglutinin-I (VAA-I) in combination with doxorubicin, cisplatin and taxol in the human lung carcinoma cell line A549 [37].

In vitro determination of cytostasis or cytotoxicity depends on assay conditions like doses used, incubation time and the cellular context. In our experiments, the cytostatic effects distinctly exceeded the cytotoxic effects for the chemotherapeutic agents and VAE alone or in combination. Most of the conventional anticancer agents are both cytostatic and cytotoxic [1]. Cytostasis can be the initial step for different mechanisms of cell death whereby the duration of mitotic arrest does not necessarily correlate with the probability of death [38]. In apoptosis-sensitive cell lines, prolonged mitotic arrest induced by antimitotic drugs causes apoptosis. In less sensitive cell lines, cells undergo slippage without division into tetraploid G1, which may be followed by p53-dependent arrest, apoptosis, or another round of mitosis [38-41]. On the other hand it is well known that mutations in the apoptotic program (i.e. p53 mutations) and up-regulated pro-survival signals (anti-apoptotic Bcl2 family members) in established cancers contribute to resistance to apoptotic cell death and are important aspects of resistance to anticancer therapies [42,43].

Iscador adjuvant to chemotherapy was reported to decrease therapy-related adverse drug reactions, to increase response rates and to improve disease symptom control, quality of life and overall survival [15,18,44,45]. In vitro and in vivo studies revealed several effects that may contribute to explain the mistletoe related clinical benefits. In cyclophosphamide exposed cells in vitro, mistletoe extracts exerted a protective effect on peripheral mononuclear cells (PBMC) from healthy donors but not on malignant Jurkat leukemia cells by the enhancement of mitochondrial activity and replication [46]. In PBMC, mistletoe extracts improved DNA repair of damaged cells [47] and reduced sister chromatide exchange [48]. Numerous effects of mistletoe extracts on the immune system are known [11]. It is hypothesized that these immunomodulating properties augment systemic antitumor effects and contribute to a reduction of chemotherapy-associated immune suppression.

Cancer cell lines have been widely used to study the biological mechanisms involved in cancer and to examine the factors influencing the response of tumors to therapeutic agents and regimens. In general, cancer cell lines show similar morphologic and molecular characteristics of the primary tumor and maintain the expression of most cancer characteristics. However, they also have a major disadvantage. Cells are removed from their natural environment and interaction and protection mechanisms otherwise available from the donor organism are eliminated. Cancer cell lines often originate from aggressive and metastatic tumors and may not properly reflect the situation in earlier stage and lower grade disease. These factors must be considered when interpreting the results of our study.

жүктеу/скачать 2.26 Mb.

Достарыңызбен бөлісу: