The incidence of cancer in pregnant women is about 0.02–3.8% and appears to be associated with the postponement of pregnancy and an early manifestation of cancer [1–3]. It is the second most common cause of death in women of reproductive age. The incidence of pregnancy-associated breast cancer is increasing as women are delaying childbirth until later [1, 4–6]. Recent data shows incidence of breast cancer during pregnancy as 1 in 3,000 to 10,000 birth deliveries, positioning these diagnosis as common as cervical uterine cancer [1, 3, 7–9]. Chemotherapy remains the cornerstone treatment for cancer. Although the drugs used in chemotherapy present a considerable carcinogenic risk to the pregnant woman as well as a teratogenic risk to the fetus and a possibility of mutagenic effects on future generations, the extent of placental transfer varies considerably [4–7, 9, 10].
Considering the risks of toxicity in pregnancy, the search for new models of care based on whole medical systems, natural products and non-pharmacological therapeutic interventions has been increasingly addressed within the concept of integrative oncology in order to improve the quality of life and survival of these patients by integrating conventional therapy [11, 12]. The search strategy for medicinal plants has resulted in the development and production of some anti-cancer agents widely used in oncology practice such as Catharanthus roseus (vincristine, vinblastine and vinorelbine), Taxus brevifolia (taxol and docetaxel), Podophyllum peltatum (etoposide and teniposide) and Camptotheca acuminata (topotecan) .
Of the integrative and complementary therapies used in oncology, extracts from the white-berry mistletoe (Viscum album L.), a hemi-parasitic plant belonging to the Santalaceae family, traditionally used in Europe, have increasingly used in clinical practice [11, 14–26].
The first meta-analysis performed in 1990 demonstrated the significant advantages of this drug in terms of overall survival and disease-free survival rates in cases of breast, lung, colorectal, stomach, uterine and ovarian tumors, and with respect to its efficacy in liver metastasis and its analgesic effect, which is mediated by endorphins [27, 28]. Four years later, a second meta-analysis reported statistical significance only with respect to breast, lung and colorectal tumors [29–32]. Later, a large prospective study evaluated 10,226 patients and concluded that Viscum album (VA) increased patients’ survival time by 40% (p < 0.001). the efficacy reported in that study corroborated the results of the meta-analysis performed in 1994 and once again included the uterus and stomach as sites that could be beneficially treated with the drug . A multicenter, retrospective cohort study conducted with 700 patients showed that a standard VAE represents a safe and effective co-adjuvant therapy for use following surgery for a primary breast tumor. This therapy results in a 4-6-fold reduction in side effects, consequently improving patients’ well being . A systematic review of controlled clinical studies evaluating the effect of a VAE on the quality of life (QoL) of cancer patients showed that it was well tolerated. Moreover, it appears to improve QoL by reducing the incidence of the side effects experienced with conventional therapies (chemotherapy, radiotherapy). This has been demonstrated both in experimental trials and in routine daily use .
In a multicenter observational study was carried out in the Network Oncology in Germany, in the period between July 2003 and June 2013, with 2,805 patients received VA therapy (all forms of administration and 478 patients via i.v. infusion (10.2% of all cancer patients and 16.4% of VA patients). Lung cancer (23% of all) followed by pancreatic (18%), colorectal (17%), and breast (17%) cancer. In addition to VA, 77.5% patients received chemotherapy, 14.3% received immunotherapy, 13.1% hormonal therapy, 11.6% bisphosphonates and 6.3% signal transduction inhibitors, 78.3% had surgery and 34.1% radiation therapy . A systematic review and meta-analysis on the survival of cancer patients treated with VA including eighty-two controlled studies indicate that adjuvant treatment can be associated with a better survival with most pronounced effects in cervical and less pronounced effects in lung cancer .
VA extracts (VAE) are composed of a complex multi-component mixture with anticarcinogenic effects. The extracts contain various biologically active substances such as glycoproteins (lectins and VA chitin-binding agglutinin – VisalbCBA), polypeptides (viscotoxins), polysaccharides (arabinogalactans), thiols (glutathione), flavonoids (quercetin derivates) and triterpenes (oleanolic acid, ursolic acid and betulinic acid) [17, 37–45]. The principal active components are the three mistletoe lectins (ML I, II, III), the isoforms of viscotoxins (A1-3, B, C1, 1-PS, U-PS) and the polysaccharide fractions [17, 43, 46–51].
Surface glycoconjugates of normal and transformed blood cells are commonly characterized by plant lectins to infer physiological significance of protein-carbohydrate interactions on cancer cells. When mannose- and galactose-binding lectins from several plants and from human serum/placenta were compared, binding of Viscum album agglutinin (VAA) to peripheral blood T-helper cells was found to be significantly higher . In addition to its role in the inductions of apoptosis and immune modulation, some in vivo studies have highlighted an anti-angiogenic effect on endothelial cells. Comparing 24 different plant lectins to characterize glycoconjugate expression during the development of 13- to 21-day-old rat embryos, the affinity of VAA increased as the endothelial cells matured [53–57].
The median lethal dose (LD50) of VAE in rats is 378 mg/kg of body weight. The stimulation of immune system in Wistar rats has been established as 1.0 ng of ML-1/kg as daily dose . The therapeutic dose of VAE to induce cytotoxicity in human neoplastic cells (Iscador® Q 10 mg/mL) is 0.143 mg/kg BW or 54 ng of lectins/kg BW, corresponding to 0.05% and 0.26% of the LD50 for rats, respectively . Safety with this dose is outstanding. Cytogenetic studies conducted with VA in vitro have reported negative effects with respect to mutagenicity for amniotic fluid cells, which serves as further evidence of the reliability of this drug [59–62].
Despite some authors’ recommendation not to use VAE during pregnancy, there is no scientific evidence of teratogenicity and/or reproductive toxicity with VA . Recently, some preclinical investigations showed that VAE is clearly non-genotoxic and exerts no relevant toxic effects on reproduction in vivo [64–66]. The objective of the present study was to gather further evidence of the safety of VAE in pregnancy by evaluating its side effects on pregnant female albino rats and their fetuses.