Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/56—Materials from animals other than mammals
  • A61K35/60—Fish, e.g. seahorses; Fish eggs
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/16—Inorganic salts, minerals or trace elements
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2200/00—Function of food ingredients
  • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
  • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2250/00—Food ingredients
  • A23V2250/15—Inorganic Compounds
  • A23V2250/156—Mineral combination
  • A23V2250/1626—Selenium
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2250/00—Food ingredients
  • A23V2250/20—Natural extracts
  • A23V2250/204—Animal extracts
  • A23V2250/2042—Marine animal, fish extracts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
  • A61N5/00—Radiation therapy
  • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy

Definitions

• the field of the invention is cancer radiotherapy.
• Radiotherapy and chemotherapy protocols utilized in the treatment of cancer can clearly benefit patients, but can be ineffective or less effective with some cancers.
• both radiotherapy and chemotherapy are associated with significant side effects, including nausea, weight loss, hair loss, damage to the gastrointestinal tract, and skin irritation.
• Mitigation of the side effects of chemotherapy are generally directed at providing symptomatic relief.
• antiemetics can be used to reduce nausea, along with diet modification and eating small, frequent meals that avoid certain foods.
• chemotherapeutic agents are selected to have reduced toxicity in order to reduce side effects, however such agents may also have reduced effectiveness against tumor cells.
• the inventive subject matter provides compositions and methods for enhancing and improving radiotherapy of tumors in a synergistic manner through the use of a nutritional supplement containing fish oil and selenium.
• One embodiment of the inventive concept is a method of treating a tumor by applying a radiotherapy protocol to a patient in need of treatment while providing the patient with a nutritional supplement containing fish oil and selenium (for example, as shown in Table 1) in an amount to provide a synergistic effect in reducing tumor volume or weight.
• a nutritional supplement containing fish oil and selenium for example, as shown in Table 1.
• the nutritional supplement is provided to the patient prior to the initiation of radiotherapy.
• a nutritional supplement can be formulated such that two or more of the components of the supplement are provided in amounts as described in Table 1.
• Another embodiment of the inventive concept is a method of reducing side while providing the patient with a nutritional supplement formulated that includes fish oil and selenium (for example, as in Table 1) in an amount to reduce a side effect of the radiotherapy protocol.
• a nutritional supplement formulated that includes fish oil and selenium (for example, as in Table 1) in an amount to reduce a side effect of the radiotherapy protocol.
• the nutritional supplement is provided to the patient prior to the initiation of radiotherapy.
• Such a nutritional supplement can be formulated such that two or more of the components of the supplement are provided in amounts as described in Table 1.
• Another embodiment of the inventive concept is a method of modulating gene (e.g. an angiogenesis-related gene, an apoptosis-related gene, etc.) expression in a tumor, by providing a nutritional supplement to a tumor or an animal having a tumor, wherein the nutritional supplement includes fish oil and selenium (for example, as in Table 1), and where the nutritional supplement is provided in an amount to modulate expression of a gene of the tumor.
• the nutritional supplement is provided to the patient prior to the initiation of radiotherapy and during radiotherapy; in other embodiments such a supplement is provided during or at the initiation of the application of radiotherapy.
• the nutritional supplement is formulated such that two or more components of the supplement are provided in amounts as described in Table 1.
• Another embodiment of the inventive concept is a method of reducing metastasis from a tumor, by providing the patient having a metastatic tumor with a nutritional supplement that includes fish oil and selenium (such as in Table 1) where the nutritional supplement is provided in an amount to reduce metastatic activity of the tumor.
• a nutritional supplement is provided either prior to or at the initiation of radiotherapy, and can be provided through the course of radiotherapy.
• the nutritional supplement is formulated such that two or more of the supplement's components are provided in amounts as described in Table 1.
• Another embodiment of the inventive concept is a method of reducing angiogenesis in a tumor, comprising providing the patient having a tumor with a nutritional supplement that includes fish oil and selenium (for example, as in Table 1) in combination with radiotherapy, where the nutritional supplement is provided in an amount to reduce an angiogenic activity of the tumor.
• a nutritional supplement is provided concurrent with the initiation of radiotherapy, and can be provided to the patient during the application of radiotherapy.
• the nutritional supplement is formulated such that two or more of the supplement's components are provided in amounts as described in Table 1.
• Another embodiment of the inventive concept is a method of reducing incidences of cancer stem cells in a tumor, by providing the patient having a tumor with a nutritional supplement that includes fish oil and selenium (such as in Table 1), wherein the nutritional supplement is provided in an amount to reduce the incidence of stem cells in the tumor.
• the nutritional supplement is provided concurrently with the application radiotherapy.
• the nutritional supplement can be formulated such that two or more components of the supplement are provided in amounts as described in Table 1.
• FIG. 1 depicts a treatment protocol in which nutritional supplementation is provided starting either 7 days prior to implementation of radiotherapy or simultaneously with tumor cell implantation. Mice were sacrificed 21 days after tumor cell implantation.
• FIGs. 2A and 2B depicts changes in body weight over time for various treatment groups.
• FIG. 2B depicts change in body weight in various treatment groups over the course of the study. Note that body weight is reported following removal of the primary tumor mass.
• FIGs. 3A to 3D show typical synergistic effects on tumor volume and weight of co-treatment with radiotherapy and the supplement containing fish oil and selenium.
• FIG. 3A shows changes in tumor volume over time for various treatment groups.
• FIG. 3B provides a detailed view of the first 11 days of treatment as shown in FIG. 3A.
• FIG. 3C provides a histogram of tumor weight for various treatment groups.
• FIG. 3D provides photographs of exemplary tumors from various treatment groups.
• FIGs. 4A to 4G FIG. 4A: Effect of treatment using radiotherapy, a supplement containing fish oil and selenium, and combined treatment on gastrocnemius muscle mass 21 days after tumor cell injection.
• FIG. 4B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on soleus muscle mass 21 days after tumor cell injection.
• FIG. 4C Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on lung (inclusive of metastatic tumor) weight 21 days after tumor cell injection.
• FIG. 4D Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on liver (inclusive of metastatic tumor) weight 21 days after tumor cell injection.
• FIG. 4A Effect of treatment using radiotherapy, a supplement containing fish oil and selenium, and combined treatment on gastrocnemius muscle mass 21 days after tumor cell injection.
• FIG. 4B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on soleus muscle mass 21 days after tumor cell injection.
• FIG. 4C Effect of treatment using radiotherapy, NutraWell supplement
• FIG. 4E Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on spleen (inclusive of metastatic tumor) weight 21 days after tumor cell injection.
• FIG. 4F provides quantitative results of studies of lung metastasis in animal subjects treated with a supplement containing fish oil and selenium and/or radiotherapy.
• FIG. 4G shows the results of studies of Ki- 67 expression in primary tumor sites and metastatic sites in animal subjects treated with a supplement containing fish oil and selenium and/or radiotherapy.
• FIGs. 5A to 5E FIG. 5A: Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on platelet count 21 days after tumor cell injection.
• FIG. 5B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on white blood cell count 21 days after tumor cell injection.
• FIG. 5C Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on lymphocyte count 21 days after tumor cell injection.
• FIG. 5D Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on granulocyte count 21 days after tumor cell injection.
• FIG. 5E FIG. 5A: Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on platelet count 21 days after tumor cell injection.
• FIG. 5B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on white blood cell count 21 days after tumor cell injection.
• FIG. 5C Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on lymphocyte count 21 days after tumor cell injection.
• FIG. 5D Effect of treatment using radiotherapy, Nu
• FIGs. 6A and 6B FIG. 6A: Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on serum albumin 21 days after tumor cell injection.
• FIG. 6B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on serum creatinine 21 days after tumor cell injection.
• FIGS. 7A and 7B FIG. 7 A: Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on serum IL-6 21 days after tumor cell injection.
• FIG. 7B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on serum IL- ⁇ 21 days after tumor cell injection.
• FIGs. 8A to 8G FIG. 8A: Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the VEGF gene in an implanted tumor 21 days after tumor cell injection.
• FIG. 8B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the BAX gene in an implanted tumor 21 days after tumor cell injection.
• FIG. 8C Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the Bcl-2 gene in an implanted tumor 21 days after tumor cell injection.
• FIG. 8D Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the caspase 3 gene in an implanted tumor 21 days after tumor cell injection.
• FIG. 8A Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the VEGF gene in an implanted tumor 21 days after tumor cell injection.
• FIG. 8B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the BAX gene in an implanted tumor 21 days
• FIG. 8E Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the BAX gene in lung 21 days after tumor cell injection.
• FIG. 8F Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the Bcl-2 gene in lung 21 days after tumor cell injection.
• FIG. 8G Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the caspase 3 gene in lung 21 days after tumor cell injection.
• FIGs. 9A and 9B depicts a testing protocol in which mice receive radiotherapy on days 8, 10, and 12, with nutritional supplementation beginning with the initiation of radiotherapy. Mice are sacrificed at day 14 or at day 24 following implantation of tumor cells.
• FIG. 9B Treatment groups derived from the protocol shown in FIG. 9 A.
• FIGs. 10A to IOC FIG. 10A: Serum albumin concentration at 14 days and 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FIG. 10B Lymphocyte counts at 14 days and 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FIG. IOC N/L Ratio at 14 days and 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FIG. 11A to 11D FIG. 11 A: VEGF expression within the tumor mass 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FITC represents VEGF- specific staining.
• FIG. 10A Serum albumin concentration at 14 days and 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FIG. 10B Lymphocyte counts at 14 days and 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FIG. IOC N/L Ratio at 14 days and 24 days following tumor cell implantation in mice treated as shown
• FIG. 11B VEGF expression within the lung (metastasis) 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FITC represents VEGF-specific staining.
• FIG. 11C EGFR expression within the lung (metastasis) 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FITC represents EGFR-specific staining.
• FIG. 1 ID EGFR expression within the tumor mass 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FITC represents EGFR-specific staining.
• FIG. 12 CD31 (cancer stem cell marker) expression within the tumor mass and in lung tissue (metastasis) 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FITC represents CD31-specific staining.
• FIGs. 13A and 13B show the presence of HlFl-a (hypoxia marker) protein within the tumor mass and in lung tissue (metastasis) 24 days following tumor cell implantation in mice treated as shown in FIG. 9A.
• FITC represents HlFl-a -specific staining.
• FIG. 13B shows results of gene expression studies of tumor samples from subjects treated with a nutritional supplement containing fish oil and selenium and/or radiotherapy.
• FIG. 14 Expression of apoptosis markers 24 days following tumor cell implantation in mice treated as shown in FIG. 9 A.
• FIGs. 15A and 15B show the results of studies characterizing PDL-1 gene expression in primary and metastatic tumor sites in animal models of human disease treated with a supplement containing fish oil and selenium and/or radiotherapy.
• FIG. 15B shows the results of studies characterizing PD-1 gene expression in primary and metastatic tumor sites in animal models of human disease treated with a supplement containing fish oil and selenium and/or radiotherapy.
• FIGs. 16A and 16B depicts a testing protocol in which mice receive radiotherapy on days 8, 10, and 12, with nutritional supplementation provided prior to tumor cell implantation, at the time of tumor cell implantation, or at the initiation of radiotherapy. Mice are sacrificed at day 21 following implantation of tumor cells.
• FIG. 16B Treatment groups derived from the protocol shown in FIG. 16A.
• FIG. 17 Photomicrographs of cross sections of the intestines of mice treated by the protocol described in FIG. 16A.
• FIGs. 18A to 18F FIG. 18 A: Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the VEGF gene 21 days after tumor cell injection.
• FIG. 18B Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the BAX gene 21 days after tumor cell injection.
• FIG. 18C Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the Bcl-2 gene 21 days after tumor cell injection.
• FIG. 18D Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the
• FIG. 18E Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the Bcl-2 gene 21 days in lung (i.e. metastasis) after tumor cell injection.
• FIG. 18F Effect of treatment using radiotherapy, NutraWell supplement, and combined treatment on expression of the Caspase 3 gene 21 days in lung (i.e. metastasis) after tumor cell injection.
• FIGs. 19A and 19B depicts a testing protocol in which mice receive radiotherapy on days 8, 10, and 12, with nutritional supplementation provided for 7 days prior to tumor cell implantation. Mice are sacrificed at day 24 following implantation of tumor cells.
• FIG. 19B Treatment groups derived from the protocol shown in FIG. 19A.
• FIGs. 20A and 20B FIG. 20A: Effect of a nutritional supplement containing fish oil and selenium on body mass in mice receiving repeated radiotherapy following tumor cell implantation using the protocol shown in FIG. 19 A.
• FIG. 20B Effect of treatment using radiotherapy, a nutritional supplement containing fish oil and selenium, and combined treatment on gastrocnemius muscle mass 21 days after tumor cell injection using the protocol shown in FIG. 19A.
• FIGs. 21A and 21B depicts a testing protocol mice in which mice receive radiotherapy on days 8, 10, and 12, with nutritional supplementation provided for 7 days prior to, the day of, or 8 days after tumor cell implantation. Mice are sacrificed at day 21 following implantation of tumor cells.
• FIG. 21B Treatment groups derived from the protocol shown in FIG. 21A.
• FIG. 22 Effect of NutraWell supplementation on body mass in mice receiving repeated radiotherapy following tumor cell implantation using the protocol shown in FIG. 21A.
• FIG. 23 Changes in tumor volume over time on repeated radiotherapy in combination with NutraWell supplement in mice treated as in the protocol shown in FIG. 21 A.
• FIGs. 24A and 24B FIG. 24A: Effect of treatment using repeated radiotherapy in combination with NutraWell supplement, and combined treatment on serum TNF-a 21 days after tumor cell injection in mice treated using the protocol shown in FIG. 21A.
• FIG. 24B Effect of treatment using repeated radiotherapy in combination with NutraWell supplement, and combined treatment on serum IL-6 21 days after tumor cell injection in mice treated using the protocol shown in FIG. 21A.
• the inventive subject matter provides compositions and methods in which a nutritional supplement that includes fish oil and selenium (for example, a supplement containing fish oil, selenium derived from selenium yeast, and certain vitamins, minerals, amino acids, and saccharides, e.g. "NutraWell”) is used in combination with radiotherapy.
• a nutritional supplement that includes fish oil and selenium (for example, a supplement containing fish oil, selenium derived from selenium yeast, and certain vitamins, minerals, amino acids, and saccharides, e.g. "NutraWell) is used in combination with radiotherapy.
• Combination therapy with radiation and such a supplement surprisingly provides a significant synergistic effect in reduction of tumor size.
• side effects of radiotherapy e.g. neutropenia, loss of body mass, loss of muscle mass, damage to acyl cells of the gastrointestinal tract, etc.
• genes related to angiogenesis and apoptosis were also found to be modulated in tumor cells on use of a supplement containing fish oil and selenium, both with and without the application of radiotherapy.
• metastasis is prevented and the growth and spread of cancer stem cells was found to be reduced.
• inventive subject matter provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
• a nutritional supplement composition as shown in Table 1 (“Nutrawell”) is provided to improve the results of radiotherapy.
• Vitamin D3 25 5000 IU
• Vitamin A Acetate 500 100000 IU
• Lact. Acidophilus (app. 10 billion total) 2 500 mg
• Lac. Bulgaricus (app. 10 billion total) 2 500 mg
• composition shown in Table 1 includes components that have various physiological and biochemical effects, including anti-inflammatory activity, lowering of blood glucose levels, lowering of cholesterol, and anti-tumor activity. Other components provide supplementation of necessary vitamins, minerals, and amino acids at elevated levels. Other components (e.g.
• compositions shown in Table 1 also includes certain flavorants (e.g. brown sugar, honey, vanilla flavor and masking agent) that serve to improve palatability and acceptance.
• Certain components e.g. honey, brown sugar, milk, rice protein, casein
• honey, brown sugar, milk, rice protein, casein can provide both flavor and caloric energy.
• Components shown in Table 1 can be provided as a single formulation (for example, as a pill, tablet, capsule, powder, liquid, suspension, etc.) or can be segregated into different formulations (for example, as pills, tablets, capsules, powders, liquids, suspensions, or combinations thereof).
• the amounts shown in Table 1 are exemplary, and represent typical daily dosages provided to an adult of normal stature and otherwise normal health. These amounts can be adjusted to account for differences in body mass, gender, medical condition, etc. For example, a relatively small patient weighing 40 kilos or less may receive benefit from dosages provided at or below the low end of the ranges provided, whereas a relatively large patient weighing 100 kilograms or more may require dosages provided at the high end of the ranges noted (or more).
• such a daily dose can be distributed as multiple doses throughout the day.
• the composition of each of such distributed doses can be identical. In other embodiments the composition of such distributed doses can be different, provided the summation of such doses provides the required supplementation.
• human tumor cells following transplantation into nude mice are treated with 1 gram per day of the nutritional supplement, radiotherapy, or 1 gram per day of the nutritional supplement and chemotherapy.
• the mice are weighed during treatment to characterize side effects such as nausea and loss of appetite.
• the mice are sacrificed and the tumor characterized. Tumor volume is determined, and the impact of therapy on organ and muscle volume is determined. The degree of neutropenia is also characterized.
• a typical protocol is shown in Table 2.
• FIG. 1 A typical treatment schedule is depicted schematically in FIG. 1. Some subjects received treatment with a supplement containing fish oil and selenium (PTN, PTRN) prior to tumor cell implantation, with a portion of these (PTRN) receiving radiotherapy. Other subject started treatment with such a supplement at the time of tumor cell implantation (TN, TRN), with some of these receiving radiotherapy (TRN). Results of body weight studies compared to control subjects (C) and subjects implanted with tumor cells and otherwise untreated (T) are shown in FIGs. 2A and 2B.
• PPN fish oil and selenium
• mice receiving both radiotherapy and the supplement containing fish oil and selenium gained weight at a significantly greater rate than those receiving only radiotherapy, indicating a reduction in side effects normally associated with this treatment mode.
• Pre-treatment with a nutritional supplement containing fish oil and selenium had a particularly pronounced effect.
• FIGs. 3A to 3D show typical synergistic effects on tumor volume and weight of co- treatment with radiotherapy and a supplement containing fish oil and selenium for similar treatment groups in a murine model of human cancer.
• FIG. 3 A shows the effect of various treatment protocols on tumor volume over the course of 3 weeks, with FIG. 3B providing a scaled view of the effect over the initial 11 days.
• treatment with a supplement containing fish oil and selenium alone provides an approximately 60% reduction in tumor volume.
• Treatment with radiation alone provides a similar reduction in tumor volume. In the absence of a synergistic effect one would therefore anticipate a reduction in tumor volume to approximately 25% of that of the untreated tumor.
• FIG. 3C shows that similar effects are found when tumor weight is characterized.
• FIG. 3D shows photographs typical examples of tumors excised from test animals following treatment; the effects of cotherapy with a nutritional supplement containing fish oil and selenium with radiotherapy is readily apparent on visual inspection. As such, it is apparent that cotherapy with a supplement containing fish oil and selenium and radiotherapy can provide a synergistic effect in reducing tumor volume and/or mass.
• FIGs. 4A to 4E show the effects of treatment with a supplement containing fish oil and selenium, radiotherapy, and cotherapy with radiotherapy using such a supplement (with and without supplement pre-treatment) on the weight of gastrocnemius muscle and soleus muscle
• test groups designated as described above.
• cotherapy with such a supplement and radiotherapy provides almost complete retention of muscle weight.
• FIGs. 4C, 4D, and 4E show the effects of treatment as described above on the weight lungs inclusive of any metastatic tumors (FIG. 4C), livers inclusive of any metastatic tumors (FIG. 4D), and spleens inclusive of any metastatic tumors (FIG. 4E).
• lack of treatment leads to an increase in weight, due at least in part to the presence of metastatic tumors. This increase is not entirely mitigated by radiotherapy alone (TR), however subjects receiving treatment with a supplement containing fish oil and selenium had organ weights similar to those of control subjects, both with and without cotherapy with radiotherapy.
• Typical metastatic sites are shown in the photographs in the left panel of FIG. 4F, and enumerated in a histogram in the right panel.
• treatment with either such a supplement (TN) or radiotherapy (TR) reduced the number of metastatic sites to some extent, however treatment with both the supplement and radiotherapy (TRN) resulted in a complete lack of apparent metastatic sites in most subjects.
• the Inventor believes that this effect on metastasis (and also on tumor size and mass, as shown above) can be due to a synergistic effect provided by the use of a nutritional supplement containing fish oil and selenium in combination with radiotherapy on tumor cell proliferation.
• the expression of the proliferation marker Ki-67 is suppressed in the primary tumor site on treatment with either a supplement containing fish oil and selenium (TN), on treatment with radiotherapy (TR), or treatment using both modes (TRN).
• Metastatic sites show a related trend, with treatment with the nutritional supplement or radiotherapy alone resulting in a moderate reduction in the expression of this proliferation marker, but surprisingly showing a synergistic effect in reducing expression of Ki-67 in metastatic sites. This indicates that use of a supplement containing fish oil and selenium can reduce tumor metastasis, including metastasis that is not prevented by radiotherapy, and can do so in a synergistic manner.
• FIG. 5A to 5E show the effects of cotherapy with a supplement containing fish oil and selenium on various blood cell populations.
• FIG. 5B shows the effects of a nutritional supplement containing fish oil and selenium, radiotherapy, and cotherapy with such a supplement and radiotherapy on white blood cells as shown in FIG. 5B, and lymphocytes as shown in FIG. 5C.
• a nutritional supplement containing fish oil and selenium can be useful to improve red blood cell, granulocyte, white blood cell, and/or lymphocyte suppression resulting from the presence of a tumor and from radiotherapy utilized in the treatment of such tumors.
• platelets were found to be elevated in untreated animals bearing tumors (T). Platelet concentrations were reduced by treatment with either a supplement containing fish oil and selenium or radiotherapy, but were most pronounced in animals receiving cotherapy with such a supplement and radiotherapy. This effect was particularly pronounced in subjects receiving pre-treatment with a supplement containing fish oil and selenium, which reduced platelet concentrations to the values found for control animals.
• Granulocytes are particularly pronounced in subjects receiving pre-treatment with a supplement containing fish oil and selenium, which reduced platelet concentrations to the values found for control animals.
• neutrophil/lymphocyte ratio relative to control animals, which is even more elevated in similar subjects receiving only radiotherapy.
• Treatment with a supplement containing fish oil and selenium was found to be effective in shifting this ratio towards a more normal value, both as a monotherapy and as a part of cotherapy with radiotherapy.
• This indicates that a nutritional supplement containing fish oil and selenium can be useful in reducing platelet concentration, granulocyte concentration, and/or neutrophil/lymphocyte ratios that are elevated due to the presence of a tumor and due to radiotherapy used to treat such a tumor.
• FIG. 6A shows the effects of a nutritional supplement containing fish oil and selenium, radiotherapy, and cotherapy with such a supplement and radiotherapy on an animal tumor model.
• serum albumin shows the effects of a nutritional supplement containing fish oil and selenium, radiotherapy, and cotherapy with such a supplement and radiotherapy on an animal tumor model.
• serum albumin shows the effects of a nutritional supplement containing fish oil and selenium, radiotherapy, and cotherapy with such a supplement and radiotherapy on an animal tumor model.
• serum albumin shows the effects of a nutritional supplement containing fish oil and selenium, radiotherapy, and cotherapy with such a supplement and radiotherapy on an animal tumor model.
• concentration an indicator of nutritional status
• Treatment with a nutritional supplement containing fish oil and selenium either as a monotherapy or as cotherapy with radiotherapy, improves serum albumin concentration- particularly when such a supplement is provided as a pretreatment. This is improved by cotherapy with a nutritional supplement containing fish oil and selenium. This indicates that treatment with a nutritional supplement containing fish oil and selenium, either as a monotherapy or as cotherapy with radiotherapy, can improve the nutritional status of tumor-bearing subjects.
• FIG. 6B shows the results of similar studies where serum creatinine (a measure of kidney function) is characterized. As shown, untreated tumor bearing subjects shown elevated creatinine concentrations indicative of kidney damage. This is marginally improved by radiotherapy alone. Cotherapy with a nutritional supplement containing fish oil and selenium and radiotherapy, however, shows a synergistic effect in reducing serum creatinine
• Cytokines [0067] The growth and spread of tumors is associated with inflammation, as is the application of radiotherapy. Surprisingly, Inventors have found that cotherapy with a supplement containing fish oil and selenium is effective in reducing the concentration of pro-inflammatory cytokines, indicating that such co-treatment is effective in reducing inflammation associated with tumors, and with radiotherapy of tumors.
• the effects of NutraWell supplement on serum concentrations of pro-inflammatory cytokines is shown in FIGs. 7 A and 7B.
• FIG. 7 A shows the concentration of IL-6 in control animals, untreated tumor-bearing animals, and tumor bearing animals treated with a nutritional supplement containing fish oil and selenium, radiotherapy, or such a supplement and radiotherapy in combination.
• FIG. 7B shows the results of similar studies of IL- ⁇ . The results with IL- ⁇ are similar to those found for IL-6. This indicates that a nutritional supplement containing fish oil and selenium can effectively reduce serum concentrations of inflammation-associated cytokines in tumor-bearing subjects, either as a monotherapy or as cotherapy with radiotherapy. The Inventor believes that such reduction is accompanied by a reduction in inflammation in such animals.
• FIG. 8A shows the results of such treatments on the expression of VEGF in tumor cells.
• FIGs. 8B and 8D show the effects of treatment with a nutritional supplement containing fish oil and selenium, radiotherapy, and cotherapy with such a supplement and radiotherapy on tumor BAX expression and metastatic (lung) tumor BAX expression, respectively.
• BAX is considered a marker for apoptosis. As shown, BAX expression in untreated tumor is low, and is not impacted by radiotherapy.
• FIG. 8D Treatment of radiotherapy or with a nutritional supplement containing fish oil and selenium alone, and is also elevated by cotherapy with such a supplement as radiotherapy (particularly when the supplement is provided as a pre-treatment).
• FIG. 8F expression of caspase 3 is reduced in metastatic (lung) tumors relative to lung tissue of control subjects.
• caspase 3 expression in such tumors is increased by radiotherapy or treatment with a nutritional supplement containing fish oil and selenium, as well as cotherapy.
• FIGs. 9A and 9B are views.
• FIGs. 10A to IOC Results from serum albumin and blood cell characterization studies following treatment with NutraWell, radiotherapy, and combined treatment with a nutritional supplement containing fish oil and selenium and radiotherapy using the protocol shown in FIG. 9A are shown in FIGs. 10A to IOC.
• serum albumin concentration is reduced in tumor bearing animals, particularly at later time points. This is improved by treatment with a nutritional supplement containing fish oil and selenium or radiotherapy as monotherapies, and by cotherapy.
• FIG. 10B tumor bearing animals showed suppressed lymphocyte counts relative to control subjects, particularly at later time points.
• FIG. IOC shows the results of similar studies wherein the neutrophil/lymphocyte ratio (NLR) was characterized. As shown, animals bearing tumors show a dramatic elevation in this value at later time points. This is reduced by treatment with a nutritional supplement containing fish oil and selenium, radiotherapy, and cotherapy with such a supplement and radiotherapy.
• NLR neutrophil/lymphocyte ratio
• treatment with a nutritional supplement containing fish oil and selenium, radiotherapy, and combined treatment with such a supplement and radiotherapy using the protocol shown in FIG. 9A also has an impact on both expression of tumor cell markers and tumor cell metastasis.
• the tumor cells selected for implantation are derived from a lung tumor and have a strong tendency to metastasize to the lung from the implantation site.
• FIGs. 11A to 11D show the results of immunocytochemistry studies of different tissues from mice treated with the protocol shown in FIG. 9A. It is notable that NutraWell supplementation alone reduces or eliminates metastasis.
• FIG. 11 A VEGF expression within the tumor of untreated mice (left panel, FITC staining) is evident. Treatment with either a nutritional supplement containing fish oil and selenium or radiotherapy alone dramatically reduced VEGF expression, as does cotherapy. Numerical results are provided in the right panel of FIG. 11 A. Similar results are found in tumors that have metastasized to the lungs, as shown in FIG. 1 IB. As shown, VEGF expression is apparent in untreated metastatic tumors (left panel, FITC staining) and is sharply reduced in animals that received treatment with a nutritional supplement containing fish oil and selenium, radiotherapy, or both. Numerical results of these studies are provided in the right panel of FIG. 11B.
• FIG. 11C Similar results are found with the expression of EGFR, overexpression of which is associated with tumors. As shown in FIG. 11C, elevated expression of EGFR (left panel, FITC staining) is evident in untreated tumors, and is reduced in subjects treated with a nutritional supplement containing fish oil and selenium, radiotherapy, or cotherapy with such a supplement and radiotherapy. Numerical results are shown in the right panel of FIG. 11C. Similar results are found for EGFR expression of tumors that have metastasized to the lungs, as shown in FIG. 1 ID.
• elevated EGFR expression (left panel, FITC staining) is evident in untreated metastatic sites, and is reduced in subjects treated with a nutritional supplement containing fish oil and selenium or radiotherapy as monotherapies, and with cotherapy using such a supplement and radiotherapy.
• a nutritional supplement containing fish oil and selenium, radiotherapy, and/or a combination of treatment with such a supplement and radiotherapy can be effective in enhancing EGFR-directed treatment protocols in individuals receiving treatment for cancer.
• FIG. 12 shows the results of immunocytochemistry studies of different tissues from mice treated with the protocol shown in FIG. 9A.
• the left panel of FIG. 12 shows the results of staining for CD31 (FITC staining), a stem cell marker, in tumor cells.
• the right panel shows similar results for metastatic cells in the lungs.
• FIG. 13A shows the results of immunocytochemistry studies of different tissues from mice treated with the protocol shown in FIG. 9A.
• the left panel shows the results of immunocytochemistry staining for HIFl-a (FITC staining) in tumor cells, while the right panel shows the results of similar staining at lung metastatic sites.
• FIG. 13B shows typical numerical results from a similar study where gene expression in tumor samples was characterized.
• both treatment with a supplement containing fish oil and selenium (TN) and pre-treatment with a nutritional supplement containing fish oil and selenium (PTN) for one week reduce tumor expression of HIFl-a, as does radiotherapy (TR).
• radiotherapy and such a nutritional supplement are used in
• Treatment with radiotherapy also shows a reduction in PD-L1 gene expression in both primary and metastatic sites, suggesting that radiotherapy alone can be used to enhance immunotherapeutic approaches to cancer treatment.
• Cotherapy with such a nutritional supplement and radiotherapy is effective in reducing PDL-1 expression in both primary tumor sites and metastatic sites, whether the supplement is provided prior to implantation (PTRN) or at the time of implantation (TRN).
• PTRN prior to implantation
• TRN time of implantation
• the effects are more marked at the primary tumor site than at metastatic sites. This suggests that cotherapy with a nutritional supplement that includes fish oil and selenium in combination with radiotherapy can render tumor cells at both primary and metastatic sites more susceptible to the patient' s immune system, and/or can enhance the effect of immunotherapy approaches to cancer treatment.
• PD-1 expression is reduced in primary site tumor cells treated with radiotherapy (TR) and enhanced in primary site tumor cells (left panel) in animals treated with a supplement containing fish oil and selenium, either prior to implantation (PTN) or upon implantation (TN).
• Cotherapy with the nutritional supplement and radiotherapy provides differential results depending on if the supplement is provided prior to implantation (PTRN) or at the time of implantation (TRN).
• tumor cells at metastatic sites showed reduced PD-1 expression relative to samples taken from control animals.
• radiotherapy resulted in an increase in PD-1 expression at metastatic sites (right panel), as did treatment with a supplement containing fish oil and selenium either prior to implantation or at the time of implantation.
• Cotherapy with radiotherapy and such a supplement provided higher levels of PD- 1 expression than those observed with monotherapy. It is apparent that treatment with a nutritional supplement containing fish oil and selenium, particularly in combination with radiotherapy, can shift PD-1 expression away from reduced expression levels seen in tumor- bearing subjects, particularly in metastatic sites.
• FIGs. 16A and 16B Another treatment protocol combining both pretreatment with a nutritional supplement containing fish oil and selenium and multiple rounds of radiotherapy typical of clinical application is shown in FIGs. 16A and 16B. In this protocol treatment with the supplement was initiated prior to tumor cell implantation, at the time of tumor cell implantation, and at the initiation of radiotherapy.
• FIG. 17 shows photomicrographs that demonstrate the effect treatment with a nutritional supplement containing fish oil and selenium on the cellular architecture of the gut during radiotherapy.
• Cellular architecture of the gut is shown for untreated control subjects (top left panel), tumor implanted subjects treated with multiple rounds of radiotherapy (to right panel), tumor implanted subjects pretreated with a nutritional supplement containing fish oil and selenium and subsequently treated with radiotherapy (lower left panel), and tumor implanted subjects treated with a nutritional supplement containing fish oil and selenium at the time of initiation of radiotherapy (lower right panel).
• treatment with a nutritional supplement containing fish oil and selenium can maintain the intestinal brush border during radiotherapy, with pretreatment apparently enhancing the intestinal brush border. This indicates that treatment with such a supplement, particularly pretreatment, can effectively address side effects of radiotherapy.
• FIG. 18A results of qPCR studies of gene expression (e.g. angiogenic factor-related, apoptosis-related, etc.) in tumor cells from mice treated by the protocol shown in FIG. 16A are shown in FIGs. 18A to 18F.
• treatment with a nutritional supplement containing fish oil and selenium reduces VEGF expression in tumor cells, as does repeated radiotherapy.
• Combined therapy with such a supplement and radiotherapy provides an enhanced reduction in VEGF expression, particularly when a nutritional supplement containing fish oil and selenium is provided prior to initiation of radiotherapy.
• FIG. 18B shows that BAX expression in tumor cells is increased by treatment with a nutritional supplement containing fish oil and selenium, and relatively unaffected by repeated radiotherapy alone. Pretreatment with such a supplement in combination with repeated radiotherapy also increased BAX expression. Similar results are found for expression of another apoptosis-related gene (Caspase 3), as shown in FIG. 18D. Results of studies of Caspase-3 expression in metastatic (lung) tumors are shown in FIG. 18F. As shown, expression of
• Caspase-3 in such metastatic tumors is elevated by treatment with a nutritional supplement containing fish oil and selenium and by repeated radiotherapy, and is similar to that of control cells when the supplement is provided as cotherapy prior to initiation of radiotherapy.
• FIG. 18C shows the results of similar studies performed on metastatic (lung) tumors. As shown, the reduction in Bcl-2 expression is reduced in a synergistic fashion on cotherapy with a nutritional supplement containing fish oil and selenium and repeated radiotherapy, particularly when the supplement is provided prior to initiation of radiotherapy.
• FIGs. 19A and 19B show a treatment protocol and related test groups (respectively) where a nutritional supplement containing fish oil and selenium is provided 7 days prior to implantation of tumor cells, with radiotherapy taking place on days 8, 10, and 12 following implantation. Mice were sacrificed on day 24 following implantation.
• a well known side effect of both cancer and repeated radiotherapy is weight loss. This can be due to wasting associated with disease and with side effects of radiotherapy.
• the effect of treatment with a nutritional supplement containing fish oil and selenium on loss of body mass and on muscle mass following repeated radiotherapy is shown in FIGs. 20A and 20B. It should be appreciated that body mass was characterized following removal of the tumor mass. As shown in FIG. 20A, when tumor mass is removed a significant decrease in remaining body mass is apparent relative to control subjects. This is improved by treatment with a nutritional supplement containing fish oil and selenium and by radiotherapy as monotherapies.
• FIG. 20B shows the weight of gastrocnemius muscle in the various test groups. Loss of muscle mass is apparent in untreated tumor bearing animals. This is marginally improved by repeated radiotherapy alone.
• treatment with a nutritional supplement containing fish oil and selenium provides significant retention in muscle mass.
• Cotherapy with a nutritional supplement containing fish oil and selenium and repeated radiotherapy provides a synergistic improvement in muscle mass relative to untreated tumor bearing subjects. It is apparent that pre-treatment with a nutritional supplement containing fish oil and selenium effectively reverses the loss of body mass (relative to control subjects) and muscle mass resulting from both the presence of the tumor and repeated radiotherapy.
• FIGs. 21A and 2 IB Another treatment protocol with related treatment groups is shown in FIGs. 21A and 2 IB, which is similar to the protocol shown in FIGs 16A and 16B.
• radiotherapy is provided on days 8, 10, and 12 following implantation of tumor cells.
• Treatment with a nutritional supplement containing fish oil and selenium is provided either 7 days prior to implantation, the day of implantation, or on the initiation of radiotherapy. Mice were sacrificed on day 21 following tumor cell implantation.
• a well known side effect of both cancer and radiotherapy is weight loss.
• the effect of treatment with a nutritional supplement containing fish oil and selenium on loss of body mass and loss of muscle mass when provided prior to and when provided coincident with the initiation of repeated radiotherapy is shown in FIG. 22.
• body mass was characterized following removal of the tumor mass.
• body weight gains over time of untreated tumor bearing subjects (following excision of the tumor) is dramatically reduced relative to control subjects. Similar losses are noted on repeated radiotherapy when used alone.
• treatment with a nutritional supplement containing fish oil and selenium provides remarkably improved body weight gains over time, both as a monotherapy and when used in combination with repeated radiotherapy. This is particularly evident with such a supplement is used as a pretreatment.
• Inventors have also found that pre-treatment with a nutritional supplement containing fish oil and selenium enhances the reduction in tumor volume seen on repeated radiotherapy, as shown in FIG. 23.
• both repeated radiotherapy and treatment with a nutritional supplement containing fish oil and selenium have a moderate effect in reducing tumor volume relative to tumors of untreated tumor bearing animals.
• tumor volume shows almost no change over time when repeated radiotherapy and a nutritional supplement containing fish oil and selenium are used as cotherapies, indicating a synergistic effect.
• FIGs. 24 A and 24B show the effect of administration of a nutritional supplement containing fish oil and selenium with repeated radiotherapy on the concentration of proinflammatory cytokines in mice treated as in the protocol shown in FIG. 21A.
• FIG. 24A shows values for serum TNF-a. It is apparent that untreated tumor bearing animals show highly elevated concentrations of TNF-a, which is reduced to some extent by repeated radiotherapy. Treatment with a nutritional supplement containing fish oil and selenium also resulted in a reduction in serum TNF-a, particularly when such a supplement was used in cotherapy with repeated radiotherapy.
• FIG. 24B shows the results of similar studies where the serum

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