Chemotherapy and mistletoe

Mistletoe therapy can be well combined with chemotherapy. Mistletoe is often given in parallel with chemotherapy to improve  tolerability and to alleviate disease- and therapy-related symptoms of chemotherapy [25, 31, 41, 42, 43, 44, 45, 46, 47, 48]. 

A multicentre, epidemiological comparative cohort study of 1,442 patients with primary, non-metastatic breast cancer showed that patients receiving mistletoe therapy in addition to standard therapy developed statistically significantly fewer side effects than patients receiving standard therapy alone [41].

A prospective two-armed study [27] also showed that breast cancer patients who received mistletoe therapy (Iscador M) developed significantly less nausea and vomiting symptoms induced by chemotherapy (cyclophosphamide + methotrexate + 5-fluorouracil regimen or epirubicin + cyclophosphamide regimen). In addition, the intake of glucocorticoids was significantly lower in the combinational group.

In a randomized controlled three-armed study in stage IA breast cancer patients, it was shown that pain and loss of appetite in the group with chemotherapy (cyclophosphamide, adriamycin and 5-fluorouracil) plus mistletoe extracts (Helixor A, Iscador M) improved significantly compared to the control group receiving chemotherapy alone [49]. An anti-nociceptive (pain-relieving) effect of Viscum album L. extracts is already known [50, 51].

In a follow-up study there was no evidence of reduced efficacy of chemotherapy for disease-free survival with parallel administration of Iscador or Helixor up to five years after the end of therapy  [46, 48]. 

It was shown that the constituents of mistletoe preparations are metabolized via the liver and excreted via both the kidneys and intestines [40]. 

In order to investigate the metabolic induction activity of total mistletoe extracts on liver cells [52] HepG2 cells were specially exposed to the mistletoe extracts abnobaVISCUM Quercus, Helixor M as well as Iscador M and Qu. Subsequently, their metabolism was investigated with respect to the cytochrome P450-dependent monooxygenase (phase I) system and the conjugation of lipophilic substances with glucuronic acid and sulfates as an expression of the phase II reaction. For the phase I reaction, the phenoxazone derivate 7-ethoxy resorufin was chosen as specific substrate for CYP 1A1 and 1A2 and aminophenazone demethylation specifically for cytochrome P450 3A1 and 3A2. The phase II reaction was measured using p-nitrophenol-UDP glucuronyl transferase.

No mistletoe preparation significantly affected the turnover rate due to CYP 3A1 and 3A2. Similarly, there was no induction of CYP 1A1 and 1A2. The p-nitrophenol conjugation showed that all preparations accelerate the conjugation.

In an in vitro study, it was examined whether inhibition of CYP 3A4 could be induced by herbal medicinal products, including mistletoe extracts [53]. It was shown that the CYP 3A4 metabolism was slightly inhibited by Iscador in vitro, but a dosage was chosen that was not clinically attainable. Therefore, it has no clinical relevance relating to systemic or intestinal interactions.

Another in vitro study investigated whether Iscador in clinically relevant concentrations influences the activity of conventional chemotherapeutic agents such as doxorubicin, gemcitabine, docetaxel, cisplatin, etc. [54]. The results show that Iscador M and Iscador Qu special do not affect the cytostatic and cytotoxic efficacy of these different chemotherapeutic agents on breast, prostate and pancreatic cancer cell lines in any of the experimental configurations used. 

Although these in vitro data cannot be directly transferred to the complex in vivo situation, especially with regard to drugs administered subcutaneously, intravenously or orally, they may contribute to the current state of knowledge on safety for cancer patients receiving mistletoe therapy in combination with chemotherapy.

A detailed phase I study was conducted to evaluate the safety and toxicity of mistletoe extracts (Helixor A s.c. up to 250 mg) and possible interactions with the standard chemotherapeutic agent gemcitabine in patients with advanced tumours [55]. There was good tolerability, no dose-limiting toxicity of the mistletoe extract and no influence on the plasma concentration of gemcitabine when administered in combination. In addition, the clinical response under combined application was similar to that of gemcitabine alone.

Cell culture experiments show that there are no risks regarding a combination of chemotherapeutic drugs and mistletoe preparations [56]. In vitro tests (2010) showed that mistletoe preparations protect healthy human immune cells (mononuclear cells of peripheral blood) but not malignant cells (malignant Jurkat cells) from the cytostatic effects of chemotherapy (4-hydroperoxycyclophosphamides) [57]. 

The treatment of 25 cell lines and 47 human tumour xenotransplants with defined mistletoe lectin content in aqueous solution showed a dose-dependent cytotoxic and anti-proliferative effect, similar to that of the doxorubicin-containing chemotherapy substance [58]. The cytotoxic effect of the aqueous mistletoe extract was 3-4 logs more potent than that of adriamycin (doxorubicin).

For the administration of mistletoe lectin I (ML-I) and paclitaxel, synergistic in vitro cytotoxicity and induction of the apoptotic cell death of hepatocarcinoma cells could be demonstrated [60]. 

The combination of mistletoe agglutinin-1 (VAA-1) with chemotherapy showed synergistic cytotoxic effects in bronchial carcinoma cells, especially in the combination of VAA-1 plus cyclohexamide [61]. 

Another in vitro study showed that the use of mistletoe extracts (Helixor A, M, P) does not inhibit the clinically relevant cytochrome P450 isoenzymes (CYP isoenzymes) [62], which play an important role in the metabolism of chemotherapeutic substances such as taxanes, cyclophosphamides, doxorubicin and vinblastine. It could be shown that no interactions between clinically relevant CYP isoenzymes and mistletoe preparations may be expected in vivo [62]. 

In the summary of the results, there are no indications that chemotherapy given in parallel is weakened by mistletoe preparations. On the contrary, they indicate a synergistic positive effect of the combination. 

 

Last update: July 15th, 2020/AT

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