TWI802808B - Use of streptococcus thermophilus strain st4 as an auxiliarie of a chemotherapeutic agent for improving diarrhea, depraved appetite, and weight maintenance - Google Patents

Abstract

The present invention provides a use ofStreptococcus thermophilus strain, ST4, in manufacturing an auxiliarie composition for relieving the side-effects of a chemotherapeutic agent in a cancer patient, wherein theStreptococcus thermophilus strain, ST4, can reduce diarrhea and depraved appetite induced by the chemotherapeutic agent, and maintain the weight of the cancer patient.

Description

Use of streptococcus thermophilus strain ST4 for preparing auxiliary composition for improving diarrhea, loss of appetite and weight maintenance caused by chemotherapy drugs

The present invention relates to the use of a Streptococcus thermophilus ST4 strain. In particular, the present invention provides an application for preparing an auxiliary composition for improving the side effects of chemotherapy drugs.

Although anticancer drugs have been updated, traditional chemotherapy drugs such as 5-Fluorouracil (5-FU) and Irinotecan are still the main drugs for cancer treatment, and their mechanism of action is to kill rapidly dividing cells Therefore, in addition to poisoning cancer cells, it will also kill rapidly dividing normal cells such as intestinal epithelial cells and mucosal cells, which will lead to mucositis, decreased water and nutrient absorption capacity, and the corresponding clinical symptoms are abdominal pain and diarrhea , loss of appetite, weight loss.

When chemotherapy drugs reduce nutrient absorption capacity and loss of appetite, patients will lose weight. When the body weight is greatly reduced, the course of chemotherapy must be discontinued, which will reduce the cure rate of cancer. Statistics show that 20% of cancer patients die from malnutrition rather than cancer itself. The study also pointed out that during chemotherapy, the maintenance of appetite and weight of chemotherapy patients is the most important key to determine the success or failure of chemotherapy. Patients with better appetite and weight maintenance not only have better treatment effects, but also faster recovery after treatment .

Streptococcus thermophilus is a common probiotic, which is often used to make yogurt, yogurt, or as a nutritional supplement. However, there have been studies on the impact of Streptococcus thermophilus on the side effects of chemotherapy drugs. It was found that Streptococcus thermophilus has no positive effect on weight maintenance (Cancer biology & therapy, 2009, 8.6: 505-511; Cancer biology & therapy, 2006, 5.6: 593-600; Scandinavian journal of gastroenterology , 2013, 48.8: 959- 968; Cancer biology & therapy ,2011,12.2:131-138), more importantly Streptococcus thermophilus may cause decreased appetite ( Cancer biology & therapy ,2011,12.2:131-138), showing that Streptococcus thermophilus may not be able to improve The appetite and body weight of chemotherapy patients even have negative effects on chemotherapy patients. However, the characteristics and abilities of different strains are variable. Therefore, through screening, it is possible to develop Streptococcus thermophilus strains that can promote appetite, maintain body weight, improve intestinal inflammation, and improve diarrhea in chemotherapy patients.

The present invention unexpectedly found that a Streptococcus thermophilus ST4 strain ( Streptococcus thermophilus ST4) isolated from the microbial community of milk raw milk can be used to prepare auxiliary compositions for improving the side effects of chemotherapy drugs, and can effectively reduce diarrhea and weight loss caused by chemotherapy , loss of appetite and symptoms of intestinal inflammation.

Therefore, the main purpose of the present invention is to provide a use of Streptococcus thermophilus ST4 strain for preparing an auxiliary composition for improving the side effects of chemotherapy drugs, wherein the composition contains an effective amount of Streptococcus thermophilus ST4 strain.

According to the present invention, the ST4 strain of Streptococcus thermophilus is deposited in Taiwan Food Industry Development Research Institute, deposit number: BCRC 910922. It was also deposited with the German Collection of Microorganisms and Cell Cultures (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) on May 28, 2019, deposit number: DSM33165

In one embodiment, the Streptococcus thermophilus strain contained in the composition of the present invention is live or dead.

In one embodiment, the composition of the present invention can be a pharmaceutical composition or a food composition.

In one embodiment, the chemotherapeutic drug is selected from 5-fluorouracil (5-Fluorouracil, 5-FU), irinotecan, oxaliplatin, doxorubicin , the group consisting of methotrexate, bleomycin and capecitabine. In a preferred embodiment, the chemotherapy drug is 5-FU.

In one embodiment, the effect of the composition is to improve the side effects of chemotherapy drugs, wherein the side effects of chemotherapy drugs are weight loss, decreased appetite, intestinal inflammation or diarrhea.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

As used herein, the singular forms "a", "an" and "the" include plural references unless the content is clearly indicated otherwise. Thus, for example, reference to "a sample" includes a plurality of such samples and equivalents thereof known to those skilled in the art.

As used herein, the term "colony-forming unit" (CFU) is defined as the number of bacterial cells as revealed by microbial production on agar medium.

As used herein, the term "amelioration" refers to treating, curing, alleviating, alleviating, altering, remediating, ameliorating, enhancing, or affecting the effect of the event or characteristic (eg, a chemotherapy-induced side effect).

As used herein, the term "adjuvant" refers to enhancing the effectiveness of chemotherapy, including increasing chemotherapy compliance and reducing chemotherapy-induced side effects.

As used herein, the term "individual" includes human and non-human animals, such as pets (such as dogs, cats, etc.), farm animals (such as cows, sheep, pigs, horses, etc.) or laboratory animals (such as rats, mice, guinea pigs, etc.) wait).

As used herein, the term "effective amount" refers to the amount of active agent or composition in an individual that is sufficient to achieve the above-mentioned therapeutic effects. The effective amount may vary, for example, depending on the type or dose of the agent or composition and the body weight, age and health of the individual to be treated.

The ST4 strain of Streptococcus thermophilus ST4 provided by the present invention is deposited in Taiwan Food Industry Development Research Institute, deposit number: BCRC 910922. It was also deposited with the German Collection of Microorganisms and Cell Cultures (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) on May 28, 2019, deposit number: DSM33165.

As used herein, " Streptococcus thermophilus " refers to a Gram-positive bacterium that is homofermentative and facultatively anaerobic, and belongs to Streptococcus viridans. The cytochrome, oxidase and catalase tests were negative, and the type A hemolytic test was positive. Not motile, no endospores.

The Streptococcus thermophilus ST4 strain of the present invention is isolated from the microbial community of raw milk. According to the analysis of mycological characteristics, the strain is a Gram-positive bacterium, which is spherical or oval, paired or long-chain, without spore formation and no motility, and grows in an anaerobic or aerobic environment without hyperactivity. Catalase and oxidase activity. Further 16S rDNA sequence analysis and VITEK identification system identification results showed that ST4 strain was confirmed as a Streptococcus thermophilus ( Streptococcus thermophilus ).

The ST4 strain of the present invention can exist in any form, including live or dead bacteria, and also includes equivalent strains with the same characteristics and the cells or products derived from these strains.

By using the deposited bacterial strain provided by the present invention as a starting material, those skilled in the art can usually obtain other mutants or derivatives thereof by conventional mutagenesis or re-isolation techniques, and the mutants or derivatives maintain or The relevant characteristics and advantages described herein of the strains forming the compositions of the invention are enhanced.

The present invention provides a use of Streptococcus thermophilus ST4 strain for preparing an auxiliary composition taken together with chemotherapy drugs, wherein the composition contains an effective amount of Streptococcus thermophilus ST4 strain to achieve auxiliary The use of chemotherapy drugs.

According to the present invention, the effect of the auxiliary composition is to improve the side effects of chemotherapy drugs.

According to the present invention, wherein the side effect of the chemotherapy drug is weight loss, loss of appetite, intestinal inflammation or diarrhea.

According to the present invention, the chemotherapeutic drugs include but not limited to 5-fluorouracil (5-Fluorouracil, 5-FU), irinotecan, oxaliplatin, doxorubicin ( doxorubicin), methotrexate, bleomycin, and capecitabine. In a preferred embodiment, the chemotherapy drug is 5-fluorouracil (5-Fluorouracil, 5-FU).

In some specific embodiments, the composition of the present invention has the effect of reducing side effects caused by chemotherapy. As shown in the examples, when the composition of the present invention is administered during cancer chemotherapy, it is found that the composition can reduce the side effects of chemotherapy, especially improve appetite, promote weight gain and prevent intestinal inflammation symptoms.

In another aspect, the present invention provides a composition comprising an effective amount of the ST4 strain of the present invention for use as a medicinal product, medicament, food, edible product, food supplement or medical food.

The composition of the invention may be in solid or liquid form and may be in particular in the form of jelly bars, brew packs, cakes, powders, lozenges or lozenges, sucking lozenges, film preparations, solutions, aerosols, granules, pills , suspensions, emulsions, capsules, enteric-coated lozenges and capsules, syrups, liquids, elixirs, candies, meal replacements, chewable tablets, suppositories, micro-enemas, creams, gels, or ointments.

Compositions according to the invention may be formulated in a form wherein the strain of the invention is the sole active agent or mixed with one or more other active agents and/or with pharmaceutically acceptable excipients in the case of food or edible products. excipients or sufficient additives or ingredients.

The composition of the present invention can be manufactured as food products of all kinds, and these food products can be manufactured by any conventional technique using conventional excipients or fillers and mixed with additives if desired.

The composition of the invention may be manufactured as a food supplement, which may be administered as such, mixed with a suitable potable liquid, such as water, yogurt, milk or fruit juice, or mixed with solid or liquid food. In some embodiments, dietary supplements may be in the form of lozenges or lozenges, pills, capsules, granules, powders, suspensions, sachets, candies, bars, syrups and corresponding administration forms, usually in unit dosage form. Preferably, the dietary supplement comprising the composition of the present invention is administered in the form of lozenges, lozenges, capsules or powders manufactured in conventional methods for the preparation of dietary supplements.

The composition of the present invention can be manufactured into various medicines, and these medicines can be manufactured by using the therapeutically effective amount of the composition of the present invention and its pharmaceutically acceptable carrier through common pharmaceutical techniques or methods. The composition of the present invention is administered orally, and may further include pharmaceutically acceptable carriers, diluents and/or excipients. The above-mentioned carrier may be a solvent, a dispersion medium, a coating, an antibacterial agent, an antifungal agent, an isotonic agent, an absorption delaying agent, and the like. The diluent can be, phosphate buffer saline, Ringer's solution or glucose solution, etc. Excipients can be calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, lactose, starch, gelatin, alginic acid, stearic acid, magnesium stearate and the like.

The above description of the present invention and the following examples illustrate the content of the present invention, but are not intended to limit the scope of the present invention.

Example 1 Streptococcus thermophilus ST4 strain the separation

The invention isolates bacterial strains from the microbial community of raw milk of cow's milk. Take raw milk and add it to MRS broth medium, culture it in an anaerobic environment at 42°C for 24 hours, spread the culture on an MRS agar plate, culture it in an anaerobic environment at 42°C for 3 days, and then collect it on the agar medium A single colony appeared and further purified to isolate Gram-positive, catalase-negative, spherical or oval, paired or long-chain Streptococcus thermophilus ST4 strains ( Streptococcus thermophilus ST4).

Example 2 Streptococcus thermophilus Mycology of ST4 strain feature

The bacteriological characteristics of Streptococcus thermophilus ST4 strain are as follows: (1) Morphological features: (a) Cell shape and Gram staining: When the bacteria are placed in MRS broth medium and cultured in an anaerobic environment at 42ºC for 24 hours, the appearance under the microscope is spherical or oval, in pairs or Long chain, no flagella, Gram stain positive, as shown in Figure 1. (b) Mobility: No movement. (c) Sporulation: No sporulation. (d) Gram stain: Positive. (2) Cultivation characteristics: (a) Medium: MRS broth medium, pH = 6.25. (b) Culture conditions: 42ºC anaerobic or aerobic environment. (3) Physiological characteristics: (a) Catalase: Negative. (b) Oxidase: Negative.

Example 3 Streptococcus thermophilus ST4 strain identification of strains

16S rDNA and VITEK systems were used for the identification of ST4 strains, and two identification methods were used to ensure the correct identification results.

3.1 16S rDNA Sequence analysis

Extract the DNA of Streptococcus thermophilus ST4 strain, amplify the 16S rDNA (ribosomal DNA) fragment, and perform agarose gel electrophoresis on the obtained PCR product to confirm that the product meets the expected size, and perform sequencing to obtain the Streptococcus thermophilus ST4 strain The 16S rDNA sequence of ST4 is shown in SEQ ID NO: 1; the ST4 strain sequence control composite sequence alignment data set (NCBI blastn) is used for sequence alignment, and the sequence alignment result is the closest to Streptococcus salivarius subsp. thermophilus ATCC 19258 ^T , similar The rate reached 99.67%.

3.2 VITEK Identification System Analysis

According to the analysis results of the VITEK semi-automatic identification system, the ST4 strain is the closest to Streptococcus salivarius subsp. thermophilus, reaching 99%, as shown in Figure 2.

According to 16S rDNA sequencing and identification, VITEK comparison results and the Approved Lists of Bacterial Names 1980 announced by the International Committee of Prokaryotic Systematics, it was shown that the ST4 strain should be Streptococcus thermophilus (the synonym of the same species is Streptococcus salivarius subsp. thermophilus).

Example 4 Streptococcus thermophilus ST4 strain Aids in weight maintenance

4.1 Reality test method

This test is to simulate the concentrated high-calorie special formula food required by cancer patients after chemotherapy, and evaluate the effect of Streptococcus thermophilus ST2, ST3, ST4 strains on weight gain. 8-week-old male Sprague-Dawley rats were used, the feeding environment was maintained at a temperature of 22 ± 2°C, the day and night cycles were 12 hours each, and the diet was taken in a free-feeding manner. During the experimental period, the normal control group was continuously fed with normal adult mouse feed LabDiet 5001, which contained 5% (w/w) oil and could provide 3.3 kcal/g; the control group and experimental groups (ST2, ST3, ST4 groups) were fed with concentrated high-calorie Feed provided 22.5% (w/w) oil and 4.4 kcal/g, and the experimental group was tube-fed Streptococcus thermophilus ST2, ST3, ST4 5×10 ⁸ CFU/day/rat daily. During the animal experiment, the feed intake was measured and recorded every day, and the body weight was precisely weighed once a day before the feed was given. The experiment lasted for 8 weeks.

4.2 Data Processing and Statistical Methods

The experimental data was statistically analyzed with IBM SPSS (Statistical Product and Service Solutions) software, the variance analysis was performed with the ANOVA program, and the comparison of significant differences was made with Duncan's Multiple Range (* p < 0.05). The experimental data results were expressed as mean ± standard The difference (mean ± SD) is expressed.

4.3 Experimental results

There was no significant difference in the average daily feed intake of animals in each group (n=5). After the 8-week test period, the animals in each group increased by an average of 239.8-315.6 g from the initial weight to the weight at the time of sacrifice, and the ST4 group compared with In other experimental groups, there was significantly higher body weight gain (Figure 3), showing that Streptococcus thermophilus ST4 has the potential to help body weight gain. In addition, the results of total visceral fat (Figure 4) showed that the experimental groups that ingested concentrated high-calorie feed were significantly higher than the normal control group, and there was no significant difference in total visceral fat among the experimental groups.

Example 5 , Streptococcus thermophilus ST4 Improve weight loss, decreased appetite, and intestinal inflammation caused by chemotherapy drugs

5.1 experimental method

The experimental animals were 5-week-old BALB/cByJNARL male mice. The temperature of the feeding environment was 23 ± 2°C, the relative humidity was 40-60%, the light cycle was 12/12 light/dark cycle, and the experimental animals were given sufficient Laboratory Rodent Diet 5001 Feed and drinking water, diet adopts free feeding mode.

After two weeks of domestication, 5-week-old mice were randomly divided into 4 groups: (1) Normal group, a total of 5 mice: received normal saline + intraperitoneal injection (ntraperitoneal injection, IP injection) normal saline. (2) 5-FU group, a total of 5 mice: given normal saline + intraperitoneal injection of 5-FU. (3) Glutamine, a total of 5 mice: L-glutamine (1 g/kg/day) + intraperitoneal injection of 5-FU was given as a positive control group. (4) ST4: A total of 3 mice were given Streptococcus thermophilus ST4 (5 x 10 ⁸ CFU/day) + intraperitoneal injection of 5-FU.

The experimental period was 18 days in total. During the experimental period, the body weight and feed intake of the mice were weighed every day, and the samples were fed orally with a gastric tube every day, and PBS or 50 mg 5-FU/kg body was injected intraperitoneally on the 11th, 12th, and 13th days weight/day, the mice were sacrificed on the 18th day, and the tissue from the cecum to the large intestine was taken to measure the length of the large intestine, which was used as an index of intestinal inflammation. On the 11th-17th day, the diarrhea index of each experimental mouse was judged by the appearance of the feces and anus of the experimental mice, the judgment method of the diarrhea index (γDiarrhea score) was based on the research of Bowen et al. ( Cancer biology & therapy , 2007, 6.9: 1445- 1450), the score ranges from 0 for asymptomatic to 3 for the most severe. The experimental process is shown in Figure 5.

5.2 Data Processing and Statistical Methods

The calculation method of body weight change, taking the body weight of the mouse on the 11th day as 100%, calculated the amount of change in the body weight of the mouse after intraperitoneal injection. The calculation method of the change in food intake, taking the average food intake of the mice on days 1 to 10 as 100%, calculated the change in food intake after intraperitoneal injection. Data are expressed as mean ± standard deviation (Mean ± SD). The difference between the 5-FU group and the 5-FU group was statistically significant by Student's t-test, when p<0.05, the difference between the 5-FU group was considered to be statistically significant.

5.3 Experimental results

Body weight changes are shown in Figure 6. The weight of the Normal group increased slowly during the experiment, while the weight of the 5-FU group continued to decline and did not recover until the end of the experiment. The body weight of the ST4 group on days 13, 17, and 18 was significantly higher than that of the 5-FU group. Group weight, and the weight began to recover on the 17th and 18th day, showing that ST4 can slow down the weight loss caused by 5-FU and promote the weight recovery.

Changes in food intake are shown in Figure 7. After intraperitoneal injection, the appetite of the Normal group did not change significantly, while the food intake of the 5-FU group continued to decrease from 11 to 15 days and did not rise on the 17th day, while ST4 The food intake of the 5-FU group on days 11 to 16 was higher or equal to that of the 5-FU group, and the appetite recovered significantly on the 17th day, even higher than the average value of 1 to 10 days, indicating that Streptococcus thermophilus ST4 can slow down the 5-FU group. FU-induced appetite reduction and promotion of appetite return to normal state.

5-FU treatment will damage the intestinal mucosal tissue and cause diarrhea. The change of the diarrhea index of the mice is shown in Figure 8. The experimental mice treated with 5-FU will have symptoms of diarrhea between 13 and 17 days, and the 5-FU group The symptoms of diarrhea were the most severe on days 14, 15, and 17. However, oral administration of ST4 can significantly improve the diarrhea caused by 5-FU, and only mild diarrhea occurred in 13-17 days, showing that ST4 can improve the diarrhea caused by chemotherapeutic agents.

When the gut becomes inflamed, the gut shortens, and the more severe the inflammation, the shorter the gut. The intestinal length is shown in Figure 9. The intestinal length of the 5-FU group was significantly shorter than that of the Normal group, indicating that 5-FU caused intestinal inflammation; the intestinal length of the ST4 group was significantly longer than that of the 5-FU group, indicating that oral administration of ST4 can prevent Intestinal inflammation caused by 5-FU.

Those of ordinary skill in the art will appreciate that changes may be made to the specific embodiments described above without departing from their broad inventive concepts. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

[Biological Material Deposit] Streptococcus thermophilus ST4 strain ( Streptococcus thermophilus ST4) is deposited in Taiwan Institute of Food Industry Development, deposit number: BCRC 910922.

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The foregoing summary, together with the following detailed description of the invention, will be better understood when read in conjunction with the accompanying drawings. For purposes of illustrating the invention, a presently preferred embodiment is shown in the drawings.

Figure 1 shows the cell shape of Streptococcus thermophilus ST4 strain.

Figure 2 provides the analysis results of the VITEK identification system for Streptococcus thermophilus ST4 strain.

Figure 3 shows the effect of Streptococcus thermophilus ST4 strain on weight gain after ingestion of concentrated high-calorie special formula food. Normal: Feed LabDiet 5001, which contains 5% (w/w) oil for normal adult rats, which can provide 3.3 kcal/g; HF: Feed concentrated high-calorie feed, which provides 22.5% (w/w) oil and 4.4 kcal/g ;ST2: Feed concentrated high-calorie feed, provide 22.5% (w/w) oil and 4.4 kcal/g, and daily tube-feed Streptococcus thermophilus ST2 5×10 ⁸ CFU/day/rat; ST3: Feed concentrated high-calorie feed Calorie feed, providing 22.5% (w/w) oil and 4.4 kcal/g, daily tube-feeding Streptococcus thermophilus ST3 5×10 ⁸ CFU/day/rat; ST4: feeding concentrated high-calorie feed, providing 22.5% ( w/w) oil and 4.4 kcal/g, Streptococcus thermophilus ST4 5×10 ⁸ CFU/day/rat was tube-fed daily. *, p<0.05.

Figure 4 shows the effect of different strains of Streptococcus thermophilus on total visceral fat formation after ingesting concentrated high-calorie special formula food. Normal: Feed normal adult rats with LabDiet 5001, which contains 5% (w/w) oil and can provide 3.3 kcal/g; HF: feed concentrated high-calorie feed, which provides 22.5% (w/w) oil and 4.4 kcal/g ;ST2: Feed concentrated high-calorie feed, provide 22.5% (w/w) oil and 4.4 kcal/g, and daily tube-feed Streptococcus thermophilus ST2 5×10 ⁸ CFU/day/rat; ST3: Feed concentrated high-calorie feed Calorie feed, providing 22.5% (w/w) oil and 4.4 kcal/g, daily tube-feeding Streptococcus thermophilus ST3 5×10 ⁸ CFU/day/rat; ST4: feeding concentrated high-calorie feed, providing 22.5% ( w/w) oil and 4.4 kcal/g, Streptococcus thermophilus ST4 5×10 ⁸ CFU/day/rat was tube-fed daily. *, p<0.05.

Fig. 5 provides a flow chart of the experimental design for improving the side effects of chemotherapy drugs by Streptococcus thermophilus ST4 strain.

Figure 6 shows the reduction in body weight caused by the reduction of 5-FU in the ST4 strain of Streptococcus thermophilus. Compared with 5-FU group, Normal group $p<0.05, glutamine group #p<0.05, ST4 group *p<0.05.

Fig. 7 shows that Streptococcus thermophilus ST4 strain improves the appetite loss induced by 5-FU.

Figure 8 shows that Streptococcus thermophilus ST4 strain improves diarrhea caused by 5-FU.

Figure 9 shows that Streptococcus thermophilus ST4 strain improves intestinal inflammation caused by 5-FU.

<110> Shengzhan Biotechnology Co., Ltd.

<120> Streptococcus thermophilus strain ST4 is used to prepare medicines for improving diarrhea, loss of appetite and weight maintenance caused by chemotherapy drugs Use of auxiliary composition

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<170> PatentIn version 3.5

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<211> 1496

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<213> Streptococcus thermophilus

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Claims (7)

A Streptococcus thermophilus ( Streptococcus thermophilus ) ST4 strain is used to prepare an auxiliary composition for improving weight loss, intestinal inflammation or diarrhea caused by chemotherapy, wherein the Streptococcus thermophilus ST4 strain is a Streptococcus thermophilus ST4 strain ( Streptococcus thermophilus ST4), deposited at the Institute of Food Industry Development, Taiwan, deposit number: BCRC 910922, and also deposited at the German Collection of Microorganisms and Cell Cultures (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH), deposit number: DSM33165. The use of claim 1, wherein the Streptococcus thermophilus ST4 strain is live or dead. As the use of claim 2, wherein the ST4 strain of Streptococcus thermophilus is a dead bacterium. The use according to claim 1, wherein the ST4 strain of Streptococcus thermophilus is taken together with the chemotherapy drug. The use according to claim 1, wherein the auxiliary composition is a pharmaceutical composition or a food composition. Such as the use of claim 1, wherein the chemotherapeutic drug is selected from 5-fluorouracil (5-Fluorouracil, 5-FU), irinotecan, oxaliplatin, doxorubicin ( doxorubicin), methotrexate, bleomycin and capecitabine. As the use of claim 5, wherein the chemotherapeutic drug is 5-FU.

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