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L AVORO ORIGINALE

R. T RIVISONNE Supportive treatments and whey proteins in cancer patients

PROGRESS IN NUTRITION Summary VOL . 13 , S uppl , 47-54, 2011 In the treatment of neoplastic patients many toxicities caused by chemo or radiotherapy are related to the formation of free radicals and to the TITOLO oxidative stress and have been treated with antioxidants products. Be - Interventi di supporto e sides some vitamins (A, E, C, carotenoids, etc) few specific antioxidants proteine del siero di latte nel are used in the supportive treatment in medical oncology: amifostine, paziente oncologico dexrazoxane, sodium 2-sulfanylethanesulfonate (MESNA), glutathione (GSH). The aminoacids included in the milk whey proteins (cysteine KEY WORDS and glutamic acid) as precursors of GSH can increase the tissue concen - Antioxidant, glutathione, whey tration of GSH, stimulate the immunologic system, detoxify potential protein, cysteine, glutamic acid carcinogens and neutralize the Reactive Oxygen Species (ROS). The milk proteins are used in the supportive treatment of the neoplastic pa - PAROLE CHIAVE tient especially for the antioxidants properties of GSH. A whey protein Antiossidanti, glutatione, proteine concentrate supplemented with a high content of cysteine and glutamic da siero di latte, cisteina, acido acid, as precursors of GSH, given to breast cancer patients under chemo glutammico or radiotherapy, has led to an increase of BAP test (plasma anti-oxidant capacity) and of d-ROMs test (plasma oxidant capacity). Cysteine as precursor of milk proteins as well as of GSH may also be considered an important agent in the supportive treatment of neoplastic cachexia. We still need controlled clinical trials and reliable guide lines in order to use natural or pharmaceutical supplements in medical oncology.

Medical Oncology - “Mazzoni Riassunto Hospital” z.t.13 - ASUR Marche Molte delle tossicità da chemioterapia e da radioterapia correlate alla for - Ascoli Piceno, Italy mazione di radicali liberi e allo stress ossidativo sono state trattate con l’impiego di anti-ossidanti. Oltre alle vitamine (A, E, C, carotenoidi, etc) ci sono alcuni particolari anti-ossidanti, che vengono impiegati nel trattamen - to di supporto in chemioterapia oncologica: amifostina, dexrazoxane, sodio 2-sulfaniletanosulfonato (MESNA), glutatione (GSH). Gli aminoacidi contenuti nelle proteine del siero di latte (cisteina e acido glutammico) in

Address for correspondence: quanto precursori del GSH sono in grado di aumentare in maniera rilevan - Dr. Raffaele Trivisonne te la concentrazione tissutale di GSH, di stimolare il sistema immunitario, Medical Oncology - “Mazzoni Hospital” di detossificare i potenziali cancerogeni e di distruggere le specie reattive z.t.13 - ASUR Marche Ascoli Piceno, Italy centrate sull’ossigeno (Reactive Oxygen Species, ROS). Le proteine del sie - E-mail: [email protected] ro di latte sono impiegate nel trattamento di supporto del paziente oncolo -

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gico specie in riferimento alle capacità antiossidanti del GSH. Un concen - trato di proteine di siero di latte addizionato di cisteina e acido glutammico (come principali precursori del GSH) in aggiunta al trattamento oncologi - co standard (radioterapia e chemioterapia) in pazienti con neoplasia della mammella ha fatto riscontrare un incremento della capacità anti-ossidante del plasma (misurata con il BAP test) e della capacità ossidante del plasma (misurata con il d-ROMs test). La cisteina come precursore sia delle pro - teine sieriche che del GSH (antiossidante cellulare) può essere considerata un importante supporto nella cachessia neoplastica. Mancano tuttora studi clinici controllati e linee guida accreditate per l’impiego degli integratori naturali o farmacologici in ambito oncologico.

Introduction - control of iatrogenic effects due organs and body systems . The most to treatment, common forms of toxicity are : Treatment of the cancer patient - prevention of relapses (tertiary - Hematologic toxicity (leukope - consists in the use of therapeutical prevention) , nia, piastrinopenia, anaemia) strategies that aim at containing , - psychosocial aspects , - Gastroenteric toxicity (mucosi - on the one hand , the evolution of - psychophysical rehabilitation , tis, nausea, vomiting, diarrhoea, the neoplastic disease and , on the - treatment of clinical symptoms constipation ) other, the side effects of the treat - and support care in advanced - Cardiac toxicity (changes in ments used . disease . heart rhythm and heart func - In oncology , therapeutic treatments Ultimately, today the oncologist tion, pericarditis ) are often integrated and consist of deals with guaranteeing the cancer - Neurological toxicity (altered surgical interventions, chemothera - patient an adequate “quality of consciousness , peripheral neu - py treatment with antiblastic drugs life” within each stage of the neo - ropathy ) (associated or not with molecular plastic disease. - Nephrotoxicity (changes in crea - target biological drugs) and radio - tinine levels , azotaemia, cystitis ) therapy treatment . The approach to - Hepatotoxicity (changes in the cancer patient is today defined Toxic effects of cancer treatments bilirubin levels , ALT, AST ) as being a “global approach” in that - Cutaneous toxicity (erythema, not only is the medical treatment One of the major problems en - desquamation, folliculitis, alope - (chemotherapy, hormone therapy) countered in oncology assistance cia ) or radiotherapy evaluated but also programs is represented by man - - Fever and infections . the following interrelated aspects are agement of treatment toxicity . Whilst the prevention measures considered : The toxic effects of chemotherapy and treatment of specific forms of - control of early and long-term and radiotherapy are due to the ac - toxicity of certain chemotherapic side effects , tion exerted collaterally on healthy drugs and subsequent complica -

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tions are well known, it has long lipoic acid, ubiquinone, etc. ) and according to study design, statisti - been hypothesized that the ad - exogenous antioxidants present in cal power, type of intervention, ministration of antioxidants dur - food or in nutritional supplements duration of observation, type of ing chemotherapy and/or radio - (ascorbic acid, alpha-tocopherol, tumour etc. and therefore, caution therapy can protect normal tissues carotenoids etc .) must be taken when considering against the toxic side effects of Antioxidants have been used in antioxidant therapy and use of nu - these treatments . oncology not only as supportive tritional supplements in general The main therapeutic effect of ra - care agents in the prevention and (4-6). diotherapy is given by the biologi - contrast of antineoplastic-treat - In a thorough review of 22 studies cal effect of the ionization of wa - ment-related effects , but also as that observed patients with breast ter molecules present in the cellu - cancer preventive agents. cancer undergoing radiotherapy, lar cytoplasm from which ROS Although antioxidants by defini - chemotherapy or hormone therapy (reactive oxygen species) , such as tion clean up free radicals, one in which several nutritional supple - superoxides and hydroxylic radi - should bear in mind that they can ments were used (vitamin C, vita - cals (free radicals) originate . Simi - also act through other mecha - min E, multivitamins, glutamine, larly, many antiblastic agents [an - nisms of action that involve cellu - glutathione, melatonin, soy thracyclines (doxorubicin, epidox - lar proliferation, apoptosis, angio - isoflavones, antioxidant combina - orubicin), platinum compounds genesis, neoplastic growth and tions ) it was impossible to reach (cisplatin, carboplatin, oxaliplatin ), metastatization processes (2). any conclusion on the antitumoural alkylating agents (cyclophos - In vitro and in vivo studies carried efficacy of these specific treatments phamide, ifosfamide) and antibi - out both in experimental animals on prevention of disease relapses otics (bleomycin, mitomycin-C)] as well as in Humans, have shown and on survival. Some of the stud - manifest their cytotoxic effect that antioxidants such as retinoids ies analysed reported that supple - through the production of ROS . (vitamin A), alpha-tocopherol (vi - mentation with antioxidants may Many forms of chemotherapy and tamin E), sodium ascorbate (vita - reduce some of the side effects due radiotherapy toxicities have been min C) and carotenoids, alone or to these treatments and in particu - treated with antioxidants as corre - in combination, induce cellular lar vitamin E has proved to have a lated with the formation of free differentiation, increase the in - positive effect on hot flushes fol - radicals and oxidative stress and hibitory effects of neoplastic lowing hormone therapy and gluta - have been the subject of many growth due to radiation and an - mine on chemotherapy-induced studies ( 1). tiblastic drugs through complex oral mucositis. Therefore, the stud - Under normal conditions the hu - mechanisms and are capable of re - ies carried out to date (clinical and man body is able to neutralise the ducing the toxicity of many an - observational) have proven to be damage caused by free radicals tiblastic drugs (3). inadequate in demonstrating the thanks to natural antioxidant de - Reviews of these studies evaluat - actual usefulness of antioxidant fence mechanisms . The body pro - ing the clinical use of antioxidants supplements in breast cancer treat - duces endogenous antioxidants in oncology have underlined some ment and further clinical trials and (superoxide dismutase , catalase , important aspects : studies carried adequately powered observational glutathione peroxidase , coenzyme out on the use of antioxidants in studies are needed in order to reach Q, melatonin, transferrin , alpha- neoplastic patients greatly differ a conclusion (7).

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One must also bear in mind that nephrotoxicity in patients who vention of peroxidase, releases the antioxidants can interfere with the have undergone cervico-facial ra - necessary H+ ions to neutralize free effects of radiotherapy and an - diotherapy (9). radicals. The active element in the tiblastic agents by neutralising or Dexrazoxane (Cardioxane TM ) is in - reaction is represented by cysteine’s reducing their therapeutic effect. dicated in association with anthra - SH-thiol group that is oxidized to Therefore, great caution is recom - cycline chemotherapy (doxoru - cysteine disulphide when perform - mended when considering the po - bicin, epidoxorubicin ) to reduce ing its antioxidant activity . tential effect that some antioxi - cardiac toxicity ( 9). Glutathione was used in a ran - dants could have in reducing ther - Furthermore, dexrazoxane domised clinical phase III trial apy efficacy ( 1). (Savene TM - Spepharm ) is indicated studying 151 patients with ovarian On the other hand, a recent re - in the treatment of the local necro - cancer, treated with cisplatin view dealt with the topic of an - tizing effect due to accidental ex - chemotherapy. Of these , 74 patients tioxidants in a “positive and en - travasation during venous infusion were also treated with 3g/m 2 of thusiastic” way and concluded by of anthracyclines leading to a likely GSH every 3 weeks : the addition of stating that: antioxidants and oth - ferrochelating effect similar to that GSH reduced peripheral nephro - er supplements when administered caused by EDTA from which toxicity, cisplatin-induced nephro - with concomitant chemotherapy dexrazoxane originates (10). toxicity and ototoxicity, improved and/or radiotherapy: 1. do not in - MESNA (Uromitexan TM ) is a thiol quality of life and reduced weight terfere with the effect of the ther - compound which acts as an antioxi - loss (there was an average weight apy; 2. increase the cytotoxic effect dant providing protection against loss of 2 Kg in patients who did not of chemo and radiotherapy; 3. inflammatory-haemorrhagic phe - receive GSH treatment ) (12). have a protective effect on normal nomena on the bladder mucosa In another phase III clinical study tissues; 4. increase patient survival caused by acrolein and other degra - GSH was used in patients with and “the use of antioxidants and dation metabolites of the antiblastic metastatic colorectal cancer and other dietary supplements” is in agents cyclophosphamide and ifos - treated with oxaliplatin-fluorouracil fact recommended “ as they are famide ( 11). chemotherapy. An intravenous dose safe and capable of improving Glutathione (GSH) has been shown of GSH of 1.5 g/m 2 every 2 weeks cancer patient treatment” ( 8). to reduce toxicity of platinum-de - was able to reduce the peripheral Then, there are particular antioxi - rived chemotherapy agents (cis - oxaliplatin -induced nephrotoxicity dants such as amifostin, dexrazox - platin, carboplatin, oxaliplatin) without reducing the clinical effica - ane, MESNA and glutathione probably due to the affinity of cys - cy of oxaliplatin (13). that are different to vitamins and teine’s SH -thiol group for heavy Therefore, GSH is used in some that have become part of common metals. Glutathione is a tripeptide protocols in association with clinical practice in the supportive (glycine, cysteine and glutamine) chemotherapy mainly in the pre - treatment of oncologic that plays an important role in the vention of neurologic toxicity . chemotherapy as they have been antioxidant mechanism as it acts at shown to have clinical efficacy . the cytoplasmic level near the mito - Whey proteins Amifostin (Ethyol TM ) is indicated chondrial apparatus, where most for the prevention of both early ROS is produced. Glutathione, Many of the effects of whey pro - and late onset of cisplatin-induced spontaneously or through the inter - teins have been studied in several

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pathological conditions associated for the anti-carcinogenic effect alpha-lactalbumin , lactoferrin ) with cancerogenesis , chemo/ra- (17, 18). that are easily absorbed at intra - diotherapy toxicity, neoplastic In particular, lactoferrin has at - cellular level increasing the level of cachexia , as well as with immune tracted a lot of attention as it glutathione (GSH) that in turn processes and pathological condi - seems to act through various anti- expresses its antioxidant action by tions of other organs and body neoplastic mechanisms inducing destroying free radicals, detoxify - systems : bone, muscle, kidney, apoptosis, inhibiting angiogenesis, ing potential carcinogens and pancreas, nervous system, vascular modulating enzymes that metabo - stimulating the immune system system etc (14). lize carcinogenic agents and acting (21). The aminoacids contained in as an iron chelating agent . In par - Oxidative stress is the condition whey proteins (in particular cys - ticular, whey seems to be able to under which tissue levels of ROS teine and glutamic acid ) being exert an antineoplastic activity also are produced in excess compared GSH precursors, are able to do due lactoferrin’s iron-chelating to the body’s natural ability to re - the following: ability, as iron is considered a mu - move them. Therefore, the use of 1. markedly increase GSH tissue tagen agent capable of causing ox - antioxidants in neoplastic cells, levels idative tissue damage (19). that have a hyper production of 2 boost the immune system An in vitro study demonstrated ROS, may be accompanied by a 3. detoxify potential carcinogens that a whey protein concentrate reduction in neoplastic growth . 4. destroy free radicals (ROS) compared to a preparation of ca - On the basis of these considera - 5. maintain proteins in a reduced sein proteins was able to increase tions, Bounous reported the re - state (15). GSH synthesis thus protecting sults related to the use of a whey Whey proteins have been widely human prostate cells from cell protein concentrate enriched with studied in animal models (rats) for death induced by an oxidant ef - casein in cancer patients . In 13 out cancer prevention and dietary sup - fect (20). of 15 patients with prostate can - plementation with whey protein To date, the ability of whey pro - cer, during the administration of leads to an increase in serum and teins to contrast cancerogenesis the whey protein concentrate a tissue levels of GSH, an increased has been demonstrated in numer - progressive reduction of PSA was splenic lymphocyte proliferation, ous animal models. observed ; in 1 patient with renal an increased phagocytosis of natu - cancer a significant reduction of ral killer T helper cells and an in - hepatic and pulmonary metastasis crease in T cell cytotoxic activity Supportive care in the cancer was observed and this lasted 3 (16). patient years ; in 1 patient with bladder The effects of whey on colon and cancer after 1 year of treatment breast tumours induced by car - Whey proteins seem to play a key with whey proteins no recurrence cinogens have been studied in ani - role in the support care of the can - was observed ( 15). mal models. Dietary supplementa - cer patient especially in relation to In a preliminary study, Bounous tion with whey was able to reduce GSH antioxidant properties . and colleagues used a whey pro - the incidence of tumours in rats Bounous demonstrated that whey tein concentrate in a small series and it is thought that lactoferrin , proteins have elevated levels of of cancer patients following the in particular, may be responsible cysteine residues (serum albumin, hypothesis according to which

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whey proteins can reduce the level Neoplastic cachexia A similar study carried out on of GSH in tumour cells (that con - cachectic patients showed that by tain elevated levels of GSH) mak - Another very important clinical adding a cycloxigenase-2 inhibitor ing them susceptible to the anti - aspect in oncology is represented to the products already in use , neoplastic effect of chemotherapy by neoplastic cachexia . A standard there was an increase in lean body (22). treatment of neoplastic cachexia mass, weight, appetite, improve - Regarding the antioxidant ability does not exist and many efforts ment of quality of life and a re - of GSH , a recent study considered have been made to improve condi - duction of fatigue (27). a whey protein concentrate en - tions in patients with cachexia . The impact of oral whey protein riched with cysteine and glutamic The following were used: medrox - supplementation was evaluated also acid (as principal precursors of yprogesterone acetate, glucocorti - in neoplastic cachexia. A recent GSH) (Prother TM ) used in addi - coids, antiserotonins to contrast study evaluated 66 patients with tion to a standard cancer treat - anorexia in the cachectic patient pulmonary cancer and 35 patients ment (radiotherapy and and stimulate appetite , prokinetic with advanced colon cancer sub - chemotherapy ) in patients with agents and antinausea drugs to jected to 6 months of oral supple - breast cancer (23) In 20 patients contrast a sense of satiety and mentation with cysteine rich whey treated for 12 months with a daily nausea due to opioids , branched proteins versus an oral supplemen - oral dose of 10 g of whey proteins chain aminoacids and eicosapen - tation with casein . Patients treated enriched with cysteine and whose tanoic acid as integrated support with casein enriched whey proteins oxidative balance was evaluated (24, 25). had a 2.5% increase in weight com - every two months, both an in - The neoplastic cachexia syndrome pared to a 2.6% loss in weight in crease in the antioxidant capacity is strictly due to a state of oxida - patients supplemented with oral of plasma (measured with the tive stress confirmed by increased casein . Cysteine, being a precursor BAP test) and in the oxidant ca - levels of ROS , reduced levels of not only of serum proteins but also pacity of plasma (measured with glutathione peroxidase and an in - of GSH (a powerful intracellular d-ROMs test) were recorded . In crease in serum proinflammatory antioxidant) may be considered as the patients with breast cancer and cytokines IL-6 (interleukin 6 ) and an important support therapy in undergoing chemo/radiotherapy TNF-alpha (tumour necrosis fac - fragile cancer patients with weight as treatment it was observed that tor alpha). The use of antioxidant loss (neoplastic cachexia) and may an increase in the consumption of agents such as alpha-lipoic acid, correct the redox state of plasma antioxidants reduced the plasmatic carbocysteine, amifostin, glu - swayed in an oxidative direction in antioxidant barrier (4), therefore tathione (GSH) and vitamins A, the cancer patient in a neoplastic the oral supplement therapy with C, E in advanced stage cancer pa - cachectic phase (28). the whey proteins used in this tients leads to the reduction of ox - study was able to progressively re- idative stress and serum levels of establish the potential antioxidant ROS and proinflammatory cy - Conclusions effect of plasma that returned to tokines and to an increase of glu - its optimal levels ( 23). tathione peroxidase activity corre - The use of natural or pharmaco - sponding to a good correlation logical nutritional supplements in with performance status (26). oncology, though supported by in -

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