Lymphoma, Chemotherapy, & Antioxidants

INTRODUCTION
Oxidative stress is defined as a type of physiological stress on the body caused by the damage done by free radicals inadequately neutralized by antioxidants. It has long been known that oxidative stress is an essential mechanism by which chemotherapy works to treat cancer. However, the question of whether this is always the case is seldom debated openly. Taking a deeper look into the research literature yields many examples where oxidative stress on cancer cells has been shown to be counterproductive. For example, a study using human Burkitt lymphoma cells found that oxidative stress actually interferes with the ability of the chemotherapy drugs doxorubicin, cisplatin, etoposide, and cytarabine to cause cancer cell death.

When oxidative stress levels are reduced in cancer cells, their growth is more easily controlled through a process called apoptosis. During apoptosis, cells are removed by the immune system before they lose their cell wall, thus avoiding an inflammatory response to the dying cells.
However, when oxidative stress levels go up, cancer cell death happens through a slower, messier, and less effective pathway called pyknosis or necrosis. Additionally, the ability of the body to “clean up” the resulting cellular debris from cancer cell death is also inhibited by oxidative stress. The body’s house-cleaning cells (called monocyte-derived macrophages) cannot function optimally under conditions of oxidative stress (i.e. low oxygen levels).

The authors of the above-mentioned study on Burkitt lymphoma cells and chemotherapy suggest that including antioxidants in the treatment protocol may enhance chemotherapy-induced apoptosis and phagocytosis. (Shacter, Williams et al. 2000) A second study, involving the chemotherapy drugs etoposide and calcimycin, confirms this finding: Human Burkitt’s lymphoma cells were unable to die quickly by apoptosis in the presence of oxidative stress and instead died using the slower and messier method of necrosis. In this study, it was found that oxidative stress inhibited apoptosis by depleting cells of their energy source, which is called adenosine triphosphate (ATP). (Lee and Shacter 1999)

Related to these observations about the relationship between cellular oxidative stress levels is the widely held view in medicine that the use of antioxidant dietary supplements diminishes chemotherapy’s effectiveness. However, when one looks more closely at the existing published science on how antioxidants and chemotherapy combine, the true answer is not so definitive. Many research studies, encompassing cell culture tests in the laboratory and also animal and some human studies, are coming to a conclusion often very different from the conventional perspective that chemotherapy and antioxidants should never be combined.

One example is a human study in which researchers discovered that higher levels of the antioxidant selenium in the blood of patients with aggressive B-cell non-Hodgkin’s lymphoma correlated with increased achievable doses of anthracycline based chemotherapy, better treatment response, achievement of long term remission, and longer overall survival. It is important to note that in this study, however, the level of selenium present in the blood of patients was from their diet; the study was not a test of supplemented selenium. (Last, Cornelius et al. 2003) As seen in this study, higher levels of natural antioxidants can help treatment outcomes.

On the other hand, the decreased levels of antioxidants (or oxidative stress) that are caused by many chemotherapy treatments correlates with increased side effects. In patients with Hodgkin’s lymphoma, chemotherapy with Adriamycin, bleomycin, vincristine, and dexamethasone significantly decreases antioxidant levels. (Kaya, Keskin et al. 2005) In children with acute lymphoblastic leukemia who received high-dose methotrexate, oxidative damage to proteins as well as other factors was related to toxic side effects. (Carmine, Evans et al. 1995)

Using antioxidants during chemotherapy is an important and controversial question among health care providers, patients, and their support teams. In previous issues of Avenues, we have researched this subject thoroughly for prostate, breast, lung, colon, and ovarian cancers. In this article, we turn our focus to lymphoma, conducting a systematic search for published research that would support or discourage the use of antioxidants in combination with chemotherapy. The overwhelming majority of studies find a favorable interaction between antioxidants and chemotherapy, providing evidence that antioxidants can decrease chemotherapy side effects, increase treatment effectiveness, and decrease resistance to chemotherapy.

For this paper, we searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world. Some of these studies are still in early stages and include only laboratory or animal data while others have advanced to include human volunteers. We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. used cancer cell cultures), used animals, or involved human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

Bendamustine

CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 2,000 mg daily. Take with meals, as curcumin can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with Bioperine, an extract from black pepper.

In non-Hodgkins lymphoma cells (not cell cultures, but rather cells taken directly from bone marrow of patients), curcumin increased bendamustine treatment effect, likely due to NF-KappaB inhibition by curcumin. (Alaikov, Konstantinov et al. 2007)

Cisplatin

TEMPOL & MNTBA
Tempol is an antioxidant drug that is used to prevent hair loss for cancer patients undergoing treatment. MnTBA is a synthetic antioxidant.

When combined with Tempol or MnTBA, cisplatin was found to induce cell death in human B lymphoma cells without any detectable oxidative stress. Furthermore, there was no inhibition of the ability of cisplatin to destroy cancer cells. (Senturker, Tschirret-Guth et al. 2002)

COMBINATIONS TO AVOID:
CISPLATIN WITH N-ACETYL CYSTEIN

In human B lymphoma cells, N-acetyl cysteine inhibited cisplatin induced cell death, but not because of interference with oxidative stress. (Senturker, Tschirret-Guth et al. 2002) N-acetyl cysteine is known to inactivate cisplatin and also decrease absorption of cisplatin into cancer cells cell. (Kroning, Lichtenstein et al. 2000)

Cyclophosphamide

METHYLSELENINIC ACID (MSA)
Methylseleninic Acid is an organic selenium compound, produced by the body’s metabolism of the mineral selenium found in foods. Brazil nuts are the single best food source of selenium. Selenium is as an antioxidant most widely known as a cancer preventive.

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium. Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms, such as of Se-Methylselenocysteine, or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

MSA increased the chemotherapeutic effect of cyclophosphamide in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of cyclophosphamide was increased from 19% (cyclophosphamide alone) to 50% (cyclophosphamide with MSA) in sensitive cells and from 7% (alone) to 22% (with MSA) in resistant cells. (Juliger, Goenaga-Infante et al. 2007)

SULFOETHYL GLUCAN
Sulfoethyl-glucan is a beta-1,3-D-glucan derivative from the baker’s yeast Saccharomyces cerevisiae. Besides stimulating the immune system, it has high antioxidant and antimutagenic activity (reduces damage to DNA). (Krizkova, Durackova et al. 2003)

» Beta-1,3 D-glucan: Typical dosages range from 100 to 500 mg per day.

Sulfoethyl glucan derived from yeast polysaccharide enhanced the effect of cyclophosphamide in mice with lymphosarcoma both sensitive and resistant to chemotherapy. (Khalikova, Zhanaeva et al. 2005; G, M et al. 2008)

RETINOIDS & MELATONIN
Retinoids are vitamin A derivatives. Vitamin A (retinol) is a fat-soluble, antioxidant vitamin important for bone growth and vision. Vitamin A is ingested in a precursor form from animal foods and is especially plentiful in cod liver oil. Other good sources include butter and egg yolks as well as whole milk, cream, and yogurt.

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

Melatonin is a hormone that is released from the pineal gland in the evening and promotes normal sleep; its secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. It is also known to reduce metastasis in cancer patients. In most published studies, melatonin shows a beneficial effect, although it has been reported that in a small proportion of people, melatonin can paradoxically cause sleep disturbance. In others, there can be residual daytime drowsiness, which is usually resolved by using a lower dose.

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2 am. To do so, one can take the melatonin at bedtime, ideally between 9 pm and 10 pm.

Twenty patients with stage III or IV low-grade non-Hodgkin’s lymphomas received one month of treatment with cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH (Adrenocorticotropic hormone).

Somatostatin is a naturally occurring hormone (which may be given as a prescription drug) that inhibits the release of growth hormone (GH, somatotropin) and thyroid-stimulating hormone (TSH). Bromocriptine is a drug used in the treatment of pituitary tumors and Parkinson’s disease and is a dopamine agonist.

This treatment was continued if patients had stable or responding disease. After one month, 70% of patients had a partial response, 20% had stable disease, and 10% progressed during treatment. Of the 70% of patients who had a partial response, none had disease progression (average follow up time was 21 months) and 50% of these patients had a complete response. Of the 20% of patients who in the first month of treatment had stable disease, 25% had a partial response and 75% progressed on therapy. Toxicity was mild and included drowsiness, diarrhea, and hyperglycemia. (Todisco, Casaccia et al. 2001)

In a case report, a patient who experienced a relapse of high-grade non-Hodgkin lymphoma two years after autologous stem cell transplant was treated with cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH (Adrenocorticotropic hormone). Side effects were minimal and the patient was able to continue normal activities. After two months of treatment, the patient had a partial response and after five months, a complete response. At the time the case report was written, the patient was in complete remission 14 months after beginning treatment. (Todisco 2006)

In a second case report, a patient with stage IV low grade non-Hodgkin lymphoma was treated with cyclophosphamide, somatostatin, bromocriptine, retinoids, and melatonin. Side effects were minimal and the patient was able to continue normal activities. After two months of this treatment, he had a partial response and after five months a complete response. At the time of the case report, 18 months after beginning treatment, the patient was in complete remission. (Todisco 2007)

Doxorubicin

COENZYME Q10 (COQ10)
CoQ10 is naturally produced in the body and is necessary for the basic functioning of cells. CoQ10 is also found in dietary sources such as fish, meat, spinach, broccoli, peanuts, and whole grains. It is a vitamin-like substance that can also act as an antioxidant. Among other functions, it is incorporated into the mitochondria of cells throughout the body and facilitates and regulates the transformation of fats and sugars into energy. Patients with heart problems often use CoQ10.

» CoQ10: Dosages range from 15 mg to 600 mg per day.

Twenty children with acute lymphoblastic leukemia or non-Hodgkin lymphoma were treated with anthracycline chemotherapy (this family of drugs include doxorubicin and daunorubicin, among others). Heart related side effects are a major concern with anthracycline chemotherapy, so ten of these children also received CoQ10 to test the ability of CoQ10 to protect the heart. The children receiving CoQ10 experienced less cardiac effects than the children receiving no CoQ10. Percentage left ventricular fractional shortening decreased more in children not taking CoQ10. Interventricular septum wall thickness decreased only in children who did not take CoQ10 and abnormalities of the septum wall motion was similarly only detected in children not taking CoQ10. Overall this study found a protective effect of taking CoQ10 with anthracycline chemotherapy. (Iarussi, Auricchio et al. 1994)

METHYLSELENINIC ACID (MSA)
MSA increased the chemotherapeutic effect of doxorubicin in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of doxorubicin was increased from 21% (doxorubicin alone) to 49% (doxorubicin with MSA) in sensitive cells and from 8% (alone) to 44% (with MSA) in resistant cells. A 50% reduction of NF-kappaB activity was seen after exposure to MSA, perhaps one of the mechanisms by which MSA works synergistically with chemotherapy. (Juliger, Goenaga-Infante et al. 2007)

VITAMIN B6 (PYRIDOXINE)
Vitamin B6 comes from a variety of dietary sources, such as turkey, tuna, spinach, banana, lentils, and potatoes.

» Vitamin B6: Typical doses range between 10 mg and 200 mg per day. Individuals using more than 100 mg per day for more than two months should be supervised by a health care professional, as chronic overdose may lead to sensory neuropathy.

To test if vitamin B6 could help prevent palmar-plantar erythrodysesthesia (PPES) or hand-foot syndrome, an animal study (randomized, double-blinded clinical trial) included forty-one dogs with non-Hodgkin lymphoma that received Doxil chemotherapy. Doxil is a drug that is made by placing doxorubicin into a fat bubble called a liposome. The dogs were randomized to receive either oral vitamin B6 or placebo daily during Doxil chemotherapy (total of five Doxil treatments of 1 mg/kg i.v. every 3 weeks). Vitamin B6 did not completely prevent hand-foot syndrome in the dogs, however it decreased the risk of serious hand-foot syndrome and therefore prevented dose reduction or discontinuation of Doxil therapy. Dogs receiving vitamin B6 came close to the cumulative target dose of Doxil at a median dose of 4.7 mg/kg (compared to the target dose of 5 mg/kg). Dogs receiving placebo were only able to tolerate a median dose of 2.75 mg/kg. There was a trend toward longer remission length in the dogs receiving vitamin B6 likely because they were able to receive more Doxil without delays or discontinuation of treatment. (Vail, Chun et al. 1998)

Etoposide

N-ACETYL CYSTEINE, TEMPOL, & MNTBAP
N-acetyl cysteine is an efficiently absorbed and used form of the amino acid L-cysteine. L-cysteine, L-glutamic acid, and glycine are the three amino acids that form glutathione, which is one of the most important and powerful antioxidants in the body.

» N-acetyl cysteine: Typical dosages range between 600 mg and 1,800 mg per day.

Etoposide was found to induce cell death in human B lymphoma cells without any detectable oxidative stress. Furthermore, the antioxidants N-acetyl cysteine, Tempol, and MnTBAP did not inhibit Etoposide induced cell death. (Senturker, Tschirret-Guth et al. 2002)

GREEN TEA EXTRACT – EPIGALLOCATECHIN-3-GALLATE (EGCG)
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol (a group of antioxidants) found in green tea.

» EGCG: One cup of green tea contains between 10 mg and 400 mg of polyphenols depending on the source, amount of leaves used, and steeping time. EGCG may be conven2iently obtained from extracts. Among the green tea extract dietary supplement products, a desirable potency is standardized to 98% polyphenols, 45% of which is EGCG.

In a lymphoma cell line called B-lymphoblastoid Ramos, EGCG enhanced the chemotherapeutic effect of etoposide. (Noda, He et al. 2007)

METHYLSELENINIC ACID (MSA)
MSA increased the chemotherapeutic effect of etoposide in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of etoposide was increased from 32% (etoposide alone) to 60% (etoposide with MSA) in sensitive cells and from 4% (alone) to 22% (with MSA) in resistant cells. (Juliger, Goenaga-Infante et al. 2007)

Methotrexate

VITAMIN A
In a prospective randomized un-blinded clinical trial, vitamin A was given with high-dose-methotrexate to children with leukemia and lymphoma to see if vitamin A could protect against chemotherapy induced intestinal malabsorption. Thirty five children participated in the trial. Twenty-two patients received a single dose of 180,000 IU before methotrexate chemotherapy and thirteen patients received chemotherapy only. There was no difference in blood, skin, and organ toxicities. Intestinal absorption was significantly better in children receiving vitamin A. Absorption was decreased in only five of twenty-two (23%) children receiving vitamin A, compared to eight of thirteen (62%) children receiving chemotherapy only. Therefore, this study found some benefit to vitamin A treatment to prevent mucosal damage and therefore malabsorption in the intestines. (Dagdemir, Yildirim et al. 2004)

Rituximab

Rituximab is a newly-developed antibody therapy, not a traditional chemotherapy.

BETA-1,3 D-GLUCAN
Beta-1,3 D-glucan is derived from yeast and is a macrophage stimulator. Macrophages are an important part of the immune system.

» Beta-1,3 D-glucan: Typical dosages range from 100 mg to 500 mg per day.

In an animal study with mice, some of which had non-Hodgkin’s lymphoma and some Hodgkin’s lymphoma, the combination of rituximab and beta-1,3 D-glucan was significantly more effective than either rituximab or beta-glucan treatment alone. Mice with widespread lymphoma had significantly increased survival in the mice receiving the combination of rituximab and beta-glucan. No toxicity due to the combination was observed. (Modak, Koehne et al. 2005)

Cyclophosphamide, Vincristine, & Doxorubicin

L-CARNITINE
L-carnitine is an antioxidant that comes from protein-rich dietary sources such as red meat and dairy. L-carnitine helps convert fatty acids into energy; as a supplement, it is used among other things for increased energy, heart health, and age related memory loss (Acetyl-L-carnitine is preferred for memory). Although often used for weight loss, no clinical evidence has emerged that supports effectiveness for this application.

» L-carnitine: Typical doses range from 300 mg to 4000 mg. If using high doses, taking half the dose twice daily is beneficial.

In a clinical trial, L-carnitine was given to investigate if it could reduce cardiotoxicity from chemotherapy. Twenty patients received 3 g of L-carnitine intravenously before each chemotherapy cycle, followed by 1 g of L-carnitine orally per day for 21 days. Another twenty patients received placebo. Chemotherapy consisted of six CHOP cycles (cyclophosphamide 750 mg/m2 in 500 mL NaCl, vincristine 1.4 mg/m2, max. 2 mg absolute; doxorubicin 50 mg/m2 in 259 mL NaCl; days 2–5: prednisolone 100 mg p.o.). Cumulative doxorubicin doses of up to 600 mg/m2 were reached in this study. No cardiotoxicity occurred in either group. Survival, quality of life, and duration of remission was the same in both groups. Thus this study found no adverse effect of L-carnitine on effectiveness of chemotherapy. (Waldner, Laschan et al. 2006)

In a previous study, fifteen cancer patients receiving doxorubicin treatment had increased cardiac abnormalities with higher cumulative doses of doxorubicin. A trend towards lower serum carnitine levels was also observed with higher cumulative doses of doxorubicin, which was what led the study authors to consider investigating the role of carnitine in prevention of cardiac side effects. (Yaris, Ceviz et al. 2002)

GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones such as genistein also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

» Genistein: A good product will use organic non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is 1,500 mg. The recommended dose for further research is between 100 mg and 1,100 mg. (Boik 2001) One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

In mice with large cell lymphoma, the CHOP chemotherapy regimen was given along with genistein (genistein was given for 5 days before CHOP). The combination of CHOP and genistein led to greater tumor growth inhibition than CHOP alone. The tumor growth was delayed 17 days in mice given the combination of genistein and CHOP and only 8 days in mice given CHOP alone. Genistein decreased NF-kappaB and increased the Bax/Bcl-2 ratio. (Mohammad, Al-Katib et al. 2003)

CONCLUSIONS
The 23 studies reviewed in this article provide compelling evidence suggesting that the question of chemotherapy in combination with antioxidants in the treatment of lymphoma deserves reconsideration, further discussion, and further research. We have reviewed cell culture, animal, and human clinical studies. It is important to note that 22 of these 23 studies identified either beneficial outcomes to combining antioxidants with chemotherapy or provided evidence dispelling the assumption that increased oxidative stress is required for chemotherapy to be effective. Although these studies are not conclusive, they nevertheless provide a basis for re-examining the long-held assumption that antioxidants are always contraindicated in the context of chemotherapy treatment for lymphoma.

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