~Cancer Radiation Therapy
Reprinted with permission of Life Extension®.
Radiation therapy is given to about 60% of all cancer patients, but it can inflict significant damage on healthy normal tissues. Radiotherapy can also cause secondary cancers after the primary cancer has been treated, which typically occur several years later. Other secondary diseases such as pneumonitis and radiation fibrosis may also occur. Radiation therapy is associated with both acute and delayed disturbances in nutritional status.
Radiation therapy relies on the free radical disruption of cellular DNA. The rationale behind damaging cancer cell DNA is that it may preclude successful division into more cancer cells or trigger cancer cell apoptosis (also known as programmed cell death). Radiation therapy can be delivered from both external or internal sources, may be high or low dose, and is often delivered with computer-assisted accuracy to the site of the tumor. Brachytherapy (or interstitial radiation therapy) places the source of radiation directly into the tumor as temporarily implanted ribbons and seeds or as permanently implanted seeds.
Newer radiotherapy technologies, such as stereotactic radiosurgery, which uses tightly focused x-rays or gamma rays to target tumors without widespread irradiation of surrounding tissues, may improve radiotherapy results. However, these approaches are limited to certain types of cancers.
Cancer often outgrows the ability of the host to supply blood vessels and oxygen. Cancer cells are therefore often found in a low-oxygen (hypoxic) environment. Hypoxic cancer cells are radio-resistant, an effect that contributes significantly to the inability of radiotherapy to control large cancers. Therapies that provide more oxygen to cancer cells help radiation work more effectively by enabling more free-radical formation. Remember: Radiation kills cancer cells by concentrating massive amounts of free radicals directly into tumors. L-arginine is a promising natural agent for enhancing oxygenation of tumor cells due to its ability to increase the serum nitric oxide level, which enhances blood flow by expanding arterial elasticity. Enhanced blood flow provides more oxygen to tumors that in turn enables radiation therapy to generate more cell-killing free radicals.
- Guarding Against Blood's Oxygen-Carrying Deficiencies
- Additional Benefits of Arginine
Consuming 20-30 grams of arginine 30-60 minutes prior to each radiation session could significantly increase the number of cancer cells killed in persons undergoing radiation therapy. Many people find it difficult to consume 20-30 grams of arginine orally. As an alternative, a physician could administer the arginine via an IV (intravenous) infusion 30 minutes before each radiation session. Arginine is available to doctors in IV dosing packs for the purpose of testing pituitary growth hormone response. However, conventional physicians are reluctant to try innovative approaches. Patients seeking to use high dose arginine prior to each radiation session have the following options:
To further saturate the tumor with more oxygen, some patients breathe pure oxygen during the radiation therapy (Kaanders et al. 2002; Zajusz et al. 1995; Evans et al. 1975)
- Swallowing 23-33 arginine (900 mg per capsule) capsules
- Mixing 2.5-3.5 tablespoons of unpleasant-tasting arginine powder and drinking the mixture
- Taking 4-6 tablespoons of an arginine-based drink called sugar-free PowerMaker II. (This makes normally unpalatable arginine acceptable to taste.)
- Finding a physician in your area who will have trained a medical technician to administer the 20-30 grams of arginine by IV therapy prior to each radiation session. (To find an innovative physician who might accommodate this IV arginine request, call (800) 544-4440.)
Guarding Against Blood's Oxygen-Carrying Deficiencies
Arginine will not be of much benefit if there is a deficiency in the ability of blood to carry oxygen (anemia). Anemia is common in cancer patients. Conventional cancer therapies, such as surgery, chemotherapy, radiation, and testosterone blockade, often induce anemia. Elevated levels of certain cytokines such as tumor necrosis factor-alpha (TNF-alpha), commonly seen in cancer patients, also suppress red blood cell formation.
The adverse effect of anemia in cancer patients is well established in scientific literature. A study conducted to systematically review the effect of anemia on survival in cancer patients found that the increased risk of mortality associated with anemia in cancer was an astounding 65% (Caro et al. 2001). Anemia is often associated with general malnutrition. Insurance companies refuse reimbursement for expensive antianemia drugs (Procrit) unless the patient is severely anemic (often 25% below the lowest number on the standard reference range). This means that cancer patients are denied access to potential life-saving drugs such as Procrit.
As already noted, in order to deliver more oxygen to the tumor, there has to be enough oxygen-carrying capacity in the blood. Indicators of oxygen-carrying capacity, such as hematocrit and hemoglobin, should be in the upper one-third range of normal prior to radiation therapy. There are nutrients that help improve anemic states, but as noted earlier, any cancer patient that is not in the upper one-third of normal should be prescribed Procrit or Epogen to naturally stimulate red blood cell production. R.A. Smith, M.D. (clinical radiation oncologist, practicing in Jackson, MS), has typically employed 1 gram of vitamin C 3 times daily and 400 IU of vitamin E daily in all patients receiving large radiation fields and has noticed regular increases in red blood cell count, white blood cell count, and platelets after such simple antioxidant intervention is initiated (Smith 2002).
Additional Benefits of Arginine
Arginine functions to enhance blood flow to tumors, thereby increasing the cell-killing effects of radiation therapy. There are additional mechanisms by which arginine may benefit the cancer patient.
Nitric oxide is generated from L-arginine by the family of nitric oxide synthase enzymes. Nitric oxide is an important molecule involved in vascular homeostasis, immune regulation, and host defense. Large amounts of nitric oxide produced for relatively long periods of time (days to weeks) in macrophages and vascular endothelial cells after challenge with lipopolysaccharide or cytokines (such as interferons) are cytotoxic for various tumor cells. This cytotoxic effect against tumor cells was found to be associated with apoptosis.
The mechanism of nitric oxide-mediated apoptosis involves several factors, including the accumulation of the tumor suppressor protein p53, damage to mitochondrial functions, alterations in the expression of members of the Bcl-2 family, activation of the caspase cascade, and DNA fragmentation. Depending on the amount, duration, and the site of nitric oxide production, this molecule may not only mediate apoptosis in target cells, but also protect cells from apoptosis induced by other apoptotic stimuli (Umansky et al. 2001).
Additionally, when nitric oxide production was inhibited, there was a significant increase in capillary formation. However, when L-arginine was introduced, capillary formation returned to baseline values, thus halting tumor angiogenesis (Phillips et al. 2001).
SIGNAL TRANSDUCTION PATHWAY INHIBITION
All cells, both normal and cancerous, have molecular receptor sites on their surface. These sites are much like locks that may be opened or activated only by the correct molecular key. Once opened, a chain of biochemical events occurs specific to that receptor. Cytokine growth factors are a class of substances that stimulate cell growth by a variety of mechanisms, specific to the receptor site that they activate.
- Genistein and Other Soy Isoflavones
- Green Tea
Radiation induces overexpression of certain receptor sites and cytokine growth factors as the cancer attempts to survive the radiation. This overexpression of cytokine growth factors, or signal transduction pathways, limits the effectiveness of radiation in causing the destruction of the cancer cells. These same pathways, when overexpressed, are implicated in tumor cells resistance to cytotoxic drugs. However, inhibition of these receptor sites, or pathways, effectively shuts down overexpression and the resistance of cancer cells to both chemotherapy and radiation.
The following natural products have been shown to be synergistic with chemotherapy and radiation, exhibiting signal transduction inhibitory effects. Specific dosing suggestions can be found in the Summary section of the protocol.
Genistein and Other Soy Isoflavones
The Foundation previously recommended that soy extracts not be used 1 week prior to, during, and 1 week after undergoing radiation therapy, based on preliminary research. However, a number of new studies indicate that this view may have been incorrect. Indeed, far from inhibiting the impact of radiation on cancer cells, research shows that genistein, an isoflavone from soy, enhances the radio-sensitivity of cancer cells (Akimoto et al. 2001).
Radiation causes cancer cells to overexpress a survival signal transduction pathway called vascular endothelial growth factor (VEGF) by 2.81-fold (Ando et al. 2000). The epidermal growth factor receptor (EGFR), important in cancer cell proliferation, is also similarly enhanced (Dangles et al.1997), and there is a significant increase in intracellular glutathione levels, all in an apparent attempt to survive the radiation (Kojima et al. 2000).
In contrast, genistein has been shown to:
Addition of genistein to cancer cell lines blocks the survival signal expressed by the cancer cells and elevates glutathione levels in a dose-dependent manner (Suzuki et al. 2002). The efficacy of radiation was strongly enhanced, suggesting genistein may be a therapeutic agent with a potent synergistic effect with radiation (Hillman et al. 2001).
- Block the induction of VEGF (Mukhopadhyay et al. 1995).
- Inhibit the expression of the EGFR (Bhatia et al. 2001).
Curcumin, an extract of the spice turmeric, is synergistic with genistein and may be effective in helping to suppress a number of escape mechanisms that are activated by radiation. These mechanisms of tumor suppression are:
- Inhibition of nuclear factor kappa-beta (NF-kB), a transcription factor that many cancers over-express and use as a growth vehicle to escape cell regulatory control. Studies showed a 41% increase in radiosensitivity with NF-kB blockade (Plummer et al. 1999; Russo et al. 2001).
- Inhibition of the EGFR site. One study noted 300% amplification in radiation-induced apoptosis with blockade of the EGFR (Dorai et al. 2000).
- Inhibition of cyclooxygenase-2 (COX-2), the enzyme involved in the production of PGE-2, a tumor-promoting prostaglandin hormone. Studies noted an amplification in radiosensitivity of 1.9-fold with the selective inhibition of the COX-2 enzyme (Zhang et al. 1999; Pyo et al. 2001).
As previously noted radiation induces cancer cells to overexpress the survival signal transduction pathway VEGF 2.81-fold. VEGF is also considered essential for tumor angiogenesis. (Angiogenesis is the process of new blood vessel formation from surrounding tissue into a tumor.) Green tea through its catechin, EGCG, a tea polyphenol, blocks induction of VEGF. In vivo studies on green tea have shown the following actions on cancer cells (Jung et al. 2001a):
Caffeine occurs naturally in green tea and has been shown to potentiate the tea polyphenols (Dulloo et al. 2000). There are many published studies supporting the use of caffeine in the treatment of cancer (Saito et al. 2003; Mercadante et al. 2001). The caffeine in green tea has a synergistic effect improving green tea�s anticarcinogenic capabilities. In SKH-1 mice at high risk for developing malignant and nonmalignant tumors, the oral administration of caffeine alone as their sole source of drinking fluid for 18-23 weeks was performed to ascertain the inhibitory effects of caffeine. The study revealed that caffeine inhibited the formation and decreased the size of both the nonmalignant and malignant tumors (Lou et al. 1999).
- 58% inhibition of tumor growth
- 30% inhibition of microvessel density
- 27% inhibition of tumor cell proliferation
- 1.9-fold increase in tumor cell apoptosis
- Threefold increase in tumor endothelial cell apoptosis
It is of interest that scientific research with caffeine lends credibility to the seemingly bizarre claims of the legendary Max Gerson, M.D., and others, who contend that coffee enemas were effective for cancer patients, especially patients with liver metastases (Gerson 1978). Caffeine has been found to improve pain relief when combined with narcotics and is found in several commonly used analgesics such as Empirin #3 (Tylenol #3) (Mercadante et al. 2001).
In cancer, p53 gene mutations are the most common genetic alterations observed (50-60%). Caffeine has been shown to potentiate the destruction of p53 defective cells by inhibiting its growth signal (G2). These effects inhibit and override the DNA-damage checkpoint and thus kill dividing cells. This ability by caffeine is important because the basis of many anticancer therapies is DNA damage destruction of the replicating cells. Caffeine uncouples cell-cycle progression by interfering with the replication and repair of DNA. Caffeine therefore serves as an agent that overrides DNA damage checkpoints that can be used to sensitize cells to the killing effects of DNA damaging drugs. This effect has been demonstrated by several research studies (Ribeiro et al. 1999; Blasina et al. 1999; Jiang et al. 2000; Valenzuela et al. 2000).
Additionally, caffeine potentiated radio-chemotherapy, sensitizing cells to the killing effects of genotoxic drugs (Tsuchiya et al. 2000). This was not the case after irradiation alone or caffeine treatment alone and was only induced by irradiation in combination with caffeine in cells with a mutant p53 gene via a p53-independent pathway (Higuchi et al. 2000). In addition, caffeine not only induced p53-independent arrest and enhanced radiation-induced apoptosis, but caffeine, in a dose-dependent manner, induced apoptosis independent of any other factors (Qi et al. 2002).
It may be more efficacious to take green tea in capsule form rather than a brewed beverage because 2 capsules exceed the phytochemical potency of 5 cups of freshly brewed green tea. An appropriate dose for VEGF-blockade would be five 350-mg capsules of a lightly caffeinated 95% green tea extract with each meal. Some people may want to use a decaffeinated green tea extract capsule toward the end of the day because 5 capsules of even lightly caffeinated green tea may be overstimulating.
Since decaffeinated green tea capsules contain 300 mg of green tea extract per capsule, 6 of these capsules should be taken during each daily interval. It is suggested that 95% green tea extract capsules be taken in 3 intervals throughout each day. A typical dose taken by a cancer patient could be 5 lightly caffeinated green tea capsules at breakfast, 5 at lunch, and 6 green tea decaffeinated capsules at dinner. Patients should be observed for agitation or overstimulation because some persons are easily stimulated by caffeine.
A new form of selenium called Se-methylselenocysteine (SeMSC) is a naturally occurring selenium compound found to be an effective agent in the prevention of cancer (Medina et al. 2001). SeMSC is a seleno-amino acid that is synthesized by plants such as garlic and broccoli. Based on its unique mechanisms of action, SeMSC could also benefit a cancer patient (Brown et al. 2001).
SeMSC induces apoptosis through caspase activation. Caspases are a class of cysteine proteases that includes several factors involved in apoptosis. Caspase participates in the molecular control of apoptosis by cleaving a subset of cellular proteins and thus dismantling the cell (Yeo et al. 2002). Additionally, SeMSC has been shown to be effective against mammary cell growth both in vivo and in vitro (Sinha et al. 1999) and has significant anticarcinogenic activity against mammary tumorigenesis (Sinha et al. 1997). Moreover, of the selenium compounds tested, SeMSC is one of the most effective chemopreventive forms (Jung et al. 2001b). Exposure to SeMSC 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). SeMSC has been shown to:
(Ip et al. 1992, 1999; Sinha et al. 1999; Dong et al. 2001; Kim et al 2001)
- Produce a 33% better reduction of cancerous lesions than selenite
- Produce a 50% decrease in tumorigenesis
- Induce apoptosis in cancer cells
- Inhibit cancer cell proliferation
- Reduce intra-tumoral microvessel density and angiogenesis
- Down-regulate VEGF essential for tumor angiogenesis (Jiang et al. 1999)
Unlike selenomethionine, which is incorporated into protein in place of methionine, SeMSC is not incorporated into any protein, thereby offering a completely bioavailable compound. In animal studies, SeMSC has been shown to be 10 times less toxic than any other known form of selenium. The recommended dose of Se-methylselenocysteine (SeMSC) is 200-400 mcg a day for cancer patients.
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