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Bovine Colostrum as Supportive Care in Anticancer Chemotherapy: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor: Jolanta Artym , Michał Zimecki
BC and its bioactive constituents (LF and others) may be used as supportive care in prevention and treatment of adverse side effects of cancer therapies. Chemotherapy with cytotoxic drugs is applied in the therapy of neoplastic and autoimmune disorders and in transplantation. Hormone therapy with anti-estrogen drugs is used to combat estrogen-receptor-positive breast cancer. Transient complications, associated with chemotherapy, include: impairment of the immune system function (due to severe atrophy of immune organs), damage to sensitive organs and tissues (where cells rapidly divide), such as bone marrow, oral, digestive and genitourinary mucosa systems, male and female reproductive cells, skin, as well as nephrotoxicity, neurotoxicity and cardiotoxicity. Hormone therapy inhibits the production of endogenous estrogens, among others, in the reproductive system. These cancer therapies are accompanied by extremely burdensome and dangerous for health and life symptoms, such as: increased susceptibility to fungal, bacterial, viral and parasitic infections, more severe infection course, neutropenia, anemia, blood-clotting disorders, fever, mucositis, nausea, vomiting, abdominal pain, constipation, diarrhea, headaches, muscle pain, fluid retention, chronic fatigue, weakness or loss of taste and smell, lack of appetite, weight loss, cachexia, anorexia, cranial neuropathy, seizure, myelopathy, peripheral neuropathy, somnolence, various dermatologic complications, such as extravasation, hyperpigmentation and hypersensitivity reactions. In anti-estrogen therapy, vaginal discharges, reproductive tract bleeding and hot flushes are additionally found.
  • bovine colostrum
  • lactoferrin
  • antitumor therapy
  • chemotherapy
  • radiotherapy

1. Chemotherapy in In Vitro and Animal Models

Cyclophosphamide (CP) belongs to the most frequently used immune suppressants in the clinic and in animal models of immunosuppression [1][2]. In a series of studies in the mouse model, LF proved effective in the reconstitution or normalization of impaired immune response. The intraperitoneal (i.p.) administration of a sublethal (400 mg/kg b.w.) dose of CP strongly suppressed delayed-type hypersensitivity (DTH) to ovalbumin (OVA) in mice [3]. Bovine LF (bLF) given per os in seven doses on alternate days reconstituted DTH and partially recovered concanavalin A (ConA)-induced splenocyte proliferation, blood leukocytosis, spleen T-cell content and number of peritoneal macrophages. bLF, given in drinking water as 0.5% addition, was also capable of elevating, by 10×, the humoral immune response (HIR) to antigen—sheep red blood cells (SRBCs), strongly depressed by a single injection of CP [4]. Other actions of bLF in CP-treated mice encompassed increases in the content of CD3+, CD4+ and Ig+ splenocytes and the proliferative response of splenocytes to ConA and pokeweed mitogen (PWM) [5]. In addition to mice, drinking bLF-containing water demonstrated the normalization of peripheral blood cell composition distorted after CP treatment regarding severe leukopenia and strong eosinophilia after CP treatment.
Bovine LF, administered in drinking water, also exhibited complete restoration of DTH response to OVA, reduced by 80% by application of methotrexate (MTX), given i.p. in 200 mg/kg b.w. dose [6]. Of interest, bLF was not able to restore primary HIR to SRBC when MTX (1 mg/kg b.w.) was applied 48 h post-immunization. Nevertheless, bLF could restore the secondary HIR after a booster immunization with SRBC. In addition, bLF regained suppressed secondary HIR to SRBC in vitro. In conclusion, although restoration of DTH by LF was preferential, the protein prevented block of activity of memory T cells in HIR.
An attempt was also undertaken to see to what extent LF contained in drinking water can restore the immune response after myeloablative chemotherapy mimicking a clinical situation with the application of CP (100 mg/kg b.w.) and busulfan (4 mg/kg b.w.), followed by syngeneic bone marrow transplant [7]. The mice not receiving bLF had significantly depressed (by 88%) HIR to SRBC. The treatment with bLF restored HIR after one month to the control levels seen in normal mice. DTH was less affected (by 50%) after chemotherapy but LF restored the response to control levels. The treatment with bLF also enhanced lympho-, erythro- and myelopoiesis in the bone marrow, to a similar degree as upon administration of human GM-CSF. This finding demonstrates a therapeutic utility of LF in chemotherapy, which may replace this costly, recombinant cytokine. Of importance, bLF used in mice for reconstitution of antigen-specific immune responses does not impair resistance to systemic infection with Escherichia coli and Staphylococcus aureus [8].
In a mouse study, a silk sericin hydrogel containing a low concentration of recombinant human LF (rhLF) was prepared to diminish pathologic changes induced by CP in the immune organs [9]. rhLF in silk cocoons was produced by a transgenic silkworm strain. The effects of this preparation were compared with a high dose of free hLF administered orally. The authors demonstrated that the protective effect of the hydrogel with regard to the structure of splenic follicles, expression of immunoregulatory mediators and intestinal flora was comparable to the protective effect provided by a high dose of oral hLF in solution form. The strategy of producing rhLF-carrying silk cocoons improves the bioavailability of oral rhLF, protected from degradation in the stomach and small intestine.
Bovine LF was also evaluated in mice treated with tamoxifen, an anti-estrogen drug used for hormone therapy of estrogen receptor (ER)-positive breast cancer and also as a chemotherapeutic in ER-negative breast cancers [10]. In a preventive model, BALB/c female mice were treated with tamoxifen (5 mg/kg b.w.) and bLF-supplemented diet (5 g/kg b.w.). At week 2, 4T1 mammary epithelial tumor cells were injected into an inguinal mammary fat pad. In a treatment model, bLF diet started 2 weeks before and tamoxifen application started after 2 weeks following tumor cell inoculation. In the tumor prevention model, the bLF supplemented diet, in combination with tamoxifen chemotherapy, caused a 4-day delay in tumor development and significantly inhibited tumor growth and metastasis to the liver and lung, as compared to control mice on a standard diet. The oral diet containing bLF reduced the loss of body weight and cancer cachexia. Tamoxifen-induced reductions in serum levels of IL-18 and IFN-γ, and intestinal cells expressing these cytokines, were prevented by bLF. The B, T and NK cells in the lamina propria and Peyer′s patches in the intestine absorbed orally applied bLF and then migrated to the 4T1 tumors. Similar efficacy of bLF and tamoxifen has been reported in the treatment of established tumors.
A series of studies was performed on weaned piglets receiving doxorubicin (DOX), which complicates cancer therapy by inducing mucositis. This is a relevant large animal model for studying mucositis and existing and potential interventions for this abnormality. The animals were fed BC to reduce the side effects of chemotherapy. In one study on weaned pigs receiving doxorubicin (3.75 mg/kg b.w.), BC (5 mL/kg b.w.) was given 3× daily, beginning a day before doxorubicin and continued to day five [11]. Doxorubicin caused decreased food intake, weight gain, diarrhea, vomiting, damage to small intestine mucosa, elevated TNF-α concentration and chlorine secretion and reduced glucose uptake. These toxic side effects were partially prevented by administration of colostrum.
In another study in weaned pigs applying a single dose of DOX, the efficacy of two formulas (BC or bovine milk enriched with whey proteins) aimed at the amelioration of the side effects was evaluated [12]. It appeared that colostrum supplementation had no consistent benefit over the milk-enriched diet on the studied parameters, such as: weight loss, intestinal morphology, digestive enzymes, gut permeability, proinflammatory cytokines, plasma C-reactive protein and citrulline levels. However, colostrum-fed piglets had lower diarrhea severity and intestinal toxicity at the end of the monitoring period.
More promising results were observed by authors in another study on preweaned 5-day-old piglets using BC and artificial control formula. The pigs treated with DOX (1 × 100 mg/m2) developed characteristic toxic effects, such as diarrhea, weight loss, leukopenia and damage and inflammation in the gut [13]. In the piglets treated with colostrum, decreased intestinal permeability, longer intestinal villi, higher activities of brush border enzymes and lower intestinal IL-8 levels were found. The authors concluded that BC could be beneficial as a diet supplement for children undergoing chemotherapy for protection against intestinal toxicity.
The effects of BC on the amelioration of toxic effects of the myeloablative procedure were also studied in a pig model [14]. Thus, 3-day old piglets were subjected to 6-day myeloablative treatment with busulfan and CP and fed BC or an artificial diet. The gut was analyzed for selected parameters on day 11 following the start of chemotherapy. Signs of gut damage, oral ulcers and hematologic toxicity were found. Although application of colostrum did not improve gut mucosal structure, the animals had reduced vomiting. In addition, such parameters of intestinal function as galactose absorption and brush border enzyme activity were much higher, and inflammatory tissue cytokine concentration, serum liver enzyme and bilirubin levels were lower in the BC-treated group. Further, despite a lower diversity of microbial strains, the presence of Lactobacilli was richer in colostrum-fed pigs.
Bovine LF protected against intestinal MTX-induced toxicity in a rat model [15]. Histopathological changes, reductions in the absorptive surface of the small intestine and increases in the intestinal barrier permeability were observed after MTX (20 mg/kg b.w.) administration. LF supplementation reversed these adverse changes. As suggested by the authors, the mechanism of action of LF may involve inhibition of endogenous glucagon-like peptide-2 (GLP-2) activity in the gut. GLP-2 is a trophic factor specific for intestinal epithelia, and blocking its activity temporarily stops cell division and protects the intestine from chemotherapy-induced toxicity. LF inhibited intestinal epithelial cell proliferation in rats and GLP-2-mediated proliferation of Caco-2 epithelial cells in vitro.
Bovine LF also protected against chemotherapy-mediated ovarian damage in a mouse model [16]. Female mice were treated with CP and a list of several ovarian genes was analyzed. Among the investigated genes, nine were down-regulated and two were up-regulated, including the LF gene. Supplementation with bLF prevented down-regulation of the ovulation-related Adamts1 and partially prevented the loss of ovarian follicles. These results indicate that LF may help protect ovulatory capacity and partially prevent oocyte depletion.
The renoprotective effect of LF was studied in rats treated with cisplatin [17]. The animals were treated with oral bLF from the day before to the fifth day after cisplatin (7 mg/kg b.w.). A reduction in renal histopathological changes (renal tubular injury, a decrease in renal cisplatin accumulation) and improvement in renal function were observed. Intravenous administration of bLF also increased the amount of urine produced.
Active BC components have multidirectional anticancer activity, best studied for LF. This protein regulates the cell cycle, inhibits proliferation, induces cell maturation and apoptosis of neoplastic-transformed cells, induces the activity of antitumor proteins (e.g., p53, p21, Rb), regulates tumor suppressor gene activity, activates cellular detoxifying enzymes, binds iron necessary for tumor growth, inhibits angiogenesis in the tumor and metastasis to distant tissues, inhibits inflammation and ROS formation (oxidative stress), increases surface receptor expression on tumor cells and facilitates their recognition by immune cells, activates immune cells (NK, lymphocytes, macrophages) and eliminates the oncogenic pathogenic microbes (e.g., papilloma virus and Helicobacter pylori) [18]. BC components can, therefore, support the elimination process of the cancer itself and protect against its recurrence and, therefore, enhance the effects of classical chemotherapy.
In recent years, innovative methods of preparing nanoparticles, liposomes and polymersomes (synthetic equivalents of natural liposomes) containing LF and active anticancer compounds were developed with the aim of more efficient penetration of drugs into tumor cells. In these preparations, LF acts both as an active therapeutic and a specific drug carrier [18][19][20]. The access of LF molecules to target tumor cells is determined by an overexpression of specific receptors for the protein (e.g., LRP1 or asialoglycoprotein receptors) on their surface. The benefits of such innovative therapy include: selective destruction of target cells, reduction in multidrug resistance of tumor cells and reduced toxicity of the therapy to the patient’s body. Such conjugates were effective in the treatment of breast cancer, retinal cancer, prostate cancer, hepatocarcinoma and glioma, among others [21][22][23][24][25].
Even a simple combination of LF with DOX improved the efficacy of prostate cancer therapy [23] with a reported better penetration of DOX into target cells and a significant (4×) increase in cytotoxicity. In addition, the LF–DOX complex effectively overcame multidrug resistance of prostate cancer cell lines. When administered to mice, the complex inhibited tumor growth, reduced signs of general toxicity, neurotoxicity and cardiotoxicity, increased the immune response (serum levels of IFN-γ, TNF-α and chemokines CCL4 and CCL17) and prolonged animal survival. The efficacy of LF-loaded liposomes and polymersomes as anticancer drug carriers was also proved. For example, polyethylene glycol (PEG)-modified liposomes containing LF and DOX were tested in the HEPG2 hepatocarcinoma model in vitro and in vivo [25]. More effective delivery of DOX to the cells and significantly better inhibition of tumor growth in mice were observed compared to treatment with liposomes containing DOX alone. An innovative approach was undertaken to treat glioma in rats by preparing biodegradable polymersomes, facilitating crossing the blood–brain barrier (BBB) and integrating with glioma-targeting moiety, containing doxorubicin, tetrandrine (overcoming drug resistance) and LF [22]. One of the most serious difficulties in treating central nervous system (CNS) tumors is the delivery of drugs across a tight BBB. In in vitro study, the polymersomes demonstrated the highest cytotoxicity against glioma C6 cells and uptake index by the cells as compared with polymersomes containing only doxorubivin, tetrandrine or LF. The pharmacokinetic and tissue distribution analysis showed that the tumor volumes in rats receiving these polymersomes were significantly smaller than in other groups, and the animals survived significantly longer than rats in other therapeutic groups.
Several studies have also demonstrated the efficacy of LF as a carrier for nanoparticles loaded with an anticancer drug. In in vitro tests, nanoparticle conjugates of carboplatin, etoposide and LF were efficiently captured and maintained in retinoblastoma cells and killed 50% more of these cells compared to standard drugs [21]. Designed LF–DOX-mesoporous maghemite nanoparticles were effective in breast cancer treatment in mice [24]. They inhibited tumor cell proliferation and metastasis and improved the animals’ condition by increasing their body weight.

2. Chemotherapy in Clinic

Colostrum and LF have often been used to ameliorate the side effects of chemotherapy in the clinic. In an open-label, prospective, randomized trial in anemia advanced cancer patients (n = 148) undergoing chemotherapy, oral bLF treatment versus intravenous (i.v.) treatment with ferric gluconate were compared [26]. Both treatments were combined with a subcutaneous (s.c.) administration of recombinant human erythropoietin. Both experimental groups showed a significant increase in hemoglobin level and no differences in hematopoiesis, serum iron and C-reactive protein levels and erythrocyte sedimentation rate. However, ferritin levels decreased in LF-treated patients and increased in the ferric-gluconate-treated group. This phenomenon may be beneficial regarding negative consequences of iron overload in anemia of cancer and chronic inflammatory diseases [27].
LF was also used to improve the immunologic status of metastatic colorectal cancer patients (n = 30) treated with 5-fluorouracil and leucovorin calcium in a double-blinded parallel randomized controlled clinical trial [28]. The patients were given bLF (250 mg/day) for 3 months. The control group received chemotherapy only. After completion of the trial, a significant improvement in several parameters, such as serum LF, glutathione-s-transferase (GST), IFN-γ, tumor marker carcinoembryonic antigen (CEA), blood cell count (WBC and RBC), renal and hepatic functions, were registered. In the LF group, patients have less severe mucositis, a lesser rate of infection recurrence and less incidence of fever than patients in the control group. As the authors suggest, oral bLF has a significant therapeutic effect on colorectal cancer patients due to its anti-inflammatory and antimicrobial activity, with better disease prognosis and improvement in patient quality of life.
LF may be used in the prevention and treatment of infectious and inflammatory complications in cancer patients treated with chemoradiotherapy, especially hematological patients undergoing hematopoietic stem cell transplantation (HSCT) after prior aggressive chemoradiotherapy. Of particular importance are the antimicrobial and immunoregulatory properties of LF, as well as the protective effect on intestinal tissues [29]. These patients are particularly susceptible to severe infections due to impaired immunity. They often develop infections with their own microflora (opportunistic infections), resistant to classical antibiotic therapy. A non-randomized clinical trial on a small group of patients (n = 14) with acute myelogenous leukemia (AML), undergoing chemotherapy, showed a protective effect of oral hLF, administered as prophylaxis, to protect against infections [30]. A delay in the onset of the first infection, a shorter duration and lighter course of infection were observed, as well as less frequent Gram “-“ and Gram “+” bacteremia and fewer antibiotics required. According to the authors, the reduction in bacterial growth in the intestine by LF is of particular importance, so this protein (alone or together with antibiotics) can be used to decontaminate the gastrointestinal tract in immunosuppressed patients.
Interesting observations were made by Russian scientists who, in two clinical trials, applied milk hLF by different routes, such as systemic (i.v.), oral or to wash body cavities and wounds [31][32]. LF preparations for systemic use (Laprot®) and per os use (Imlac®) were developed in Hertsen Moscow Oncological Institute (Moscow, Russia). The aim of the first trial was to determine the protective properties of these preparations in patients (n = 150) undergoing chemo- and chemoradiotherapy for advanced (stage III-IV) tumors [32]. LF preparations reduced the number of total and local toxic reactions in the oropharyngeal and esophageal zones by an average of 20%, as well as their intensity. Changes in blood biochemical parameters (bilirubin level, aminotransferase activity), oxidative stress indices and neutrophils activity correlated with the improvement in clinical status. The healing period of toxic lesions in the oropharyngeal zone and esophagus was shortened two-fold in patients taking Imlac® compared to patients not treated with LF.
In another clinical trial, Laprot® (i.v. or locally on the wound) in patients with severe inflammatory and septic complications, following surgical interventions for various primary conditions (malignant tumors, tuberculosis of the lungs and other organs, multi-organ trauma, infections after soft tissue and bone surgery) was used [31]. In the patients, treated with i.v. LF, stimulation of antioxidant defense, decreased intensity of oxidative process, normalization the lymphocytic component of immunity and hematological and biochemical parameters in blood, resolution of polyorgan and primarily hepatic failure, were observed. In locally LF-treated patients, a regression of local pyoinflammatory processes was registered.
In a multicenter, blinded, placebo-controlled, randomized trial, bLF, administered in a medical food product (ice cream), protected cancer patients (n = 197) from diarrhea and neutropenia during chemotherapy [33]. The mean number of days with patient diary-recorded chemotherapy-induced diarrhea (CID) was lower in the experimental versus the placebo group. CID reported during the doctor’s rounds, as well as neutropenia, was diagnosed in a lower proportion of the patients. CID, due to therapy-related mucosal toxicity and bowel mucositis, is a common adverse effect of many chemotherapy regimens and has a great impact on a patient’s quality of life. The alimentary tract mucositis, that is reported in 30–80% of patients administered cytotoxic drugs, increases mortality and morbidity and raises the cost of patient care [34].
In a two-center, randomized, double-blind, placebo-controlled clinical trial, involving children (n = 62) with acute lymphoblastic anemia (ALL) and gastrointestinal toxicity during induction chemotherapy treatment, daily oral BC or placebo for four weeks was administered [35]. The patients were monitored for fever, bacteremia, need for antibiotic treatment and mucosal toxicity. No differences between the groups were found regarding fever, need for antibiotics and incidence of bacteremia. However, the peak of severity of oral mucositis as well as the weekly peak of self-reported oral mucositis were significantly lowered in BC-supplemented patients. According to the authors, although prophylactic BC administration did not affect inflammation and infectious morbidity, it may have a mitigating effect on mucositis in children with ALL treated with induction chemotherapy.
Cancer chemotherapy is often associated with taste and smell abnormalities (TSAs) that impair food intake, medication use and quality of life for patients [36][37]. To alleviate TSA, the cancer patients (n = 26) receiving chemotherapy were treated orally with 750 mg bovine LF for 30 days, and after an additional 30 days without LF treatment, TSAs were determined via a taste and smell questionnaire (TSQ), including: taste (score 0–10), smell (score 0–6) and composite scores (0–16) (0 = no TSA) [38]. A statistically significant improvement for the combined and individual senses was reported (from baseline to day 60 mean composite TSQ score improved by 3.8, taste by 1.9 and smell by 1.8). The authors suggest that the observed effect may be due to the inhibition by LF of lipid oxidation in the oral cavity (which is one of the causes of TSA).
In another clinical trial, cancer patients (n = 19) were treated with bLF with the same protocol as above. Saliva was collected on days 0, 30 days of LF supplementation and 30 days after cessation of LF treatment [39]. The chemotherapy was associated with high TSA and a loss of the most relevant salivary proteins. LF application significantly decreased salivary iron, increased α-amylase and zinc-α-2-glycoprotein (Zn-α-2-GP), immunoglobulin (Ig) heavy chain, annexin A1 and proteinase inhibitor. At the last time point, further increases in salivary protein: α-amylase and short palate, lung and nasal, epithelium carcinoma-associated protein 2 (SPLUNC 2) were found and TSA score was significantly lower. This effect lasted at least 30 days. Patients with taste disorders have a lower abundance of Zn-α-2-GP, prolactin-inducible protein (PIP) and other proteins in saliva, which suggests that these proteins have a critical role in taste and smell preservation [39]. As the authors conclude, LF supplementation in cancer patients can improve the taste, smell and oral immunity.
Children (n = 64) undergoing chemotherapy for ALL and suffering from oral mucositis were included in the next randomized clinical trial [40]. A toothpaste containing salivary enzymes, proteins and BC (Bioxtra® Welwyn, Herts, UK) was used at least twice a day in parallel with standard fluoride toothpaste in the control group. Although the investigated toothpaste did not improve the overall quality of life, its application showed some benefits, as documented in a form of Oral Health Impact Profile questionnaires.
LF can also protect against complications from other drugs used to treat cancer patients, such as bisphosphonates. Some patients may develop serious complications from taking these drugs, for example, osteonecrosis of jaws characterized by non-exposure or exposure of the necrotic bone [41]. The aim of the open-label non-randomized clinical study was to improve quality of life, controlling pain, managing infection and preventing necrosis in this category of patients (n = 32), treated orally with bLF [42]. Control patients, after removal of necrotic bone and antibiotic therapy, received a standard procedure by the application of a sterile gauze on the wound closure, and a greasy sterile gauze soaked with bLF was applied in an experimental group. In addition, the experimental patients carried out home care with orally orosoluble tablets containing 50 mg of bLF (GENGI-FOR®, Forhans-Uragme, Rome, Italy) until complete wound healing. The application of LF significantly shortened time of wound closure (1–2 weeks) compared with the conventional treatment (2–3 months). It should also be mentioned that a beneficial effect of LF on wound healing could be explained by its action on the keratinocyte and fibroblast functions, induction and resolution of inflammation, regulation of re-epithelialization and angiogenesis and other processes during complex wound healing [43][44][45].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11010114

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