~Cancer Radiation Therapy, Part 2
REDUCING TUMOR CELL GLUTATHIONE LEVELS
It has been found that cancer cells and normal cells respond differently to nutrients and drugs that affect glutathione status. The concentration of glutathione in tumor cells is higher than that of the normal cells that surround them. This difference in glutathione status between normal cells and cancer cells is believed to be an important factor in the resistance of cancer cells to chemotherapy (Fojo et al. 2003; Townsend et al. 2003). Whey protein concentrate has been shown to selectively deplete cancer cells of their glutathione, thus making them more susceptible to cancer treatments such as radiation and chemotherapy.
- Vitamin A
- Alpha-Interferon and Retinoic Acid
Tumor cell glutathione concentration may be among the determinants of the cytotoxicity of radiation. Rapid glutathione synthesis in tumor cells is associated with high rates of cellular proliferation. Depletion of cancer cell glutathione in vivo decreases the rate of cellular proliferation and inhibits cancer growth (Kennedy et al. 1995).
It is difficult to reduce glutathione sufficiently in tumor cells without placing healthy tissue at risk. A compound that can selectively deplete the cancer cells of their glutathione, while increasing or at least maintaining the levels of glutathione in healthy cells, such as whey protein, is efficacious (Bounous 2000; Tsai et al. 2000).
Cancer cells treated with whey proteins are depleted of their glutathione and their growth is inhibited, while normal cells have an increase in glutathione and increased cellular growth. These effects were not seen with other proteins. Selective depletion of tumor cell glutathione may render cancer cells more vulnerable to the action of radiation (Bravard et al. 2002) and meanwhile protect normal tissue from the deleterious effects of radiation (Savarese et al. 2003; Kennedy et al. 1995).
The exact mechanism by which whey protein achieves this is not fully understood, but it appears that it interferes with the normal feedback mechanism and regulation of glutathione in cancer cells. Glutathione production is inhibited by its own synthesis. Since baseline glutathione levels in cancer cells are higher than those of normal cells, it is probably easier to reach the level of negative-feedback inhibition with the cancer cells' glutathione levels than with the normal cells' glutathione levels.
Cancer patients undergoing radiation therapy may consider taking 30-60 grams a day of whey protein concentrate in divided doses, starting at least 10 days before beginning therapy, during therapy, and then continuing for at least 10 days after completion of the therapy.
Vitamin A May Improve the Tolerance and Effectiveness of Radiation Therapy
Radiation-induced lung injury frequently limits the total dose of thoracic radiotherapy that can be delivered to a patient undergoing radiation therapy, limiting its effectiveness.
Supplemental vitamin A may reduce lung inflammation after thoracic radiation and be an important radio-protective agent in the lung of cancer patients as it is in animals (Redlich et al. 1998).
Researchers have also reported the radio-protective effect of beta-carotene from a study conducted on over 700 children exposed to radiation by the Chernobyl nuclear accident. Natural beta-carotene protected against the susceptibility of lipids to oxidation and may act as an in vivo lipophilic antioxidant or radioprotector. Patients undergoing radiotherapy should consider taking vitamin A 25,000 IU a day.
Caution: Vitamin A is one of the few vitamins with a well-recognized hypervitaminosis syndrome. See the vitamin A precautions in Appendix A: Avoiding Vitamin A Toxicity to avoid toxic overdose, particularly if multivitamins already contain large doses of vitamin A.
Radiation Therapy Reduces Taurine
The amino acid taurine is severely depleted when people undergo radiation therapy. A possible therapeutic effect of taurine supplementation relative to radiation therapy has been suggested (Desai et al. 1992). Supplementing with 2000 mg a day of taurine is therefore recommended to people undergoing cancer radiation therapy.
Benefits of Melatonin
Radiation requires the presence of oxygen to generate free radicals to kill tumor cells. It is well-established, however, that most human tumors are poorly oxygenated (hypoxic) because of blood perfusion and diffusion limitations (Vaupel et al. 2001), intermittent blood flow in the tumor microcirculation (Hill et al. 1996), and the occurrence of anemia in cancer patients (reduced hemoglobin indicates reduced oxygen levels) (Auclerc et al. 2003; Thomas et al. 2002). In fact, radiation therapy itself usually induces anemia, which is associated with a poor prognosis in cancer patients (Harrison et al. 2002). Melatonin stimulates platelet production (thrombopoiesis) (Lissoni et al. 2001) and has been shown to effectively treat cancer patients with low platelet counts and anemia (Lissoni et al. 1997).
Moreover, melatonin has an anti-serotonergic effect, which means that it may block the inhibition of blood flow by serotonin (Bubenik et al. 2002). This consequently may increase blood flow and allow restoration of the microcirculation, which is compromised in the tumor microenvironment (Vaupel et al. 2000). Melatonin may improve the blood supply to the tumor, increasing tumor oxygen levels and thus increasing radiation-induced tumor cell death (by overcoming radio-resistance) (Hockel et al. 1996).
In addition, melatonin is lipid soluble and can presumably cross the blood tumor barrier as it does the blood-brain-barrier (Bubenik et al. 1998). Melatonin may further increase the delivery of radiation to poorly oxygenated regions within the tumor microenvironment, consequently increasing the effectiveness of this anticancer treatment. Radiation, which frequently causes inflammation of the mucosa (mucositis), may substantially reduce melatonin levels in the body (Karbownik et al. 2000) by damaging the mucosa of the gastrointestinal tract where melatonin is known to be localized (Bubenik et al 2002).
Patients with brain glioblastoma generally experience a poor survival rate, which is typically less than 6 months. A radio-neuroendocrine approach utilizing radiotherapy with melatonin supplementation (20 mg) in brain glioblastoma patients showed that the likelihood of survival at one year was significantly higher in those who received melatonin with radiotherapy versus radiotherapy alone (Lissoni et al. 1996). Moreover, patients had reduced radiation and steroid-related toxicities when melatonin was consumed nightly (Lissoni et al. 1996).
It recently has been suggested that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia (Delagrange et al. 2003). Therefore, melatonin supplementation may prolong the survival of patients undergoing radiotherapy (Blask et al. 2002).
Melatonin also may provide relief from the detrimental side effects of radiation treatment (Jatoi et al. 2002) (including toxicity to the heart, kidneys, and nervesŚcardiotoxicity, nephrotoxicity, and neurotoxicity, respectively), immune suppression, pain, anemia, fatigue, and sleep disturbances (Lissoni et al. 1996). Supplementing cancer patients with melatonin may have some benefit for successful radiotherapy (Sener et al. 2003).
Benefits of Alpha-Interferon and Retinoic Acid
It is well established that solid tumors contain hypoxic areas and that oxygen levels in such areas will cause tumors to be resistant to ionizing radiation (Vaupel et al. 2001). Inoperable cervical cancer is normally treated with radiotherapy. Several in vivo and in vitro studies suggest an improvement of radiosensitivity by adding retinoids and alpha-interferon in squamous cell cervical cancer treatment (Dunst et al. 1999).
In a 2-week pretreatment study with retinoic acid plus interferon-alpha-2a prior to definitive radiation therapy in cervical cancer patients, complete clinical remission of the local tumor in 19 of 22 patients after radiotherapy and additional retinoic acid plus interferon-alpha-2a treatment was reported. In primarily hypoxic tumors, four out of five achieved complete remission (Dunst et al. 1998).
During radiotherapy of cervical cancer patients with well-oxygenated tumors, 87% (20 of 23) achieved a clinically complete response using radiotherapy plus 13-cis-retinoic acid/interferon. In patients with primarily hypoxic tumors, all six patients whose primarily hypoxic tumors showed an increase of the median oxygen levels achieved a complete remission. In contrast, only four of seven patients with low pretreatment and persisting low median oxygen achieved a complete remission. Evident changes occur in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median oxygen was found. An additional treatment with 13-cis-retinoic acid and interferon further improve the oxygenation status (Dunst et al. 1999).
If you (or a member of your family) are undergoing radiotherapy, this new information should be brought to your physician's attention.
Possible Benefit of Ginseng
In animal studies, when ginseng was administered along with radiation therapies, a far greater percentage of the animals survived in the ginseng-supplemented group, compared with the group administered radiation without ginseng (Yonezawa et al. 1981; Rhee et al. 1991; Kim et al. 1993, 1996). Cancer patients should consider taking 2-4 capsules daily of Sports Ginseng by Nature's Herbs, which combines Korean and Siberian ginseng.
COMPLICATIONS CAUSED BY RADIATION THERAPY
Radiation-induced pneumonitis can be treated with antioxidants; however, the exact cause of pneumonitis is not known. Pneumonitis is thought to occur as a result of excessive generation of free radicals in healthy tissue following radiotherapy.
In vitro studies have shown that large doses of radiation can cause membrane lipid peroxidation and the oxidation of protein groups. Radiation-induced pneumonitis was studied using 25 patients who underwent radiotherapy for inoperable nonsmall cell lung cancer. Blood samples were taken over a 3-month period, and it was found that 40% (10 of 25) of the patients developed pneumonitis and that these patients had significantly higher levels of free radicals and iron in their blood. Iron is a catalyst for free-radical reactions (Jack et al. 1996).
A serious side effect from cancer radiation therapy is fibrosis to healthy tissues. Fibrosis is an inflammatory condition that causes progressive scarring to healthy tissue that can lead to debility or death. Antioxidants not only have been shown to prevent fibrosis, but also to reverse it. It would appear that patients undergoing radiation procedures might derive therapeutic and protective benefits if they consumed the proper antioxidants before, during, and after therapy. The downside, critics argue, is that long-term survival studies of radiation patients supplementing with high doses of antioxidants are lacking.
Radiation fibrosis is an extreme complication, without effective treatment, after radiation therapy. Surgical removal and healing of a radiation-induced fibrosis is rarely successful.
One published case involved a 58-year-old woman who developed a radiation fibrosis in the irradiated area of a squamous cell carcinoma. Following the surgery, the woman was treated with a combination of pentoxifylline tablets (400 mcg 3 times daily) and vitamin E (one 400-mg capsule each day). The woman tolerated the treatment well and a noted improvement in the condition of the affected skin was seen, beginning at 4 months. A decrease in skin thickness could be demonstrated from the sixth month on, with the patient experiencing no side effects from this protocol. The data indicate a therapeutic effect on radiation-induced fibrosis by the synergistic administration of pentoxifylline and vitamin E. Pentoxifylline is a prescription drug that inhibits abnormal platelet aggregation and may allow more blood flow to the irradiated area (Gottlober et al. 1996).
Another study reported a "striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol." Researchers reported a 50% regression of superficial radiation-induced fibrosis after a 6-month administration of pentoxifylline and tocopherol (vitamin E) in half of the patients studied (Delanian 1998).
The study also reported on a 67-year-old woman with a bulky radiation-induced fibrosis who, 10 years previously, had received radiochemotherapy for a small cell thyroid carcinoma with severe acute radiation side effects. She had palpable cervicosternal fibrosis measuring ~108 cm, with local inflammatory signs and functional consequences (cough, restricted cervical movement, dyspnea, and bronchitis). A CT scan revealed deep radiation-induced fibrosis extending from the vocal cords to the carina, with laryngotracheal compression, but without cancer recurrence. The patient received pentoxifylline (800 mg a day) and vitamin E (1000 IU a day), orally administered daily for 18 months. The patient exhibited clinical regression and functional improvement at 6 months and complete response with no measurable fibrosis at 18 months (Delanian 1998).
The combination of pentoxifylline and vitamin E seems to promote a significant anti-fibrotic effect by reversing deep radiation-induced fibrosis (Lefaix et al. 1999).
Individuals receiving treatment for cervical cancer, prostate cancer, or colorectal cancer may find significant relief from the effects of radiation-induced proctopathy by taking oral vitamin A. Radiation-induced anal ulcers characterized by diarrhea, urgency, rectal pain, rectal bleeding, and fecal incontinence may occur 6 months or more after irradiation of prostate and pelvic irradiation. In a double-blind placebo-controlled trial, Levitsky et al. (2003) successfully treated both male and female patients having radiation-induced anal ulcers with oral vitamin A. The trial group consisted of 14 males and 2 females with a median age of 71. Of the enrolled patients, 13 had been treated for prostate cancer, 2 had been treated for cervical cancer, and 1 had been treated for rectal cancer. Eight patients were randomized for vitamin A (8000 IU twice daily) and 8 patients were randomized for placebo.
After 3 months, 7 of 8 patients (88%) had a significant reduction in symptom parameters based on Fisher's Exact Test versus 2 of 8 patients (25%) who responded to placebo. Five nonresponders to placebo were then given the same therapeutic dose of vitamin A, and responded favorably to treatment. The researchers concluded that the vitamin A-treated test subjects showed a significant reduction in symptoms of proctopathy as compared to placebo. Improved rectal function and decreased bleeding were attributed to the wound healing and repair properties of vitamin A.
Continued . . .
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