Mitigation of Chemotherapy Side Effects
- Vitamins E and C and N-Acetyl-Cysteine
- Whey Protein
- Antinausea Drugs
- Shark Liver Oil
- Protecting Immune Function
- Enhancing Immune Function
Cancer chemotherapy is known to produce severe side effects such as heart muscle damage, gastrointestinal damage, anemia, nausea, and lethal suppression of immune function.
Nutrients and hormone therapies can be used to mitigate the toxicity of chemotherapy. Bolstering the immune system may help alleviate or lower the severity of the complications associated with chemotherapy. As discussed earlier in this protocol, however, using natural antioxidants to protect against chemotherapy side effects could possibly reduce the cancer cell-killing efficacy of the cytotoxic drug(s). Regrettably, there are no survival studies to verify the long-term effects of using natural therapies to mitigate the toxic effects that chemotherapy inflicts on healthy cells. In other words, we know that certain nutrients can protect against the immediate toxic effects of chemotherapy, but we do not know if this protection extends to cancer cells in such a way as to diminish survival.
For those who choose to use antioxidants to protect against chemotherapy side effects, supplementation with these nutrients should be initiated several days or even weeks before any planned chemotherapy is begun and should be continued well after the chemotherapy has been completed.Vitamins E and C and N-Acetyl-Cysteine
Vitamins E and C and N-acetyl-cysteine (NAC) can protect against heart muscle toxicity for cancer patients undergoing high doses of chemotherapy. A controlled study examined the effects of these nutrients on cardiac function on a group of chemotherapy and radiation patients. One group was given supplements of vitamins C and E and NAC, while the other group was not supplemented. In the group not supplemented, left ventricle function was reduced in 46% of the chemotherapy patients compared to those who took the supplements. Furthermore, none of the patients from the supplement group showed a significant fall in overall ejection fraction, but 29% of the nonsupplement group showed reduced ejection fraction (Wagdi et al. 1996).
Another study showed vitamin C improved the antineoplastic activity of the chemotherapeutic drugs doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells. Patients reported improved appetite while taking vitamin C, as well as a reduced need for painkillers.
Vitamin E has been shown to protect against cardio-myopathies induced by chemotherapy. Vitamin E has also been used in combination with vitamin A and CoQ10 to reduce the side effects of the chemotherapy drug Adriamycin (doxorubicin). Vitamin E is complementary to chemotherapy in that it boosts the effectiveness of the drugs. One study showed enhanced efficacy of both 5-FU and doxorubicin against human colon cancer cells with vitamin E (Chinery et al. 1997).Note:
Fluorouracil, or 5-FU, is an antineoplastic agent used in the palliative management of certain cancers.
The mechanism of action of vitamin E appears to be the induction of the tumor suppressor protein p21. The dry powder succinate form of vitamin E appears to be most beneficial to cancer patients. The more common acetate form has proven ineffective in slowing cancer cell growth in some test tube studies, whereas natural dry powder vitamin E succinate has shown efficacy (You et al. 2001).
Still another study specifically suggested that cancer patients treated with Adriamycin should supplement with vitamins A and E and selenium to reduce its toxic side effects (Faure et al. 1996).CoQ10
CoQ10 is used with vitamin E to protect patients from chemotherapy-induced cardiomyopathies. CoQ10 is nontoxic even at high dosages and has been shown to prevent liver damage from the drugs Mitomycin C and 5-FU. Adriamycin-induced cardiomyopathies have been prevented by concomitant supplementation with CoQ10.
Some studies indicate that CoQ10 should not be taken at the same time as chemotherapy. If this is true, it would be disappointing because CoQ10 is so effective in protecting against Adriamycin-induced cardiomyopathy. Adriamycin is sometimes used as part of a chemotherapy cocktail. Until more research is known, it is not possible to make a definitive recommendation of whether to take CoQ10 during chemotherapy.Selenium
Selenium has been used in combination with vitamin A and vitamin E to reduce the toxicity of chemotherapy drugs, particularly Adriamycin (Faure et al. 1996; Vanella et al. 1997). The synergistic effect of vitamin E and selenium together to enhance the immune system is greater than either alone. A new form of selenium is Se-methylselenocysteine (SeMC), a naturally occurring selenium compound found to be an effective chemopreventive agent. SeMC is a selenoamino acid that is synthesized by plants such as garlic and broccoli. SeMC has been shown to induce apoptosis in certain ovarian cancer cells (Yeo et al. 2002) and to be effective against breast cancer cell growth both in vivo and in vitro (Sinha et al. 1999). SeMC has also demonstrated significant anticarcinogenic activity against mammary tumorigenesis (Sinha et al. 1997). Moreover, a study has demonstrated that SeMC is one of the most effective selenium chemopreventive compounds, inducing apoptosis in leukemia HL-60 cell lines (Jung et al. 2001a). Some of the most impressive data suggest that exposure to SeMC blocks clonal expansion of premalignant lesions at an early stage. This is achieved by simultaneously modulating certain molecular pathways that are responsible for inhibiting cell proliferation and enhancing apoptosis (Ip et al. 2001).
Unlike selenomethionine, which is incorporated into protein in place of methionine, SeMC is not incorporated into any protein, thereby offering a completely bioavailable compound for preventing cancer. Therefore, 200-400 mcg of SeMC a day is suggested for cancer patients. Please note that selenium also possesses antioxidant properties, so its use before, during, or immediately after chemotherapy could theoretically inhibit the actions of certain chemotherapy drugs.Whey Protein
Glutathione balance is very important for the cancer patient. Glutathione is an antioxidant that protects cells from toxic chemotherapeutic compounds. It is also understood that glutathione in the cancer cells is actually very high and acts to protect against the destructive actions of chemotherapy and radiation. Some patients, when using whey, find it actually lowers the cancer cell glutathione levels, allowing the chemotherapy and radiation to be more effective at destroying the cancer.
A group of researchers showed that tumor cell glutathione concentration may be among the determinants of the cytotoxicity of many chemotherapeutic agents and radiation, and an increase in glutathione concentration in cancer cells appears to be at least one of the mechanisms of acquired drug resistance to chemotherapy. Whey proteins used in combination with glutathione appear to reduce the concentrations of glutathione in cancer cells, thereby making them more vulnerable to chemotherapy while maintaining or even increasing glutathione levels in normal healthy cells.
Researchers found that cancer cells had reduced glutathione levels in the presence of whey protein while at the same time normal cells had increased levels of glutathione levels with increased cellular growth of healthy cells. The study concluded: "Selective depletion of tumor GSH may, in fact, render the malignant cells more vulnerable to the action of chemotherapeutic agents" (Kennedy et al. 1995).
Glutathione production in cancer and healthy cells is negatively inhibited by its own synthesis. Because glutathione levels are higher in cancer cells, it is believed that cancer cells would reach a level of negative-feedback inhibition for glutathione production more easily than normal cells.
Chemotherapy patients should consider taking 30-60 grams a day of whey protein concentrate 10 days before initiation of chemotherapy, during the chemotherapy, and at least 10 days after the chemotherapy session is completed.Note:
If blood testing shows that chemotherapy has suppressed the immune system, patients should insist that their oncologists use the appropriate immune restoration drug(s) as outlined later in this protocol.
Research using whey protein concentrate has led researchers to a discovery regarding the relationship between cancerous cells, glutathione, and whey protein concentrate. As mentioned, it was found that whey protein concentrate selectively depletes cancer cells of their glutathione, making them more susceptible to cancer treatments such as radiation and chemotherapy (Bounous 2000; Tsai et al. 2000).
This difference in glutathione status between normal cells and cancer cells is believed to be an important factor in cancer cells' resistance to chemotherapy.Antinausea Drugs for Chemotherapy Patients
Nausea is one of the most common and most difficult aspects of chemotherapy for cancer patients. Nausea can have secondary effects on cancer patients by interfering with their eating habits during and immediately after chemotherapy.
Drugs to mitigate chemotherapy-induced nausea include Kytril, Megace, and Zofran. The high cost of some of these drugs has kept many cancer patients not covered by insurance from obtaining one of these potentially beneficial drugs. If you are receiving chemotherapy and are experiencing nausea, you should be able to demand that any HMO, PPO, or insurance carrier pay for this class of drug. These kinds of drugs can enable a cancer patient to tolerate chemotherapy long enough for it to possibly be effective. An interesting study evaluated glutathione and vitamins C and E for their antiproperties. Cisplatin-induced vomiting in dogs was significantly reduced by glutathione and vitamins C and E. The antinauseate activity of antioxidants was attributed to their ability to react with free radicals generated by cisplatin. Ginger extract has also been shown effective in reducing nausea symptoms (Keating et al. 2002).Shark Liver Oil (Not Shark Cartilage)
Chemotherapy causes a reduction in blood cell production. A natural therapy to restore healthy platelet production is 5 capsules a day of standardized shark liver oil, containing 200 mg of alkylglycerols a capsule. Studies have shown that shark liver oil can boost the production of blood platelets. Studies have also shown the immune-enhancing capabilities of shark liver oil (Pugliese et al. 1998).
Shark oil capsules should be taken at a dose of 5 capsules containing 200 mg of active alkylglycerols for a maximum duration of 30 days. A complete blood count (CBC) and platelet count should be obtained weekly to monitor the effectiveness of shark liver oil and to prevent against excessive platelet production, that is, values greater than 400,000. Platelet counts exceeding 400,000 have been associated with increased risks of both thrombosis and hemorrhage.MelatoninMelatonin Precautions
(10g-1) Melatonin has been shown to protect against chemotherapy-induced immunosuppression. Melatonin mediates the toxicity of chemotherapy and inhibits free-radical production (Lissoni et al. 1999). In a randomized study to evaluate the effect of melatonin on the toxicity of chemotherapy drugs, patients receiving melatonin with chemotherapy had lower incidences of neuropathies, thrombocytopenia, stomatitis, alopecia, malaise, and vomiting. The appropriate dose was between 30-50 mg at bedtime (Lissoni et al. 1997a). Another study reported similar results (Lissoni et al. 1997b). This study suggests that adding melatonin to a chemotherapy regimen may prevent some toxic effects of the chemotherapy drugs, especially myelosuppression (suppression of blood cells and platelets produced in bone marrow) and neuropathies (abnormality of nerve functioning both within and outside the central nervous system). It is important to understand that melatonin protects against toxicities such as thrombocytopenia but does not readily reverse them. If melatonin is considered, it should start before chemotherapy is initiated.
Melatonin may also be an especially effective and safe therapy to correct thrombocytopenia, a condition characterized by a decrease in the number of blood platelets. A study was performed to evaluate the influence of melatonin on chemotherapy toxicity. Patients randomly received chemotherapy alone or chemotherapy plus melatonin (20 mg each evening). Thrombocytopenia was significantly less frequent in patients treated with melatonin (Lissoni 2002).
Malaise and lack of strength were also significantly less frequent in patients receiving melatonin. Finally, stomatitis (inflammation of the mouth area) and neuropathy were less frequent in the melatonin group. Alopecia and vomiting were not influenced (Lissoni et al. 1997b). This pilot study seems to suggest that administration of melatonin during chemotherapy may prevent some chemotherapy-induced side effects, particularly myelosuppression and neuropathy.
Oncologists often prescribe drugs (Leukine) that work in a similar way as melatonin to protect the immune system. Leukine, for instance, is a granulocyte/macrophage colony-stimulating factor drug that can restore immune function debilitated by toxic cancer chemotherapy drugs. If you are on chemotherapy and your blood tests show white blood cell immune suppression, you should request the appropriate immune restoration drug (such as Leukine or Neupogen) from your medical oncologist.
Studies have shown that melatonin specifically exerts colony-stimulating activity and rescues bone marrow cells from apoptosis induced by cancer chemotherapy compounds The number of granulocyte/macrophage colony-forming units has been shown to be higher in the presence of melatonin. The dose used in the studies was between 30-50 mg nightly (Maestroni et al. 1994a; 1994b; 1998).
Melatonin has been seen to enhance the anticancer action of interleukin-2 (IL-2) and to reduce IL-2 toxicity when used in combination. Melatonin used in association with IL-2 cancer immunotherapy has been shown to have the following actions:
- Amplification of IL-2 biological activity by enhancing lymphocyte response and by antagonizing macrophage-mediated suppressive events
- Inhibition of production of tumor growth factors that stimulate cancer cell proliferation by counteracting lymphocyte-mediated tumor cell destruction
- Maintenance of a circadian rhythm of melatonin, which is often altered in human neoplasms and influenced by cytokine exogenous injection
The subcutaneous administration of 3 million IU a day of IL-2 and high doses of melatonin (40 mg each evening orally) has appeared to be effective in tumors resistant either to IL-2 alone or to chemotherapy. The dose of 3 million IU a day of IL-2 is a low dose, while serious toxicity normally begins at 15 million IU a day.
European oncologists have treated numerous end-stage solid tumor patients with the melatonin/IL-2 combination. The conclusion drawn from clinical studies is that melatonin protects against IL-2 toxicity and synergizes with the anticancer action of IL-2 (Conti et al. 1995). The combination strategy was shown to be a well-tolerated therapy to control tumor growth.
In the largest clinical study to date, the effects of melatonin were evaluated in 1440 patients with untreatable advanced solid tumors. One group received supportive care alone, while the other group received supportive care plus melatonin. In a second study, the influence of melatonin on the efficacy and toxicity of chemotherapy was evaluated in 200 metastatic patients with chemotherapy-resistant tumors. These patients were randomized to receive chemotherapy alone or chemotherapy plus melatonin. In both studies, 20 mg of melatonin were given orally during the dark period of each day. The results showed that frequency of cachexia, asthenia, thrombocytopenia, and lymphocytopenia was significantly lower in patients treated with melatonin compared to those who received supportive care alone.
Moreover, the percentage of patients with disease stabilization and the percentage with 1-year survival were both significantly higher in patients concomitantly treated with melatonin than in those treated with supportive care alone. The objective tumor response rate was significantly higher in patients treated with chemotherapy plus melatonin than in those treated with chemotherapy alone. In addition, melatonin induced a significant decline in the frequency of chemotherapy-induced asthenia, thrombocytopenia, stomatitis, cardiotoxicity, and neurotoxicity. These clinical results demonstrate that melatonin may be successfully administered in the supportive care of untreatable advanced cancer patients and for the prevention of chemotherapy-induced toxicity (Lissoni 2002).Table 3: Summary of Studies Using Melatonin
Lissoni's Phase II Randomized Clinical Trial Results
||No. of Patients
|Metastatic Nonsmall Cell Lung
Metastatic Nonsmall Cell Lung
|Supportive Care Only
|Compiled by Cancer Treatment Centers of America and published in the March 2002 issue of Life Extension magazine.|
The Life Extension Foundation introduced the world to melatonin in 1992, and it was the Life Extension Foundation that issued the original warnings about who should not take melatonin. These warnings were based on preliminary findings, and in two instances, the Foundation was overly cautious.First, we suggested that prostate cancer patients might want to avoid high doses of melatonin.
However, subsequent studies indicated that prostate cancer patients could benefit from moderate doses of melatonin, although the Foundation still advises prostate cancer patients to have their blood tested for prolactin. (Prolactin is a hormone secreted by the pituitary gland. Its role in the male has not been demonstrated, but in females, prolactin promotes lactation after childbirth.) Melatonin could possibly elevate prolactin secretion, and if this were to happen in a prostate-cancer patient, the drug Dostinex (0.5 mg twice a week) could be used to suppress prolactin so that the melatonin could continue to be taken (in moderate doses of 1-6 mg each night). Please note that the starting dose of Dostinex is 0.125 mg twice a week. If well-tolerated, increase to 0.25 mg twice a week. If again well-tolerated after 2 weeks, then increase to 0.5 mg twice a week while checking morning fasting prolactin levels.Some physicians initially thought that melatonin should not be taken by ovarian cancer patients, but a study in Oncology Reports indicated that high doses of melatonin may be beneficial in treating ovarian cancer.
In this study, 40 mg of melatonin were given nightly, along with low doses of IL-2, to 12 advanced ovarian cancer patients who had failed chemotherapy. While no complete response was seen, a partial response was achieved in 16% of patients, and a stable disease was obtained in 41% of the cases (Lissoni et al. 1996). This preliminary study suggested that melatonin is not contraindicated in advanced ovarian cancer patients. It is still not known what the effects of melatonin are in leukemia; therefore, leukemia patients should use melatonin with caution.Protecting Immune Function
Cancer patients using cytotoxic chemotherapy drugs should ask their oncologist to place them on FDA-approved immune-protective medications concurrently with chemotherapy. Leukine in particular partially restores immune cell production lost due to the toxic effects of chemotherapy. The primary benefit of Leukine is to stimulate macrophage production to prevent bacterial infection in the chemotherapy patient. Macrophages also engulf cancer cells and assist in their destruction by the immune system (Kobrinsky et al. 1999). In one study, patients with refractory (resistant to treatment) solid tumors treated with standard chemo-therapy and Leukine had a 33.3% objective response rate versus 15% with chemotherapy alone (Baxevanis et al. 1997).
The timing of administration of colony-stimulating drugs such as Leukine is crucial. The oncologist should not wait until there are toxic bone marrow effects to prescribe them. The administration of Leukine should be timed to be initiated 24-48 hours after the last round of chemotherapy in order to prevent a dangerous nadir (precipitous decline) in immune cells (granulocytes). The proper administration of Leukine can dramatically reduce the immune damage that chemotherapy inflicts on the body and increase the cancer cell-killing efficacy of conventional chemotherapy drugs.Enhancing Immune Function
Alpha-interferon and/or IL-2 are immune cytokines (regulators) that should also be considered by some cancer patients. Interferon directly inhibits cancer cell proliferation and has already been used in the therapy of hairy cell leukemia, Kaposi's sarcoma, and malignant melanoma and squamous cell carcinomas. IL-2 allows for an increase in the cytotoxic activity of natural killer (NK) cells. An oncologist must carefully administer these drugs because they can produce temporary side effects. A significant side effect of interferon is that it can leave some patients temporarily debilitated. That is one reason why interferon has not become more popular. A cancer patient has to weigh the benefit of achieving complete tumor eradication in relation to the debilitation occurring during the time of active therapy. A typical dose of alpha-interferon is 3 million IU administered by self-injection daily for 2 weeks. To mitigate the debilitating effects, most patients take interferon for 2 weeks and then skip 2 weeks. IL-2 has been self-administered by subcutaneous injection to cancer patients in the dose of 3-6 million IU a day for 5-6 days each week.Note:
Interferon has been shown to work on squamous cell carcinomas but not on more common adenocarcinomas.
Retinoic acid (vitamin A) analog drugs enhance the efficacy of some chemotherapy regimens and reduce the risk of secondary cancers. These vitamin A analog drugs have been shown to work well when taken in conjunction with alpha-interferon. Ask your oncologist to consider prescribing vitamin A analog drugs such as Accutane (13-cis-retinoic acid) or Vesanoid (all-trans retinoic acid). The use of a retinoid drug therapy depends on your type of cancer. Some cancers have historically responded well to retinoid drug therapy while others have not. The tumor cell testing recommendations in the protocol Cancer Therapy: The Critical Factors can help determine whether retinoid drug therapy is appropriate. Your attending oncologist must carefully prescribe the use and dosage of potentially toxic retinoid drugs such as Accutane.
Some cancer patients produce too many T-suppressor cells that shut down optimal immune function. The administration of drugs such as cimetidine helps to prevent cancer cells from prematurely shutting down the immune system. Cimetidine, also known as Tagamet, is an over-the-counter medication that blocks the action of histamine on stomach cells and reduces stomach acid production. An immune cell blood test will reveal the status of your T-helper cells, T-suppressor cells, and natural killer (NK) cell count and activity. A suggested cimetidine-dosing regimen is 800 mg each night. Cimetidine also interferes with metastasis by blocking the expression of an adhesion molecule known as E-selectin that enables cancer cells to bind to blood vessel walls and start metastatic colonies.
Cimetidine may increase the toxicity of certain chemotherapy drugs. One study showed that cimetidine increased blood concentrations of the drug epirubicin used to treat breast cancer (Murray et al. 1998), while another study showed that cimetidine combined with 5-fluorouracil dramatically improved survival in certain types of colon cancer (Matsumoto et al. 2002). If you are taking cimetidine, tell your oncologist so that the dose of a chemotherapy drug can be adjusted if necessary.Natural Approaches to Enhancing Chemotherapy EfficacyFish Oil and Chemotherapy
Fish oil may enhance the effectiveness of cancer chemotherapy drugs. A study compared different fatty acids on colon cancer cells to see if they could enhance Mitomycin C, a chemotherapy drug. Eicosapentaenoic acid (EPA) concentrated from fish oil was shown to sensitize colon cancer cells to Mitomycin C (Tsai et al. 1997). It should be noted that fish oil also suppresses the formation of prostaglandin E2, an inflammatory hormone-like substance involved in cancer cell propagation.
In another study, a group of dogs with lymphoma was randomized to receive either a diet supplemented with arginine and fish oil or just soybean oil. Dogs on the fish oil and arginine diet had a significantly longer disease-free survival time than dogs on the soybean oil (Ogilvie et al. 2000).Caffeine and Chemotherapy
The use of caffeine in combination with chemotherapy has been shown in published studies to enhance the cytotoxicity of chemotherapy drugs. Caffeine occurs naturally in green tea and has been shown to potentiate the anticancer effects of tea polyphenols. The Journal of Nutrition and Cancer reported a study in which SKH-1 mice at high risk of developing malignant and nonmalignant tumors received oral administration of caffeine as their sole source of drinking fluid for 18-23 weeks. The study revealed that caffeine inhibited the formation and decreased the size of both nonmalignant tumors and malignant tumors (Lou et al. 1999).
In cancer, p53 gene mutations are the most common alterations observed, occurring in 50-60% of patients, including those with carcinomas and sarcomas. Caffeine has been shown to potentiate the destruction of p53 defective cells by inhibiting growth in the G2 phase. This ability of caffeine is important because the basis of many anticancer therapies is the use of genotoxic agents that damage DNA and destroy the replicating cells. Caffeine uncouples cell-cycle progression by interfering with the replication and repair of DNA. Caffeine therefore serves as a model compound establishing the principle that agents which override DNA damage checkpoints can be used to sensitize cells to the killing effects of genotoxic drugs. This effect has been demonstrated by several independent research studies and reported in a number of primary journals (Blasina et al. 1999; Ribeiro et al. 1999; Jiang et al. 2000; Valenzuela et al. 2000).Theanine and Chemotherapy
L-theanine is a unique amino acid, naturally occurring in green tea, shown in one study to enhance Adriamycin concentration in tumors 2.7-fold and reduce tumor weight 62% over controls, whereas Adriamycin by itself did not reduce tumor weight at all (Sugiyama et al. 1998). (Adriamycin is an anthracycline antibiotic having a wide spectrum of antitumor activity.) Additionally, L-theanine was shown to reverse tumor resistance to certain chemotherapeutic drugs by forcing more of the drug to stay inside the tumor. It does not, however, increase the amount of drug in normal tissue, which sets it apart from other drugs designed to overcome multidrug resistance (Sadzuka et al. 2000a).Theanine Makes Chemotherapy Work
In 1999, researchers performed a study testing the use of theanine in conjunction with a drug similar to doxorubicin known as idarubicin. The use of idarubicin has been tried in drug-resistant leukemia cells, but it caused toxic bone marrow suppression and, therefore, could not be used.
Researchers wanted to see if theanine would cause the drug idarubicin to work. In the first experiment, about one-fourth of the standard dose of idarubicin was used. At this dose, the drug usually does not work, and it also does not cause toxicity. When combined with theanine, however, idarubicin worked but still without toxicity. Tumor weight was reduced 49%, and the amount of drug in the tumors doubled. In the next experiment, theanine was added to the usual therapeutic dose of idarubicin. Theanine increased the effectiveness of the drug and significantly lessened the usual bone marrow suppression. Leukocyte loss was reduced from 57% to 37% (Sadzuka et al. 2000c).
Part of theanine's amazing performance can be attributed to mimicking glutamate, an amino acid that potentiates glutathione. Cancer uses glutathione to detoxify chemotherapeutic agents, barricading chemicals from cells and inhibiting a kill. Theanine's structural similarity is the key, crowding out glutamate transport into tumor cells. Cancer cells (in confusion) erringly take in theanine, and theanine-created glutathione results. Glutathione (created by theanine) does not detoxify like natural glutathione, and instead blocks the ability of cancer cells to neutralize cancer-killing agents. Deprived of glutathione, cancer cells cannot evict chemotherapeutic agents, and the cell dies as a result of chemical poisoning (Sadzuka et al. 2001b).Continued . . .
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