TW201014599A - Use of cysteine-rich whey derived protein in patients receiving chemotherapy or radiotherapy to improve patient survival - Google Patents

Abstract

A cysteine-rich undenatured whey-derived protein formulation did not interfere with the tumor-cytotoxic effects of chemotherapy and radiation therapy and did not have a negative effect on the clinical outcome, that is, negatively affect survival and increase mortality. Indeed, use of a high-cysteine undenatured whey derived protein in the treatment of cancer patients resulted in an increase in patient survival.

Description

201014599 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a cysteine-rich protein-containing formulation and its use in the treatment of cancer patients to improve patient survival and quality of life. [Prior Art] 某些 Some of the documents listed at the end of the specification are referred to herein, and the entire contents of these documents are incorporated herein by reference. In this specification, these publications are referred to by the numbers in parentheses. For cancer patients, oxidative stress is a hardship and a gift. Oxidative stress plays an important role in the tumor toxic effects of chemotherapy (chemotherapy) and radiation therapy (radiotherapy), but inadvertently produces significant side effects on the patient's own tissues. Evidence suggests that the loss of sputum cell mass (cancer cachexia) is to some extent caused by abnormal inflammation (13 ' 15 ) ' and is highly correlated with oxidative shift in plasma redox states, usually by reduction The above oxidative conversion (16) is inferred for the decrease in the proportion of oxidized cysteine. - - . . . . . - A large reduction in weight usually affects the quality of life of cancer patients and raises the same rate of morbidity and mortality (5, 10, I 8, 25). In general, attempts to prevent loss of body cell mass through nutritional adaptation have not produced satisfactory results (丨2, 丨3, M, 22, 25, 27). However, for different types of cancer Preliminary studies have shown that the use of bran 201014599 glutathione (GSH) precursor, ethionylcysteine, can reverse the loss of body cell mass and oxidative conversion in plasma redox states (16). This study did not indicate efficacy in terms of survival. Several redox-regulated signaling pathways are known to be involved in 'dissimilation reactions' (Reference 11 has a review).

Gustavo B〇un〇us et al. previously disclosed a variety of biologically active, undenatured whey protein concentrates and isolates that are useful for φ to promote tissue GSH concentrations and for immune response, host treatment of cancer Resistance, as well as immune enhancement, have an effect. No. 5,290, 571; More specifically, 'Bounous et al. previously disclosed an anti-cancer therapeutic composition' which comprises a whey protein concentrate' wherein increasing the Gsh of the cells protects the target cells against carcinogens (U.S. 5,888,552). ❹ In addition, specifically, it has been shown that whey protein concentrate can be used in a method of treating cancer. Under the premise of not being limited to any particular theory, . . . . . . . . . . . . . . . . . . . . . . . The delivery of branyl cysteine, an intensive cysteine delivery system for undenatured whey protein, may involve inhibition of replication of the formed cancer cells. However, 'tumor-cytotoxic effects due to cancer chemotherapy and radiotherapy are usually'. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4,24). 201014599 Because semi-proline is a limiting biosynthesis precursor of glutathione (GSH), it can slow down oxidative stress. The use of radioactive and/or chemical agents to treat cancer produces free radicals in the cells' and this therapy relies on its oxidative destruction to eliminate cancer cells. Antioxidants protect normal cells from acute and long-term free radical damage, and can impede the overall outcome of cancer treatment and even worsen mortality (ie, reduce patient survival); therefore, whether the antioxidants can target tumors in related fields Cells provide the same protection. 胄 doubts and reservations (4). SUMMARY OF THE INVENTION After careful study, the inventors have unexpectedly discovered that when a large amount of cysteine-rich undenatured whey-derived protein is used to treat cancer patients receiving chemotherapy and/or radiotherapy, the survival rate of the patient can be improved. It can also improve other indicators, such as reversing cancer-related weight loss, reversing the loss of body cell mass, improving hand grip and quality of life,

Kamofsky status, anxiety, nervousness and anxiety, appetite and depression. Specifically, based on the above conflicting aspects, the inventors confirmed that the cysteine-rich undenatured whey-derived protein formulation does not interfere with the tumor-cytotoxic effects of chemotherapy and radiotherapy, and does not resemble certain individuals. Worried about the greedy effect of clinical outcomes, that is, does not negatively affect survival and increase mortality. The inventor found that the use of high-cysteine undenatured whey-derived protein in the treatment of cancer patients with 201014599 resulted in an increase in beam survival. Accordingly, an aspect of the present invention relates to a cysteine-rich deuterated whey-derived protein and a formulation thereof, which are useful for treating a cancer patient' to improve patient survival. Another aspect of the invention relates to a dose of a cysteine-rich whey-derived protein, said dosage range being about 5 to 30 grams of egg white protein per day, preferably in the range of about 5 A range of 25 g/day, more preferably about 13-2 g/day' and most preferably about 3 g/day. Another aspect of the present invention relates to a method for treating a cancer patient and a method of using the same using a cysteine-rich whey-derived protein to improve patient survival while improving other quality of life. In particular for the treatment of patients receiving chemotherapy, radiation therapy or both, and the use of the cysteine-rich protein to prepare a formulation or medicament for such use. [Embodiment] The inventors confirmed that cysteine-rich undenatured whey-derived protein and its formulation can improve patient survival rate in patients undergoing chemotherapy and radiotherapy. In a placebo-controlled, double-blind clinical trial, casein was replaced with a homocysteine-derived whey-derived protein formulation. Specifically, the inventors explored whether it is possible to improve the survival rate of cancer patients by improving the survival rate of cancer patients by homocysteine-derived whey-derived protein formula (as compared to road proteins), such as weight loss and other indicators of life quality 201014599. Reduced body cell mass. Road protein is the most important protein substrate in clinically used enteral nutritional supplements, and casein is used in related experiments because it contains only a small amount of cysteine. Since cysteine is a limiting biosynthesis precursor of GSH, it is believed to slow the oxidative stress. The homocysteine-derived whey-derived protein is designed to have a higher cysteine content than the usual whey protein (see Table 1). The heat of these two proteins is roughly equal to the nitrogen content. Both protein supplements must be compared under the general ® protein uptake architecture. Some of the results point to lower protein intake in patients with terminal cancer, even in patients who use commercially available nutritional supplements (14' 17). According to a recent review of protein requirements (20)', even in healthy individuals of the same age, such protein intake may not be sufficient to support nitrogen balance. Some recent studies of patients with pancreatic cancer have shown that supplements containing complex proteins can provide modest improvements', but the individual contributions of these proteins are unknown (1, 2 丨4). There is a lack of nutrition in protein intake for cancer patients, and the quality of protein is currently considered to be particularly important because it is impossible to overcome the lack of a specific protein in the composition by increasing protein intake. Table 1: Amino acid composition of cysteine-rich protein (Cysp) and control protein (casein). 201014599

CysP cool protein cys 0.50 0.05 met 0.14 0.18 glu 1.15 1.41 asp 1.04 0.56 leu 1.02 0.66 ile 0.46 0.37 val 0.46 0,49 ala 0.55 0.32 ser 0.39 0.50 giy 0.22 0.20 iys 0.74 0.49 arg 0.18 0.26 his 0.11 0.15 pro 0.36 0.88 phe 0.23 0.28 tyr 0.24 0.25 thr 0.40 0.32 trp 0.08 0.03 Note: The amino acid content is in mol/kg. 201014599 Patient Recruitment, Trial Profile, Baseline Characteristics, Compliance The patient enrollment period was from January 2003 to February 2006 (Appendix 1-5). A total of 66 patients with lung cancer and 22 patients with rectal cancer were recruited and randomly assigned to groups in two independent trials. Only 7 patients met the per protocol (PP) requirements of the test plan and took a minimum of 75 〇/. Test medication (see Appendix 2). Therefore, all patients who returned the canister and completed at least a second visit (referred to as “evaluable W”) were included in this analysis. The trial profile (Figure )) that can be used to assess rectal cancer patients does not match the baseline data, and the number of samples is too small to be statistically significant. Specifically, S 'mean age (63 6: ±: 1 〇 ^ VS 41.7: ± 7 years old), baseline TNF-α concentration (1 > 8 ± vs 7 vs 3 ± ± 9 pg / mi), also the face The proline concentration (592 ± 129 VS. 461 ± 1〇〇 and ESAS 8 (1.25 ± 2.82 VS. 7.00 ± in) were not compatible with the baseline parameters, so 'here only from the test layer of lung cancer patients Results (Table 2) The average compliance of 35 evaluable lung cancer patients who took the protein or sputum containing semi-deaminated protein was 44% and 34%, respectively, and Μ土, which means ^ ^ ^ ^ ^ ^ « Τ ^ 13 ^ / θ ^ ^ ^ ^ ^ t 0 ^ ^ The term "protein" refers to pure protein without any additives.

Assigned group - - _ Number of samples Ν Complex protein CysP - 17 18 10 201014599 (32) (34) Female / male 6/11 4/14 (11/12) (6/28) Age (years) 63.5 ± 10.9 64.3 ± 10.7 (63.6 ± 11.4) (63.8 ± 10.1) Height (cm) 167.2 ± 8.4 169.5 ± 11.7 Weight (kg) 64.5 ± 16.7 66.1 ± 14.3 Body cell mass (kg) 22.5 ± 6.8 22.4 ± 4.6 CRP (mg/L ) 47.4 ± 45.6'," 35.3 ± 54.1t!tt (73.3 ± 82.7) u (60·1 ± 81.3 ) n TVFa ( pg/mL ) 15.5 ±52.3 丨 2.6 ± 1.7JM 丨丨 (10.4 ± 38·5 ) "· (2.6 ± 1.5 )... IL-6 ( pg / mL ) 6.2 ± 3.9 4.6 ± 3.3 bran tyrosine (μΜ) 551 ± 160§ 564 ± 147 (513 ± 182 ) (566 144 144) cystamine Acid (μΜ) 29.0 ± 15.5§ 30.7 ± 14.9 RBC-GSH (μΜ) 476 ±219 443 ± 292 Hand grip (kg) 28.6 ± 10.7 29.0 ± 8.6 Body function index (units) 78.2 ± 7.3 78.9 ± 8.3 ESAS 8 ( units Constipation 2.94 ± 3.55§ 1.67 ± 2.59 (2.59 ± 3.23 ) (2.09 ± 2.84) * Data ± standard deviation (SD) is calculated for patients who complete at least the second visit. The data refers to all patients randomized to the group 11 201014599. All groups are mainly composed of Caucasians (>85%). tCRP (C-reactive protein 'C-reactive protein) data only from 15 Casein treatment and 16 patients treated with IMN1207 (CysP). *TNFa data were obtained from 15 patients treated with casein and 17 patients treated with IMN1207 (CysP) ία. § Data from 16 Patients with road protein therapy 0 Those skilled in the art can understand the meaning of whey protein and the source of such protein. For related content, refer to the above patent of B〇un〇us et al., and the patent also proposes production undenatured. Standard techniques for whey proteins, isolates and concentrates. The cystine egg is self-quality. The above-mentioned labeling method can prepare undenatured milk.

For example, ultrafiltration techniques or ion exchange chromatography can be used to separate and purify whey proteins, protein fragments, and peptides, according to standard procedures currently in widespread use. The (four) technique known in the art can be used to obtain the semi- albumin acid-enriched mixture described in the present application, and after such content, the milk protein concentration can be facilitated. The formulation of the mixture of the substance and the mixture is made into a patent of the appropriate Bounous et al. 12 201014599 Radiotherapy and chemotherapy are often used to treat cancer in patients. These treatments are understood by those skilled in the art (see, for example, reference (4)). In this study, chemotherapy drugs used alone or in combination were: CARBOPLATIN, CISPLATIN, OXALIPLATIN, GEMCITABINE, CAPECITABINE, TAXOTERE, ETOPOSIDE, LEUCOVORINE, IRINOTECAN, 5-FLUOROURACIL, and cyclic guanamine phosphate. Positive effects of cysteine-rich protein on survival in patients receiving chemotherapy and/or radiotherapy in a randomized group of 66 lung cancer patients and 22 rectal cancer patients, 25 with 36 lung cancer patients and 8 with 15 Patients with rectal cancer died within 6 months and 12 months, respectively, for disease-related reasons during the trial (see Figure 1). For the two treatment branches of all cancer cohorts, the Kaplan-Meier survival curves for both (see Appendix 8) ❹ did not differ (Figure 2A). However, for the two treatment branches of 35 evaluable patients See _ (Fig. 2B). There is a difference between the two. (p. = 0.024; 95% dangerous 'by.., 0.067 to 0.916. about ': 8〇% of the rich: cysteine Patients treated with protein and less than 50% of the control group survived for more than 12 months. The survival rate of lung cancer patients (n = 28) who received chemotherapy and / or radiotherapy (Figure 2C) also showed Rich. There is a positive trend in the group containing cysteine protein (ρ = 0.058). Compared with patients treated with casein, it can be diagnosed until the 6-month visit cycle is completed and the rich is accepted. Patients with cysteine-containing proteins have their bodies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Status) also showed a positive trend (p = 〇〇9) compared to the baseline value (Table 3). However, the physical function status of the two treatment branches was not There is a clear distinction, which may be due to the small number of surviving patients. In view of the poor condition of the patient and the inability to continue due to death or other reasons, the number of patients is decreasing. Appealing to assess patients (35 in total) seems to be a suitable approach. This analysis shows that between the two groups receiving casein treatment and receiving cysteine-rich protein treatment, the sixth week after starting treatment, The change in body weight was significantly different (4.^^3900/0 (^=^) and + 1.36 ± 2.94% (n=18); p = 〇.〇38). In order to explain during the test period In the middle and right blocks of Table 3, the change between the baseline and the last observed value obtained from the Last_observaU〇n_carded f〇rward (L0CF) method (see Appendix 8) is presented, respectively. The average of the coups observed at 6 weeks, 3 months, and 6 months (or last observation). Throughout the observation period, changes in body weight were significantly different between treatment groups (Table 3). Accepting though In the group treated with cysteine protein, the changes in body cell mass were also different from those in the control group (p = 〇〇1) and also different from baseline values (P = 0.02). However, data on body cell mass were obtained. It is called, but it is because its standard deviation is large, and therefore it can only be regarded as supporting evidence. 201014599 Table 3: Effect of protein supplements on objective parameter changes 6 months value 4 LOCF value 卞 6 weeks , 3 months and 6 months, the average value of _ relative or absolute change of casein CysP casein CysP cool protein CysP change N = 8 N=13 N=17 N= 18 Ν=17 N=18 Weight (%) • 1.01 士8.52 +2.38士7.21 -2.63±8.07s +2.50±6.74s -1.88±5.46β Hl.79i4.4511 Cl: (-8,14/+6.11) (-1.98/+6.73) (-6.78/+ 1.52) (-0.85/+5.85) (-4.69/+0.93) (-0.43/+4.00) Body cell mass +10.34±14.10 +14.09±15.84** -5.47±34.63tf +11.55±18.05tni, -2.85± 30.93 明+8.34±17.89® (%) Cl:(-23.00/+43,69) (+3.46/+24.73) (-23.27/+12.33) (+1.93/+21.16) (-18.76/+13.05) ( -1.20/+17.87) Grip strength (%) +8.49±16.21 +1 2.41±16.52BI1 •2,22±22_57 +2.57 Earth 24.75 +0.17±18.38 +2.50±18.87 Cl: (-6.49/+23.48) (+2.43/+22.39) (-13.83/+9.38) (-9.73/+ 14.88) (-9.28/+9.62) (-6.88/+11.89) Body function index +3.75±11.88 +5.38±10.50*** -2·94士17_23 +0.56±16.62 -2·16±11·28 +2.50 ±11.98 (units ) Cl: (-6.18/+13.68) (-0.96/+11.73) (-11.80/+5.92) (-7.71/+8.82) (-7.96/+3.65) (-3.46/+8.46)

*The data shows the mean value of the values measured at the 6th month of the visit. Soil S.D., Confidence intervals (C.I.) is 95%. t Patients who completed at least two visits were observed at the end of their measurements. * The average of three values for each patient. The above three values are the values measured at weeks 6, 3 and 6 months. Bold data indicates statistical significance. s Difference between different groups P = 0.049. 11 differences between different groups P = 0.036. 15 201014599 "Different from baseline = 0.015." Using the Kruskal-Wallis test, the difference between the different groups was p = 0.010. ^ The difference from the baseline is corp.=0.022. Ss using the Kruskal-Wallis test, the difference between the different groups p = 0.005 ° 1111 and the baseline difference P = 0.0019. The difference from the baseline is 0.089. The results of the two treatment arms showed no significant differences in the changes in the two branches at the laboratory endpoint (lab〇rat〇ry end P〇int), including sputum reactive proteins, TNF-oc, IL-6, and albumin. Concentration (data not shown). In patients treated with semi-deaminated protein, cercosin oxime (-58.9 ± 242.7 vs. ± 110.7 ± 300.7 μΜ) (see Appendix 7) and plasma cysteine (+9.8 ± 23.5 V5. ± 34,8:,: 150A}-LM) The change in © presents a higher value, but this difference is not a statistically significant difference. The higher standard deviation shows that the data is not very accurate. Effects on changes in quality of life (see Appendix 6) Prior to death, certain quality of life parameters deteriorated significantly in a short period of time, including hand grip, physical function status, feelings of stress and anxiety (McGill Q〇LC2), and Appetite and Care Camp (ESAS) (see Appendix 6) 'The observations from a subgroup of 6 patients showed that these measurements were taken within 17 days of death. Regardless of the treatment group of 2010, 2010, for the treatment group, compared with the other 29 people, the body function index of the above-mentioned .6> and its recognition of the patients on the ό ό Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Guangdong τ h trail life. 0 quality parameters (feeling ^ ^ ^ , fistula) are greatly reduced and statistically

Significance (P < 0. 〇 5). From: J in the remaining 29 patients (this person constitutes the majority of the ethnic group, and its φ female, called the family, the last data of 2 patients were 41 days before the death, respectively | Among the collected collections, all of the above parameters of group (4)#*, ▲^^, with cysteine-rich protein (4) showed significant improvement (compared with baseline values). On the other hand, the group treated with casein did not show a significant improvement in the female $73 (Table 4). In addition, in other McGU1 or ESAS parameters, there is no significant change to the g-square &# (data not shown). The rest of the patients who died in Yan, the squatting between the three treatment branches of the eight + green mouth and the other patients' comprehensive treatment branches can be found in their physical function status, tension and anxiety, discomfort and anxiety (not Show) there are significant differences. The intercept point between the 17th day and the 41st day is an arbitrarily selected time point.

Table 4: Relative or Absolute Changes in Changes Based on Data Measured on Death Days ---------- The Suns of the Caves: The Change in Casein% of CystP Samples (η) 13 16 Weight (%) -3.09 ± 8·60§ + 2.46 ± 6.90§ Hand grip strength (%) 1.71 ±21.45 + 9.10 ± 16.62 丨丨Cl: +0.24/+17 96 Body function index...(single +2.31 ± 13.01 + 5.00 ± 9.66** digits) ----- 17 201014599

McGill QOLC2 (unit) 0.23 ± 3.24 -1.53 ± 2.50", J tension and anxiety CI: -2.92/-0.15 ESAS 2 (unit)... -0.85 ± 3.83 -1.20 ± 2.68^·[ Feeling uncomfortable ---- ----_ ESAS 5 (unit) -1.23 ±5.40 2.07 ± 2.60SS i Loss of appetite Cl: (-3.51/-0.62) ESAS 11 (unit)... -0.54 ± 4.22 -Ι.όΟΐΖ.Ί?11 Β, * Melancholy Cl: -3.14/-0.06

CysP=Cycemia-rich protein Subjectively satisfied with physical, emotional, social, spiritual and economical feelings. Only from I5 patients, McGill QOL and ESAS data. For more information on McGill QOL and ES AS parameters, see References 23-25. Rough thinking data indicates statistical significance. 〇 § Differences between different groups = 〇. 〇 64 11 Differences from baseline = = 0.044 "Difference from baseline / > = 0.056 η Difference from baseline P = 0.03 3 ^ Difference from baseline household = 0.105 §§ Difference with baseline corpus = 0.008 1111 Difference with baseline household = 0.042 Clinical assessment of disease activity 201014599 The recorded disease activity (disease progression, stabilization or degeneration) was changed between the two treatment groups and There were no significant differences. Side effects Among the 33 lung cancer patients assigned to the cysteine-rich protein-treated group, 4 complained of possible protein-related conditions (ie, one patient felt moderately nausea) One patient felt moderate nausea plus abdominal discomfort; one patient had mild vomiting; and one patient felt dry mouth mucous. One patient complained that the degree of nausea was slightly elevated 'this may be related to protein). Among patients with rectal cancer who were assigned to the cysteine-rich protein-treated group, one patient developed severe vomiting, moderate diarrhea, and moderate nausea. These symptoms may be associated with eggs. Qualitative. One of the 33 lung cancer patients assigned to the casein treatment group developed mild nausea, which may be related to protein; and two patients developed a protein-related condition (ie, one patient) © mild temporary vomiting; and one patient with mild and moderate constipation.) Among the rectal cancer patients assigned to the casein treatment group, one patient developed mild nausea, and this symptom was absolutely Protein-related; and a patient with mild constipation, which may be related to protein poorness. The results show that the survival rate of non-small cell lung cancer patients who received chemotherapy, radiotherapy or both treatments was not supplemented by rich The cysteine-containing protein is reduced. In fact, the results show that the survival rate of patients with 19 201014599 can be improved by supplementing the sputum-containing valproate protein derived from undenatured whey protein. Therefore, the relevant results are not only reduced for Treatment with certain antioxidants may interfere with the cytotoxic effects of chemotherapy and radiotherapy and therefore Doubts about increased mortality (see Reference 4' 9' 24); also reduce concerns that certain nutritional formulas may contribute to tumor growth. Critical data (including patient compliance and statistical analysis) About 5 to 30 g/day of cysteine-rich protein for treatment of patients with m-incubation, and cancer-related weight loss and body cell quality in patients with anti-rotational lung cancer, although according to patients The average dosage of the patient to be administered is about 13 g/day, and the dosage range to be administered should be about 5 to 3 g/day, preferably about 5 to 25 g/day, more preferably about 13 -20 g / day, and the best is 13 g / day, in order to improve the survival rate of cancer patients receiving chemotherapy or radiotherapy. The above effects are unexpectedly related to the improvement of muscle strength and certain quality of life parameters. This is based on the exclusion of data from the collections collected shortly before death: due to cercosylglycine and cysteine The data of amino acid did not produce statistically significant differences. The data generated by the Xiangguan test could not confirm that "weight loss may be mainly related to cysteine and bran glycine". The data does not exclude other amino acids other than cysteine or other properties of cysteine-rich proteins (eg, digestibility), etc. (also) may be useful for the observed effects. However, other cysteine derivatives have been observed in previous studies to increase body cell mass (16, 20), and the most important difference between the two proteins used in this study is the content of cysteine, 201014599 &gt The facts can support the role of cysteine in it. The 耷-derived protein is specially designed to have a higher content of cysteine (compared to normal whey protein), and cysteine is not only a biological sigma precursor of protein, but also a cellular antioxidant-bron The biotin of glutamic acid is a precursor. It is known that the decrease in body cell mass in elderly and cancer patients is associated with oxidative conversion in plasma redox states (16), and some redox-sensitive message transduction pathways are involved in the dissimilation reaction (Reference 1 1 has a review) Introduction); the above facts can also support the role of glutathione in these consumptive reactions. These facts can link the different effects of the two proteins in this test to establish a molecular mechanism. The test results confirm the important predictions of the hypothesis. Oxidative stress is also known to be involved in the side effects of chemotherapy and aesthetic therapy (4, 9, 19, 23). Plasma glutathione after radiotherapy is associated with squamous cell carcinoma in the head and neck of the patient. (3) 4 However, the experimental data clearly show that patients are supplemented with cysteine-rich undenatured whey-derived protein. Tumors that interfere with chemotherapy and radiation therapy, cytotoxicity beta should increase mortality; and in fact lead to increased patient survival. The preferred effect of a cysteine-rich protein is very important for these patients compared to casein because patients often feel full enough to make them unable to use more protein. The mean compliance was less than 50% in both treatment groups, which could correspond to approximately 3 grams of protein per 曰. This also echoes the generally low dietary protein intake of cancer patients (14, 21). This study also showed that in patients with advanced non-small cell lung cancer, cysteine-rich protein was able to effectively support the increase in body mass and the increase in body mass in the body. In addition to the dying patients, the muscle function and several quality of life parameters of other patients also increased. From these data, it can be seen that if the data of a patient who is dying is mixed with data from a patient who survives the entire or most of the trial period, the efficacy of the treatment may be neglected. Crevicular CRP: C-reactive protein; EPO: erythropoietin; ESAS: Edmonton symptom Assessment Scale; HR: hazard ratios LOCF: last observation carried forward; PP: per protocol; QOL: quality of life; TNF-α: tumor necrosis factor a . Appendix: Patients and Methods 1. Trial Design This multicenter, randomized, double-blind, phase 2 trial (Health Canada Health Canada No. 085 608) was designed to evaluate the enrichment of cysteine protein/mass fraction 'Immon IMN 1207./( Immunotec Research Ltd

Vaudreuil, QC, Canada) Consumptive response in preventing two patients (ie, patients with metastatic rectal cancer or 3B (IIIB) to stage 4 (IV) non-small cell lung cancer for more than six months) Effectiveness and security. The test is administered by oral administration of a rich cysteine protein or .., . . . . . . . . 22 201014599 : Open a (way protein) to replace the placebo. Participants received 7 volumes at the time of trial and one month of return visit, and the internal shock was powdered. Subjects will also receive a 1 〇 = = vibrator, mixer and medication guidelines to a (factor λ 10 g) drug. Other standard test medications are administered along with the type of cancer used to treat the cancer and the standard treatment. ,

2. Test drug The amino acid analyzer is used to determine the amino acid composition of the protein rich in hemi-deaminated acid and the control group protein (Table 〇. by Immunotec Research, Ltd and Wen $ state called

Pharmaceutical c〇rp〇rati〇n (Canada) collaborates to prepare cysteine-rich proteins and casein, and to label, package, and test and transport products. The product complies with all the safety testing practices of the Canadian Department of Health. 201014599 And reliable contraceptive methods are needed for women who are likely to become pregnant. Excluded patients have a history of angioedema, allergic reactions to any substance used in the test, uncontrolled metastatic brain tumors, milk protein intolerance, ascites, leeches, marked anemia, or taking N _ acetylated cysteine, specific fatty acid (〇MiP〇iCacid), or dried whey protein supplement. ❹ 4. Determination of sample size According to historical data, patients in the control group were expected to have a 4% reduction in mean weight during the 3-month period, with a standard deviation of 4%. When a = 0.05 and the sample size is 2 X 30 patients, a 8% chance is expected to detect a hypothetical 3% difference between the two treatment groups. 5. Recruitment, randomization and evaluation Patients were randomly assigned to group and data management by GEREQ (Montreal, Quebec). Data monitoring and site visits were conducted by Canreg, Inc. (Dundas, Ontario). In the clinical trial center (ie Department of Oncology at McGill University, Montreal; Cross Cancer Institute, Edmonton; Juravinski Cancer Center, Hamiltonj and Allan Blair Cancer Center, Regina), the patient's recruitment, recruitment and screening 'select it is.. No qualified . . . In the independent biostatistics company (GEREQ), which is not in the center, the patients were divided into two experimental groups of lung cancer and rectal cancer, and they were randomly divided into two treatment branches. Save the blinding code in the statistician's office 24 201014599. In the trial premises, the randomized group was treated before (week), 6th, 3rd, and 6th: at the beginning of the treatment. At the above-mentioned time, the laboratory will be tested in the clinical examination, and the body function status of the blood and the urine will be 3, and the hand grip strength will be positive and the restaurant (8). (6, 7), and = force strength 'and will carry out „sweeping cat or face as a cancer of the patient ΠΓ::. The laboratory test carried out includes blood 概 标 、 、, urine analysis And the pregnancy test is for women.) Record this information in the test site. Compliance depends on the intake of the test drug, which can be determined by the weight of the canister returned by the patient. Through uncomfortable side effects (including death) The central collection of data is used to continuously monitor safety. 6. Primary and secondary endpoints Primary endpoint (Primaryendp0int) is the absolute change in body weight (%) and absolute changes in body cell mass after a period of six months. The secondary end p〇int includes strength assessment using hand dynamics, body function status 1 based on McGiu q〇l quality of life assessment (8), and the Ehrlich symptom assessment scale ( ES Symptom load based on AS) (sympt〇m (4)) (6, 7), mortality, change of glutathione in red blood cells, semi-proline, erythropoietin (EPO) s 6 (IL-6), tumor necrosis factor alpha (TNF-α) and C-reactive protein (CRP) are also concentrated in the night, and disease activity (disease, stabilization or degeneration). 201014599 7. Body Cell quality and blood parameters were determined using bioelectrical resistance analysis (Biodynamics, Model Model 450,

Seattle, WA) determines body cell mass (16). Within 8 hours of the analysis, the patient was asked to drink only 400 ml of water and was unable to eat. Clinical evaluation and certain laboratory tests (including c_reactive protein., CRP) were performed directly at the test site. Analysis of sputum soil amino acids, EPO, IL-6 and TNF-ot was performed centrally at the Clinical Research and Clinical Trials Laboratory (Hamilton, Ontario, Canada). The amino acid analyzer is used to determine the free blood amino acid including cysteine. The glutathionine was evaluated by Immunosciences Lab., Inc. (Beverly Hills, CA, U.S.A.) using the commercially available test kit BIOXYTECH R GSH-420TM (Catalog No. 21023). A 0.5 ml blood sample was centrifuged at 2,500 g for 5 minutes at 4 ° C to obtain red blood cells. After the plasma was removed, the cells were washed 3 times with cold saline, resuspended in 4 volumes of cold water' and thoroughly subjected to vortex treatment (v〇rteXed). Then, 0.1 ml of the lysate (lySate) was mixed with 0.3 ml of the aqueous solution of trichloroacetic acid in a microcentrifuge tube for at least 15 seconds of vortexing, followed by 1 at room temperature. 〇, 〇〇〇g the rate of centrifugation for 5 minutes. The obtained supernatant (volume about 2. 2 ml) and 2. 2 ml of Yuan Chong (.pH. 7.8, including potassium., phosphate/diethylene. triaminepentaacetic a'cid/lubrol, ie, acid unloading / two Ethylene triamine pentaethylene. 26 201014599 acid / ethylene glycol laurate) and 0.2 ml of reducing agent ([tris (2-carboxyethyl) phosphine in HC1] ' is a solution of tris(2-hexylethyl)phosphine hydrochloride ) Mix evenly. After adding 0.2 ml of chromogen (1-methyl-4-chloro-7trifluoromethylquinolinium methylsulfateinHC, a solution of methyl sulfate 1-methyl-4-qi-7-trifluoromethylquinoline in hydrochloric acid), mix the solution again. Then, it was mixed with 0.2 ml of a color developer (aqueous sodium hydroxide solution). After incubation at room temperature for 30 minutes in a dark room, the absorbance spectrum at 420 nm was measured. 8. Statistical analysis Statistical analysis was performed by an independent statistical agency (Boreal Primum, Montreal, Quebec). Data from the two test layers (disease sites) were analyzed separately and expressed as mean ± standard deviation (SD). The statistical effect was used to assess treatment outcome by comparison with the control group (bilateral r-test for independent variables, unless otherwise stated) and relative φ baseline values (t-test for strain numbers). Comparisons between treatment groups were based on data from the 6th or final observations of patients who completed at least two visits. Survival curves were plotted using Kaplan-Meier estimates for treatment and compared to the results of the log-rank test. The risk ratio (HR) is estimated using the c〇x proportional-risk model. The result is judged by a value of 7?. /? The value is less than < 0.05. .......... .... There is statistical significance. Although the specific preferred embodiment of the present invention is disclosed above with reference to the accompanying drawings, it is readily apparent to those skilled in the art that the present invention is not limited to the precise Various modifications and changes may be made thereto without departing from the spirit and scope of the invention as defined in the appended claims. references

1. Barber MD. Ross JA. Voss AC. Tisdale MJ. and Fearon KC. The effect of an oral nutritional supplement enriched with fish oil on weight-Joss in patients with pancreatic cancer. Br J Cancer 8]: 80-86. 1999 2. Bauer JD. Capra S. Nutrition intervention improves outcomes in patients with cancer cachexia receiving chemotherapy: a pilot study. Support Care Cancer 13: 270-274. 2005. 3. Bohn SK. Smeland S. Sakhi AK. Thoresen M. Russnes KM. TausjO J. Svilaas A. Svilaas T. and Blomhoff R. Post-radiotherapy plasma total glutathione is associated to outcome in patients with head and neck squamous cell carcinbma. Cancer Lett 23 8: 240-247. . 2006. 4. Borek C. Dietary antioxidants and human cancer. Integr Cancer Ther 3: 333-341. 2004. 5. Bruera E. ABC of palliative care: anorexia, cachexia 28 201014599 and nutrition. BMJ 315: 1219-1222. 1997. 6. Bruera E. Kuehn N. Miller MJ. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients, J Palli At Care 7: 6-9, 1991. 7. Chang VT. Hwang SS. Feuerman M. Validation of the Edmonton Symptom Assessment Scale. Cancer 88: 2164-2171.2000.

8. Cohen SR. Mount BM. Living with cancer: "good" days and "bad" days: what produces them? Can the McGill Quality of Life Questionnaire distinguish between them? Cancer 89: 1854-1865.2000. 9. Coia LR Moyland OJ. Introduction to clinical radiation oncology. Madison. WI: Medical Physics

Publishing, 1998. 10. Davidson W, Ash S, Capra S, Bauer J, and Cancer Cachexia Study Group. Weight stabilization is associated with improved survival duration and quality of life in unrespectable pancreatic cancer. Clin Nutr 23: 239-247, 2004 11. Orage W. Redox regulation in anabolic and catabolic processes. Curr Opin Clin Nutr Metab Care 9:]90-195.2006. 12. Evans WK, Nixon DV, Daly JM. A randomized trial 201014599 of oral nutritional support versus ad lib nutritional JClin Oncol5: 113-124.,.1987. 13. Fearon KC, Voss AC, and Hustead OS. Definition of cancer cachexia: effect Of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am J Clin Nutr 83: 1345-1350, 2006.

❸ 14. Fearon KCH, von Meyenfeldt MF, Moses AGW, Van Geenen R, Roy A, Gouma 01, Giacosa A, Van Gossum A, Bauer J, Barber MD, Aaronson NK, Voss AC, and Tisdale MI. Effect of a protein And energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomized double blind trial. Gut 52: 1479-1486, 2003. 15. Glare P. Clinical predictors of survival in advanced cancer. J Support Oneal 3: 331-339, 2005. 16. Hack V, Breitkreutz R, Kinscherf R, Rohrer H, Biirtsch P, Taut F, Benner A, and Droge W. The redox state as a correlate of senescence and wasting and as Blood 92: 59-67, 1998. 17. Hutton JL, Martin L} Field CJ, Wismer WV, Bruera ED, Watanabe SM, and Bracos VE. Dietary patterns in patients with advanced cancer: implications for 30 201014599 anorexia-cachexia therapy. Am J Clin Nutr 84: 1163-1170, 1998. 18. Inagaki J, Rodriguez V, Bodey GP. Causes of death in cancer patients. Cancer 33 : 568-573, 1974.

19. Jonas CR, Puckett AB, Jones DP, Griffith DP, Szeszycki EE, Bergman GF, FUIT CE, Tyre C, Carlson JL, Galloway JR, Blumberg 18, and Ziegler TR. Plasma antioxidant status after high-dose chemotherapy: a randomized Am J Clin Nutr 72: 181-189, 2000. 20. Mantovani G, Madeddu C, Maccio A. Cancer-related anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond Current treatment Cancer Epidemial Biomarkers Prevent 13: 16511659, 2004. 21. Millward OJ, Jackson AA. Protein/energy ratios of current diets in developed and developing countries compared with, a safe p.rotein/energy ratio:, implications for recommended protein and amino Acid intakes. Public ... . .... . ...

Health Nutr 7: 387-405, 2004. [Review]. 22. Ovesen L, Allingstrup L, Hannibal J, Mortensen EL, and Hansen OP. Effect of dietary counselling on food intake, body weight, response rate, survival, and quality . . . . . . . of life in cancer patients undergoing chemotherapy: a .... .... ........ : 31 201014599 prospective, randomized study. J Clin Oncol 11: 2043- 2049, 1993. 23. Schmidt-Ullrich RK. Molecular targets in radiation oncology. Oncogene 22: 5730-5733, 2003. 24. Seifried HE, Anderson DE, Sorkin BC, and Costello RB. Free radicals: the pros and cons of antioxidants J Nutr 134: 3143S-3163S, 2004.

25. Stratton RJ, Elia M. A critical, systematic analysis of the use of oral nutritional supplements in the community. Clin Nutr 18: S29-S84, J 999. 26. Warren S. The immediate causes of death in cancer. Am J Med Sei 184: 610-615, 1932. 27. Yavuzsen T, Davis MP, Walsh 0, LeGrand S, and Lagman R. Systematic review of the treatment of cancer-associated anorexia and weight loss. J Clin Oncol 23: 8500-851 J, 2005. [Simple illustration] ..... . . . . . . Figure 1 presents a trial of a casein treatment group and a cysteine-rich protein treatment group. Overview. Figure 2 presents the Kaplan-Meier survival curve for lung cancer patients. [Main component symbol description] 32

Claims (1)

201014599 VII. Patent application scope: A cysteamine-rich protein) can be associated with patient survival. Acid undenatured whey-derived protein (whey derived chemotherapy, radiotherapy or both treatments combined with an increase in the effective amount of a cysteine-rich undenatured whey-derived egg which can be combined with chemotherapy, radiation therapy or both Therapeutic combination is used to improve the survival rate of cockroaches. ~ The cysteine-rich protein described in claim 1 or 2 of the patent scope contains at least 0.5 mole of cysteine per kilogram. The cysteine-rich protein is administered daily at a dose of about 5 to 3 grams. ❹ 5. The cysteine-rich protein of claim 4, which is A dose of about 5 to 25 grams is administered daily. 6. The cysteine-rich protein as described in claim 5, which is administered daily at a dose of about 13 to 20 grams. The cysteine-rich protein of claim 6 which is administered daily at a dose of about 13 grams. . . . . . . . . . . . . . . . . . . . . . The use of whey-derived protein for the manufacture of a medicament for the treatment of a A cancer patient is to increase the survival rate of a patient receiving chemotherapy, radiation therapy, or both of the above treatments. 9. The use of claim 8, wherein the protein is administered at a dose of about 5 to 30 grams per day. Ο 10. The application of claim 8 or 9, wherein the patient is receiving treatment for lung cancer.