CA2244608C

CA2244608C - Nutritional product with high fat, low carbohydrate and amino acid imbalance

Info

Publication number: CA2244608C
Application number: CA002244608A
Authority: CA
Inventors: Michael A. Pellico
Original assignee: Individual
Current assignee: Individual
Priority date: 1997-12-24
Filing date: 1998-07-31
Publication date: 2002-12-17
Anticipated expiration: 2018-07-31
Also published as: US5817695A; ES2215278T3; EP0925726B1; DE69821329D1; DE69821329T2; CA2244608A1; EP0925726A1

Abstract

A nutritional product is provided for cancer patients comprising, as per caloric requirement, a low concentration of carbohydrate, a high concentration of fat and an imbalance of amino acids wherein L-phenylalanine, L-tyrosine and L-methionine are present in the below normal concentrations and L-leucine is present in substantial excess of normal concentrations to suppress cancer growth and as an adjunct to conventional cancer therapies.

Description

1 Nutritional Product With High Fat Low Carbohydrate And Amino Acid Imbalance 4 1. Field Of The Invention This invention relates to enteral nutritional products for cancer patients and, more particularly, to enteral nutritional products comprising high fat, low carbohydrate and an elemental amino acid profile having a selected amino acid imbalance for suppressing tumor growth.
11 2~ Background Of The Invention 12 During the 20th century the average life expectancy 13 for Americans has increased by almost 25 years. The 14 significant gains in lifespan have been largely due to improved preventive health measures and advances in sanitation 16 and nutrition, as well as the treatment of infectious 17 diseases. This prolongation of life expectancy has produced 18 a significant population of aged people with a high incidence 19 of cardiovascular and neoplastic disorders. These disease groups currently account for approximately 70% of the total 21 annual deaths in the United States of America (Committee on 22 Diet, Nutrition, and Cancer, Assembly of Life Sciences, 23 National Research Council: Diet. Nutrition and Cancer, Natl.
24 Acad. Press, Washington, D.C., 1982). Consequently, a major Part of our health care expenditures and allocations of funds 26 for biomedical research have been directed to the treatment of 2~ malignant neoplasms. Despite these efforts, overall, age 28 adjusted mortality from neoplasms has remained constant, 1 although there have been serious reductions in the mortality 2 from some of its rarer forms, such as Hodgkin' disease, 3 childhood leukemia, and seminomas.
4 A diverse array of mechanisms can lead to the characteristic alterations implicated in neoplastic 6 transformation. Present research has shown that human 7 neoplasms arise as a direct consequence of an accumulation of 8 genetic alterations involving two main classes of genes:
g photo-oncogenies and tumor suppressor genes (Marshall C: Tumor suppressor genes. Cell 64 : 313-326, 1991; Bode B, Kaiser HE, 11 Goldfarb RH: Immunophenotypicaly varied cell subpopulations 12 in primary and metastatic human melanomas. Monoclonal i 13 antibodies for diagnosis, detection of neoplastic progression 14 and receptor directed immunotherapy. Anticancer Res 16: 517 531, 1996: Bode B, Groger AM, Bode B Jr, Siegel E, Kaiser HE:
16 I~unocytochemical detection of p53 protein overexpression in 17 primary human osteosarcomas. Anticancer Res 17: 493-498, 18 1997). Oncogenies result from an activating mutation 1g generating an enhancement of intracellular protein quantity.
Tumor suppressor genes, on the other hand, are commonly 21 inactivated via either mutation or deletion or the 22 physiological function of the gene product is inhibited by 23 binding of inactivating molecules. Observations of the 24 expression of the deleted in colorectal cancer (DCC) gene product, for instance, have demonstrated a significant 26 correlation between DCC protein presence and cellular 27 differentiation and carcinogenesis (Hedrick L, Cho KR, Fearon 2g ER, Wu T-C, Kinzler KW, Vogelstein B: The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes 2 Dev 8: 1174-1183, 1994).
Mutations resulting in an oncogene have been 4 established as dominant genomic alterations, whereas tumor suppressor gene mutations are recessive, requiring loss of 6 function at both alleles for initial neoplastic development.
7 In all cases of neoplastic cell transformation there are three 8 important pre-malignant changes: 1) overexpression of a gene and its product; 2) alteration of a gene product; and 3) inactivation of an encoded protein (Perry ME, Levine AJ:
11 Interactions between tumor suppressor gene and oncogene 12 Products. Mount Sinai J Med 61: 291-299; Talib VH, Pandey J, 13 Dhupia JS: Molecular markers in cancer diagnosis. Ind J
14 Pathol Microbiol 38: 1-3, 1995; Jacobson DR., Fishman CL, Mills NE: Molecular genetic tumor markers in the early diagnosis and 16 screening of non-small-cell lung cancer. Annals Oncol 6 17 ~(Suppl 3): S3-S8, 1995: Bugert P, Kovacs G: Molecular 18 differential diagnosis of renal cell carcinomas by 19 microsatellite analysis. Am J Pathol 149: 2081-2088, 19961 Dietzmann K, von Bossanyi P, Sallaba J, Kirches E, Synowitz 21 HJ, Warich-Kirches M: Immunohistochemically detectable p53 and 22 mdm-2 oncoprotein expression in astrocytic gliomas and their 23 correlation to cell proliferation. General Diagn Pathol 141:
24 339-344, 1996).
Neoplastic cells with a highly malignant 26 immunophenotype (IP) are not stable; their genetic alterations 27 can be rapid and dramatic, resulting in cell dedifferentiation 2g and regional tumor heterogeneity (Volpe JP: Genetic 1 instability of cancer: Why a metastatic tumor is unstable and 2 a benign tumor is stable. Cancer Genet Cytogenet 34: 124-134, 3 1988; Bode B, Zeltzer PM, Saldivar V, Kemshead J:
4 Immunophenotyping of childhood astrocytomas with a library of monoclonal antibodies. Int J Cancer 45: 1079-1087, 1990; Bode 6 B, Bode B Jr, Groger AM, Siegel SE, Kaiser HE: Clinical and 7 prognostic significance of Ki-67 and proliferating cell 8 nuclear antigen expression in childhood primitive neuroectodermal brain tumors. Anticancer Res 17: 189-196, 1997; Bode B, Bode B Jr, Groger AM, Siegel SE, Kaiser HE:
11 Nm23/nucleoside diphosphate (NDP) kinase expression in human 12 malignant melanomas. Significance and implications in tumor 13 biology. Anticancer Res 17: 505-512, 1997).

Nutrition in Neoplastic Transformation and Malignant Disease 16 Pro~Lression 17 During the early years of experimental oncology, 18 daily food intake and various other dietary habits were 19 mentioned among various environmental factors which could initiate and modify tumor formation and progressive growth in 21 laboratory animals (Moreschi C: Beziehungen zwischen Ernahrung 22 and Tumorwachsten. Zeitschr Immunitatsforsch 2: 651-685, 23 1909; Rous P: The influence of diet on transplanted and 24 spontaneous mouse tumors. J Exp Med 20: 433-451, 1914). More detailed observations exploring the relationship between 26 nutrition and carcinogenesis in various mammals, and animal 27 models of human malignancies have been reported in the past 40 28 years. During this decade, the era of "Nutritional Oncology"

I I

1 has begun (Ottery FD: Rethinking nutritional support of the 2 cancer patient: the new field of nutritional oncology. Sem 3 Oncol 21: 770-778, 1994). Recently, the National Cancer 4 Institute (NCI) estimates that at least 35% of all human neoplasms are associated with the daily qualitative and 6 quantitative intake of food and the nutritional habits in various countries. As a specific example, women in Japan, consuming the traditional Japanese diet, have a relatively low rate of breast carcinoma (BC). When these and other women immigrate to the U.S.A., their likelihood of developing BC
11 significantly increases. Epidemiological studies in humans 12 have established an association between a high rate of 13 neoplastic transformation and a normal diet high in saturated 14 fat and animal protein (Giuliano AE: A high fiber defense against breast cancer. Los Angeles Times, October 20th issue, 16 1997). The reason that fat may promote BC is that fat cells 17 represent a major place of estrogen alterations in the human 18 body. Estrogen allows BC cells to grow faster and 19 progressively alter their IP towards a more dedifferentiated (i.e. embryonal) one, and furthermore reduces the efficacy of 21 the cellular immune response in eliminating neoplastically 22 transformed cells of the primary tumor mass and countering the 23 formation of distant metastases. The antioxidants, such as 24 vitamins A, C and E, as well as soybean have been implicated in reducing the likelihood of BC.
26 The normal development and growth of any 27 multicellular organism requires controlled interactions 28 between cells in the organism. Growth control depends on a I I

1 variety of signaling mechanisms. The growth of cancer may 2 demonstrate the failure of such control mechanisms.
3 In a cancer, cell proliferation usually continues 4 independent of a requirement for new cells and differentiation is impaired.
The ability of cancer cells to invade other tissue and to spread by metastasis to other parts of the body where they can generate new tumors is an indication of the malignant nature of a cancer and is the major factor that leads to the death of the host.
11 Current accepted treatments of tumors usually 12 involves methods of interfering with cell division. The 13 methods most commonly used are hypothermia, radiation, 14 chemotherapy or combinations of them.
Since both radiation and chemotherapy interfere with 16 a cell's ability to divide, rapidly dividing cells such as 1~ cancer cells are the most affected.
1g However, radiation and chemotherapy are not specific 19 against cancer cells. They interfere with any cell in the Process of division. Many millions of normal cells are also 21 in the process of division at any period in time. Thus 22 radiation and chemotherapy also inhibit the normal cell 23 division of heathy tissue. This is an especially critical 24 problem for certain organs such as skin, glands, bone marrow, the mucosa and kidneys which have a high rate of cell 26 turnover.
2~ The inability of radiation and chemotherapy to 2g distinguish between abnormal tissue and healthy tissue is an 1 important limiting factor for radiation and chemotherapy.
2 Quite often it is a race patients lose.
Other methods to kill tumor cells are also being used with varying degrees of success. Hypothermia, in which the tumor is heated to temperatures which cause the death of 6 the tumor, is somewhat successful especially in conjunction with radiation and chemotherapy.
Photosensitizing the tumor cell is another treatment which has had some success . However, so far all these methods have had at best partial success due to factors such as 11 toxicity to the patient or the tumor becoming resistant to the 12 treatment.
13 Knowing the limitations of current treatments, my 14 invention takes a unique approach.
My invention is based on the known metabolic 16 differences between most tumors and healthy cells. In fact my 1~ invention also takes advantage of the metabolic differences 18 between a healthy person and a person acting as a host to a 19 cancer.
Cancer cells have different metabolic requirements 21 in at least three major categories.

23 PROTEINS METABOLISM: In the cancer patient with cachexia the 24 obvious sign of protein deficiency is the loss of skeletal muscle mass. The decreased muscle protein synthesis occurs 26 even in a diet which has adequate amounts of amino acids and 2~ calories. Also observed is that some patients with neoplastic 2g diseases, especially leukemia, excrete in their urine novel proteins and peptides.
There is evidence that these proteins are produced by the tumor. Other abnormalities in protein metabolism seem to indicate that the cancer patient cannot undergo metabolic adaptation to decrease food intake. Cancer cells, because of their rapid growth, often require greater amounts of proteins.

8 CARBOHYDRATE METABOLISM: Repeated clinical and experimental observation shave documented abnormal carbohydrate metabolism in cancer patients. Abnormalities have been noted in 11 Peripheral tissue glucose disposal, hepatic glucose production 12 and whole body glucose oxidation and turnover.
13 Cancer patients as a group have abnormal or diabetic 14 glucose tolerance. The profound alternations observed in carbohydrate metabolism in dogs and humans with cancer result 16 in a net energy gain by the tumor and a net energy loss by the 17 host (Ogilvie, 1989; Ogilvie and Vail, 1990; Vail et al., 1990 1g b). Glucose is the preferred substrate for energy production 1g in tumor cells. Yet even today TPN treatment (Total Parentenol Nutrition) which is given to the vast majority of 21 cancer patients is a 50% dextrose (glucose) solution!
22 Following is a table from the 1991 publication of Clinical 23 Oncology Textbook of the American Cancer Society.

SUGGESTED DAILY TPN REGIMEN FOR AN ADULT CANCER PATIENT

A. PROTEIN-CALORIE KCAL

700m1 50% DEXTROSE 1,190 400m1 20% LIPID EMULSION 880 1000m1 10% AMINO ACID SOLUTION 400 6 TOTAL CALORIES 2,470 TOTAL CALORIE: PROTEIN NITROGEN RATIO 154:1 TOTAL VOLUME 2,100 ml MULTIVITAMIN

PREPARATION one vial/day VITAMIN K1 10 mg/once wk HEPARIN 8000.u/day GLUTAMIC ACID 4 g/dad 16 B ~DITIVES

ELECTROLYTES SODIUM CHLORIDE 60-140 me/day POTASSIUM CHLORIDE 60-100 me/day MAGNESIUM SULFATE 8-10 me/day CA; CHI, G;ICPMATE 9, Eq/day POTASSIUM PHOSPHATE 30-45 me/day 22 T~CE MINERALS COPPER

MANGANESE one vial/day CHROMIUM

IRON 1 mg/day I I

1 As one can see it has a very high percentage of 2 dextrose, a polymer of glucose. In fact, half the calories of this diet come from sugar.
4 Studies by Holroyde and Reichard (Carbohydrate metabolism in cancer cachexia; Cancer Treatment Rep. 65:61-65 6 (1981) have suggested that the increased rate of total glucose turnover seen in cancer patients with weight loss could be 8 accounted for by enhanced Cori cycle activity.
Under normal conditions, the body utilizes glucose through aerobic metabolism via the krebs cycle. Cancer cells 11 possess all the enzymes necessary to carry out aerobic 12 metabolism by the krebs cycle but for obscure reasons, the 13 tumor preferentially metabolizes glucose by anaerobic 14 glycolysis, fonaing lactate as an end product. The 38 moles of ATP normally formed per mole of glucose in aerobic 16 metabolism is lost; instead only two moles of ATP per mole of 1~ glucose are formed during the anaerobic production of lactate.
18 The lactate is then converted back to glucose in the liver by 1g the Cori cycle, resulting in a net loss of four ATP's and two GTP's for every glucose molecule produced.
21 The tumor ends up gaining energy while the host has 22 a dramatic energy loss. (Ogilvie, Nutrition and Cancer;
23 Veterinary Clinics of North America: Small Animal Practice -24 Vol. 20, No. 4, 1990).
26 LIPID METABOLISM: Abnormalities in host lipid metabolism occur during tumor growth in both animals and man.
2g Hyperlipidemia and depletion of lipid stores are the main 1 gross abnormalities resulting from this abnormal fat 2 metabolism. Animal experiments support the findings of enhanced lipid mobilization and decreased lipogenesis by 4 adipose tissue in the tumor-bearing host.
Although many tumors can oxidize fatty acids 6 rapidly, other less well differentiated ones have essentially lost the ability to use them as fuel.
On the basis of these many observations of the metabolic abnormalities of cancer cells, researchers in the Past have tried to control cancer growth by dietary 11 manipulation but with very little success.
12 A report by Mead-Johnson states:
13 "Five medical investigator groups reported use of 14 diets low in the amino acids, phenylalanine and tyrosine on 23 cancer patients having various melanomas and carcinomas. In 16 21 of the 23 cases, no improvement in condition was noted 17 during the course of dietary treatment. Only 2 patients l8 showed some improvement in condition, and it is uncertain that 19 dietary management contributed to this in any significant way.
This data does not support the use of low phenylalanine/
21 tyrosine diet powder in the management of malignant melanomas 22 and carcinomas." (Mead-Johnson, Products for Dietary 23 Management of Inborn Errors of Metabolism and Other Special 24 Feeding Problems).
Dr. Theologides in Cancer Cachexia; American Cancer 26 Society - Cancer 43:2004-2012, 1979 states "even with forced 27 feeding and total parental hyper alimentation, the process of 2g wasting is only temporarily reversed."

1 An article by Dr. Dempsey and Dr. Mullen in Cancer, 2 January 1, supplement 1985, states: "Currently there is little compelling data to support the use of specialized amino acid formulae in the malnourished cancer patient with normal liver and kidney function."
Although studies so far have not been able to show 7 that cancers can be controlled by dietary manipulation, there 8 is a large amount of evidence that nutritional support such as TPN (Total Parenteral Nutrition) can cause tumor growth.
"Malnourished animals that undergo nutritional 11 repletion orally (steiger et al. 1975) or with TPN (Daly, 12 Copeland and Dukrick 1978) may have a significant increase in 13 t~or growth" (Clinica Oncology, Holleb, Fink, Murphy 1991).
14 Thus, it is of great concern in the clinical setting that nutritional support may support tumor growth. Yet although 16 TPN has been shown to promote the growth of tumors, the vast 17 majority of cancer patients still receive TPN!
18 So while special diets have failed to adequately 19 check the growth of tumors, total nutritional support is also not the answer.
21 My discovery is in understanding how cancer grows 22 and why the prior special diets have failed. My invention is 23 a special diet (formula) that interferes with the cancer's 24 unique nutritional requirements in three major areas, amino acids, fats (lipids) and carbohydrates.
26 By careful manipulation of the proportions of each 27 group and combining them into one complete diet, I have 28 developed a formula which essentially "starves" a tumor by 1 limiting what it needs for its explosive, uncontrolled growth.
2 Because a tumor's metabolic requirements are substantially different than normal cells, the host is not 4 harmed by this diet and actually greatly benefits nutritionally.
6 The prior art discloses nutritional products for use 7 by cancer patients.
8 U.S. Patent No. 5,081,105 (Bristian, 1992) discloses, as nutritional support therapy for cancer patients, a parenterally administered diet containing a structural lipid 11 that includes a medium chain fatty acid, and an omega-3 fatty 12 acid to modify tumor growth rate, tumor fractional synthetic 13 rate, and tumor protein breakdown rate.
14 U.S. Patent No. 5,547,927 (Cope et al., 1996) discloses, as nutritional support therapy for patients 16 undergoing radiation therapy and/or chemotherapy, an enteral 17 nutritional product containing a soy protein hydrolysate, pea 18 protein, whey protein and a source of fat wherein the ratio, 19 by weight, of the sum of the m-6 fatty acids to the m-3 fatty acids is in the range of about 1.3:1 to 2.5:1.
21 Also, U.S. patent No. 5,661,123 (Stalker et al., 22 1997) discloses, as nutritional support for malabsorbing 23 patients, an enteral composition that includes a peptide based 24 protein source of hydrolyzed whey, a lipid source, and a carbohydrated source wherein the protein source includes 26 approximately 22% to about 27% of the total calories, and the 27 composition has a caloric density of approximately 1000_Kca/L
28 and a low osmolality of approximately 300 to 450 mOsm/KgH20.

2 An important object of this invention is to provide a new and improved diet for cancer patients through the 4 formulation of an enteral nutritional product with an elemental amino acid profile having a selected amino acid 6 imbalance for suppressing tumor growth.
7 Another obj ect of this invention is to provide a new 8 and improved diet for cancer patients through the formulation of an enteral nutrition product which is high in fat, low in carbohydrates, and contains an amino acid profile having a 11 selected amino acid imbalance, for suppressing tumor growth.
12 Upon further study of the specification and claims, 13 additional objects and advantages will become apparent to 14 those skilled in the art.

lII SUMMARY OF THE INVENTION

In accordance with this invention, there is provided 4 an elemental nutritional product for cancer patients comprising:
6 ( a ) carbohydrate in an amount from about 2 to about 15% of the per day total caloric requirement, 8 (b) fat in an amount from about 40 to about 80% of the per day total caloric requirement, and (c) a protein component defined by an amino acid 11 Profile to 100% of the per day total caloric requirements, 12 said amino acid profile including L-phenylalanine in an amount 13 from about 0 to about 5 wt. %, L-tyrosine in an amount from 14 about 2 to about 6 wt.%, L-methionine in an amount from about 5 to about 11 wt.%, and L-leucine in an amount from about 20 16 to about 35 wt.%, with said wt.% being based on the total 1~ weight of the amino acid profile.

1g DETAILED DESCRIPTION
The elemental nutritional products of this invention 21 comprises carbohydrate, fat, and a protein component defined 22 by a pre-selected amino acid profile.
23 The amino acid profile includes essential and non-24 essential amino acids wherein L-phenylalanine is present in an amount from about 0 to about 5 wt.% and, preferably, in an 26 amount from about 2 to about 4 wt.%, L-tyrosine is present in 2~ an amount from about 2 to about 6 wt.% and, preferably, in an 2g amount from about 3 to about 5 wt.%, L-methionine is present 1 in an amount from about 5 to about 11 wt. % and, preferably, in an amount from about 7 to about 9 wt. %, L-glutamine is present 3 in an amount from about 2 to about 5 wt. %, L-lysine is present 4 in an amount from about 2 to about 6 wt.%, L-leucine is present in an amount from about 20 to about 35, wt.% and, 6 preferably, in an amount from about 24 to about 31 wt.%, and L-arginine HC1 is present in an amount from about 20 to about g 25 wt.%, with said wt.% being based on the total weight of the amino acid profile.
An important feature of this invention is to limit 11 one or more of the essential amino acids to a small percentage 12 of the needs of the tumor. Although the limitations of non-13 essential amino acids is not as critical, the diet also 14 includes careful control of and limitations on tyrosine, a non-essential amino acid, because it can be biochemically 16 converted into phenylalanine.
Since a cancer's amino acid requirements exceed 1g those of normal cells, selective reduction in the diet of one 19 or more amino acids can suppress the growth of the cancer. By analogy, an illustrative example can be found in the dietary 21 requirements of phenylalanine for a child and for an adult.
22 The daily child requirements for phenylalanine is 141 mg/kg 23 whereas the daily adult requirement for phenylalanine is only 24 16 mg/kg. Although this analogy is not perfect, it is apparent that a child and a tumor are rapidly growing and, 26 thus, have a higher level of amino acid requirements than an adult. By careful control of certain amino acids, the diet 2g described herein deprives the tumor of its requirements for 1 both rapid growth and repair.
2 Carbohydrate is generally present in the nutritional product in an amount from about 2 to about 15% of the total 4 caloric requirement and, preferably, in an amount from about 5 to about 10% of the total caloric requirement.
6 Many tumors have an enhanced requirement for glucose and are capable of altering the host's ability to utilize 8 glucose so that the tumor is assured of an adequate supply that is necessary for its rapid growth. Thus, the tumor is not just a passive growth, but an active parasite which is 11 forcing the host to feed it. The diet herein is extremely low 12 in carbohydrates to prevent the tumor from using its preferred 13 energy source. This diet allows only enough glucose to enter 14 the blood to ensure that the body receives a barely adequate supply. The tumor is thereby deprived from an essential 16 requirement for growth and repair.
17 Fat is generally present in the nutritional product 18 in an amount from about 40 to about 80% of the total caloric 19 requirement and, preferably, in an amount from about 50 to about 70% of the total caloric requirement.
21 Many types of tumors lose their ability to utilize 22 fatty acids as an energy source and, as to those tumors which 23 do not completely lose their ability to utilize lipids, they 24 cannot metabolize lipids with the same ease as they would glucose, which is their preferred energy source. Accordingly, 26 the nutritional product provides most of its calories in the 2~ form of lipids, not glucose. Also, the lipids present in the 2g nutritional products are so selected as to be nutritionally 1 useful to the host and less so to the tumor. By reason of 2 these considerations, the nutritional product has a high 3 percentage of fish oils containing omega-3 fatty acids.
4 In addition, it is important to note that the tumor, an active parasite, can also get its nutritional requirements 6 from the host through biochemical manipulation of the host.
7 The ability of the tumor to derive nutrients from the host 8 causes inanition, weakness, tissue wasting, and organ 9 dysfunction. The term "cancer cachexia" has been adopted to describe these conditions. Thus, regardless of diet, the 11 tumor continues to grow at its own genetically determined 12 rate. However, some studies show that the amino acid 13 L-leucine can block this metabolic pathway of the tumor.
14 Therefore, the nutritional product has a high percentage of L-leucine so as to inhibit the tumor from cannibalizing the host 16 whereby the tumor is forced to grow on a nutritionally 1? incomplete diet and, as a result, the tumor cannot maintain 1$ its rapid growth.

2o ExAMPLEs 21 The following examples further illustrate the 22 invention. The mineral mix and the vitamin mix are the same 23 in each example and, therefore, the ingredient listing for 24 each mix is not repeated after Example 1.
Examvle 1 27 L-ALANINE 45 gm L-ARGININE HCL 60.5 gm 2$ L-ASPARTIC ACID 93.5 gm 1 L-CYSTINE 23 gm L-GLUTAMIC ACID 339.5 gm GLYCINE 52 gm L-HISTIDINE HCL 43 gm L-LEUCINE 145.5 gm 4 L-LYSINE HCL 118 gm L-METHIONINE 47.5 gm L-PROLINE 177.5 gm 6 L-SERINE 91 9m L-THREONINE 65 gm L-TRYPTOPHAN 21.5 gm L-TYROSINE 2.250 gm 8 L-VALINE 107 gm TAURINE 10 gm CORN STARCH 986 gm SUCROSE 100 gm ~D 6 5 0 gttt CORN OIL 500 gm 11 COD LIVER OIL 50 gm ALPHACEL NON-NUTRITIVE BULK 850 gm 12 ETHOXIQUIN 1.250 gm DICALCIUM PHOSPHATE 125 gm 14 CALCIUM CARBONATE 30 gm DIPOTASSIUM PHOSPHATE 50 gm SODIUM CHLORIDE 37.5 gia MAGNESIUM SULFATE 7H20 30 gm COPPER SULFATE 5H20 0.250 gm 17 MANGANESE SULPHATE H20 0.250 gm ZINC CHLORIDE 1.100 gm 18 POTASSIUM IODIDE 0.030 gm SODIUM SELENITE 0.015 gm 19 AMMONIUM MOLYBDATE 0.010 gm SODIUM FLUORIDE 0.030 gm CHROMIUM CHLORIDE 6H20 0.065 gm ALUMINUM CHLORIDE 0.100 gm VITAMIN MIX

VITAMIN A ACETATE (500,000 U/gm) 0.200 gm 23 VITAMIN D2 (850,000 U/gm) 0.013 gm VITAMIN E (250 U/gm) 3 9m 24 MENADIONE 0.250 gm THIAMINE HCL 0.110 gm RIBOFLAVIN 0.110 gm D CALCIUM PANTOTHENATE 0.330 gm 26 NIACIN 0.500 gm PYRIDOXINE HCL 0.110 gm 27 FOLIC ACID 0.004 gm BIOTIN 0.002 gm 28 VITAMIN B-12 (0.1-s TRIT) 0.150 gin 1 CHOLINE CHLORIDE 25 gm INOSITOL 0.550 gm 0.550 gm 4 In this diet the amino acids Tyrosine and Phenylalanine are quite low. The Phenylalanine is only 0.09%
6 of an adults normal requirement. The Tyrosine is only 0.8% of 7 an adult's requirements.
8 However the Carbohydrate level is somewhat higher than ideal.

Example 2 12 L-ALANINE 45 gm L-ARGININE HCL 60.5 gm 13 L-ASPARTIC ACID 93.5 gm L-CYSTINE 23 gm L-GLUTAMIC ACID 339.5 gm 14 GLYCINE 52.5 gm L-HISTIDINE HCL 43 gm L-ISOLEUCINE g5 16 L-~UCINE 145.5 gm L-LYSINE HCL 118 gm L-METHIONINE 47.5 gm 18 L-PROLINE 177.5 gm 19 L-THREONINE 65 gm L-TRYPTOPHAN 21.5 gm L-TYROSINE 2.250 gm L-VALINE 107 gm 21 TAURINE 10 gm CORN STARCH 100 gm 22 S~DINE OIL 915 gm D 150 gm 23 CORN OIL 500 gm COD LIVER OIL 350 gm 24 ALPHACEL NON-NUTRITIVE BULK 1,121.0 gm ETHOXIQUIN 1.250 gm In this diet the Phenylalanine and Tyrosine are at 27 the same levels as Example #1.

28 The Carbohydrate level, however, has been reduced to 1 a low level. There is zero percent sucrose and the cornstarch 2 has been lowered from 197 g/kg of diet to 20 g/kg.
3 The Carbohydrate calories have been replaced by fat.
In this example we are using primarily sardine oil, cod liver oil, corn oil, and a small amount of lard.
6 Example 3 8 L-ALANINE 45 gm L-ARGININE HCL 60.5 gm L-ASPARTIC, ACID 93.5 gm L-CYSTINE 23 gm L-GLUTAMIC ACID 339.5 gm GLYCINE 52.5 gm 11 L-HISTIDINE HCL 43 gm 12 L-~UCINE 145.5 gm L-LYSINE HCL 118 gm 13 L-METHIONINE 47.5 gm L-PHENYLALANINE 2 9~

14 L-PROLINE 177.5 gm L-SERINE 91 gm L-THREONINE 65 gm L-TRYPTOPHAN 21.5 gm 16 L-TYROSINE 2.250 gm L-VALINE 107 gm 17 TAURINE 10 gm CORN STARCH 100 gm 18 MENHADEN 915 gm D 150 gm 19 CORN OIL 500 gm COD LIVER OIL 350 gm ALPHACEL NON-NUTRITIVE BULK 1,121.0 gm ETHOXIQUIN
1.250 gm 22 In this diet the formula is the same as Example #2 23 except that the sardine oil has been replaced by menhaden oil.
24 Example 4 26L-ALANINE 45 gm L-ARGININE HCL 60.5 gm 27L-ASPARTIC ACID 93.5 gm L-CYSTINE 23 gm 28L-GLUTAMIC ACID 339.5 gm GLYCINE 52.5 gm L-HISTIDINE HCL 43 gm 2 L-ISOLEUCINE 95 gm L-LEUCINE 172 gm 3 L-LYSINE HCL 118 gm L-METHIONINE 47.5 gm 4 L-PHENYLALANINE 2 gm L-PROLINE 177.5 gm L-SERINE 91 gm L-THREONINE 65 gm 6 L-TRYPTOPHAN 21.5 gm L-TYROSINE 2.250 gm 7 L-VALINE 107 gm TAURINE 10 gm 8 CORN STARCH 100 gm SARDINE OIL 915 gm LARD 150 gm CORN OIL 500 gm COD LIVER OIL 350 gm ALPHACEL NON-NUTRITIVE BULK 1,074.5 gm 11 ETHOXIQUIN 1.250 gm 12 In this diet the amino acids Leucine has been 13 increased to four times its normal amount. A normal adult 14 diet requires approximately 45 mg per kg/day. This diet contains 860 g/kg.
16 Example 5 18 L-ALANINE 45 gm L-ARGININE HCL 150 gm 19 L-ASPARTIC ACID 93.5 gm L-CYSTINE 23 gm L-GLUTAMIC ACID 339.5 gm GLYCINE 52.5 gm 21 L-HISTIDINE HCL 43 gm L-ISOLEUCINE 95 gm 22 L-~UCINE 145.5 gm L-LYSINE HCL 118 gm 23 L-METHIONINE 47.5 gm L-PHENYLALANINE ' 2 gm 24 L-PROLINE 177.5 gm L-SERINE 91 gm L-THREONINE 65 gm L-TRYPTOPHAN 21.5 gm 26 L-TYROSINE 2.250 gm L-VALINE 107 gm 27 TAURINE 10 gm CORN STARCH 100 gm 28 SARDINE OIL 915 gm ~D 150 gm 1 CORN OIL 500 gm COD LIVER OIL 350 gm ALPHACEL NON-NUTRITIVE BULK gm 1,136.0 ETHOXIQUIN 1.250 gm In this example the amino acid Arginine has been increased from 12 g/kg to 30 g/kg.

The amino acids Phenylalanine and Tyrosine are at the levels of Example #1.

811 Example 6 COMPONENT SR

L-ALANINE 45 gm L-ARGININE HCL 60.5 gm L-ASPARTIC ACID 93.5 gm 11 L-CYSTINE 23 gm L-GLUTAMIC ACID 600 gm 12 GLYCINE 52.5 gm L-HISTIDINE HCL 43 gm L-~UCINE 145.5 gm 14 L-LYSINE HCL 118 gm L-METHIONINE 47.5 gm L-PROLINE 177.5 gm L-THREONINE 65 gm 17 L-TRYPTOPHAN 21.5 gm L-TYROSINE 2.250 gm 18 L-VALINE 107 gm 19 TAURINE 10 gm CORN STARCH 100 gm SARDINE OIL 915 gm 150 gm 500 gm 21 CORN OIL 350 gm COD LIVER OIL

ALPHACEL NON-NUTRITIVE BULK 1,136.0 gm 22 ETHOXIQUIN 1.250 gm 24 In this example the amino acid L-Glutamine is 1.0 g/kg. This is about 3 times less than normal requirement.

Example 7 3 L-ALANINE 45 gm L-ARGININE HCL 60.5 gm 4 L-ASPARTIC ACID 93.5 gm L-CYSTINE 23 gm L-GLUTAMIC ACID 339.5 gm GLYCINE 52.5 gm 6 L-HISTIDINE HCL 43 gm L-ISOLEUCINE 95 gm 7 L-LEUCINE 145.5 gm L-LYSINE HCL 65 gm 8 L-METHIONINE 47.5 gm L-PHENYLALANINE 2 gm L-PROLINE 177.5 gm L-SERINE 91 gm I'-T~ONINE 65 gm L-TRYPTOPHAN 21.5 gm 11 L-TYROSINE 2.250 gm L-VALINE 107 gm 12 TAURINE 10 gm CORN STARCH 100 gm 13 SARDINE OIL 915 gm LARD 150 gm 14 CORN OIL 500 gm COD LIVER OIL 350 gm ALPHACEL NON-NUTRITIVE BULK 1,136.0 gm ETHOXIQUIN 1.250 gm 17 In this diet the amino acid L-Lysine is 0.50 g/kg.

18 This is approximately 50 percent of the normal levels.

19 Example 8 21 L-ALANINE 45 gm L-ARGININE HCL 150 gm 22 L-ASPARTIC ACID 93.5 gm L-CYSTINE 23 gm 23 L-GLUTAMIC ACID 600 gm GLYCINE 52.5 gm 24 L-HISTIDINE HCL 43 gm L-ISOLEUCINE 95 gm 2 L-~UCINE 14 5 . 5 gm L-LYSINE HCL 118 gm 26 L-METHIONINE 47.5 gm L-PHENYLALANINE 2 gni 27 L-PROLINE 177.5 gm L-SERINE 91 gm 2g L-THREONINE 65 gm 1L-TRYPTOPHAN 21.5 gm L-TYROSINE 2.250 gm 2L-VALINE 107 gm TAURINE 10 gm CORN STARCH 100 gm MENHADEN OIL 915 gm 4~gD 15 0 gm CORN OIL 500 gm COD LIVER OIL 350 gm ALPHACEL NON-NUTRITIVE BULK 817.5 gm 6ETHOXIQUIN 1.250 gm 7 In this tormuta zne c:arnonyarazes nave Deen reaucea 8 to a very small percentage. The majority of the calories come from fat and a very small percentage from the proteins. Also, this diet is low in phenylalanine and tyrosine.
1l One can readily understand that different tumors may 12 require different amino acid combinations.
13 The diet described herein will be the only source of 14 nutrients for the patient. This diet is a powder which is adapted to be mixed with water and consumed. The diet is 16 based on approximately 1500 calories/day. Since there are 4 17 calories/gram of diet, the patient will ingest 375 grams of 18 this diet per day. However, the actual amount of the diet 1g will depend on the patient's age, weight and resting metabolism. A significant factor associated with the diet is 21 the blood levels for phenylalanine and tyrosine. The adult 22 daily requirement for the combination of phenalanine and 23 tyrosine is about 14 mg/kg body weight per day.
24 It is necessary to carefully control the three major components of the diet. If any one of the components is not 26 strictly controlled, the tumor is given a nutritional escape 27 route.

n 1 Also, the concentration of the bulking agent as set 2 forth in the examples can be increased or otherwise adjusted to mask the pungent taste associated with the elemental amino 4 acids and provide a more bland tasting enteral nutritional product.
6 The diet described herein is particularly adapted for use in conjunction potent therapies including radiation 8 and chemotherapy.

:A 02244608 1998-07-31

Claims

1. An elemental nutritional product for cancer patients comprising:
(a) carbohydrate in an amount from 2 to 25% of the total caloric requirement, (b) fat in an amount from 40 to 80% of the total caloric requirement, and (c) elemental essential and non-essential amino acids to 100% of the total caloric requirement and defining an amino acid imbalance wherein:
phenylalanine is present in the elemental amino acids in an amount up to wt%, L-tyrosine is present in the elemental amino acids in an amount from 2 to 6 wt.%, L-methionine is present in the elemental amino acids in an amount from 5 to 11 wt.%, and L-leucine is present in the elemental amino acids in an amount from 20 to 35 wt.%.

2. The nutritional product of claim 1 wherein carbohydrate is present in an amount from 2 to 15 wt%.

3. The nutritional product of claim 1 wherein fat is present in an amount from 60 to 75 wt.%.

4. The nutritional product of claim 3 wherein the fat source contains omega-3 fatty acids.

5. The nutritional product of claim 1 wherein phenylalanine is present in the elemental amino acids in an amount from 2 to 4 wt.%.

6. The nutritional product of claim 1 wherein L-tyrosine is present in the elemental amino acids in an amount from 3 to 5 wt.%.

7. The nutritional product of claim 1 wherein L-methionine is present in the elemental amino acids in an amount from 6 to 9 wt.%.

8. The nutritional product of claim 1 wherein L-leucine is present in the elemental amino acids in an amount from 24 to 30 wt%.

9. An elemental nutritional product for cancer patients comprising:
(a) carbohydrate in an amount from 2 to 15% of the total caloric requirement, (b) fat in an amount from 60 to 75% of the total caloric requirement, and (c) elemental essential and non-essential amino acids to 100% of the total caloric requirement and defining an amino acid imbalance wherein:
phenylalanine is present in the elemental amino acids in an amount from 2 to 4 wt%, L-tyrosine is present in the elemental amino acids in an amount from 3 to wt%, L-methionine is present in the elemental amino acids in an amount from 6 to 9 wt.%, and L-glutamine is present in an amount from 2 to 5 wt.%, L-lysine is present in an amount from 2 to 6 wt.%, L-arginine HCl is present in an amount from 20 to 25 wt.%, and L-leucine is present in the elemental amino acids in an amount from 24 to 30 wt.%.

10. The nutritional product of claim 9 wherein the fat source contains omega-3 fatty acids.