Composition for preventing and treating lung cancer

Abstract

The present invention relates to the use of 5-methyltetrahydrofolate in preparing products for preventing and treating lung cancer. Compositions prepared from 5-methyltetrahydrofolate and its salts provided by the present invention can be used to prevent and treat lung cancer in specific populations, with minimal side effects, embodying the advantages of precision medicine.

Description

Technical Field

[0001] The invention relates to application of 5-methyltetrahydrofolate (5-MTHF) in preparing products for preventing and treating lung cancer, and belongs to the field of pharmacy. Background Art

[0002] According to the 2018 World Cancer Report (Globocan), there are approximately 14.09 million new cancer cases and 8.2 million deaths worldwide each year. Lung cancer leads the list with approximately 1.825 million cases and 1.590 million deaths. In my country, lung cancer currently ranks first among the top ten malignant tumors, with an annual incidence of 787,000 cases. The incidence rate is higher in men than in women. In my country, lung cancer deaths total 631,000, still ranking first among the overall cancer population. Lung cancer deaths account for 29.28% of all cancer deaths in men and 22.99% in women. The mortality rate from lung cancer increases with age.

[0003] Folic acid, a B vitamin, plays an important role in cell division, growth, and the synthesis of nucleic acids, amino acids, and proteins. Following oral administration, folic acid is reduced to dihydrofolate and then tetrahydrofolate by dihydrofolate reductase during gastrointestinal absorption and transport to peripheral tissues. Tetrahydrofolate is an essential coenzyme in DNA synthesis. The 5th and 10th hydrogen atoms in the molecule serve as carriers of one-carbon units. One-carbon units, including CH3, CH2, and CHO, participate in important biochemical reactions in the body, including the remethylation of homocysteine ​​(Hcy) to methionine, which then loses its methyl group in a two-step reaction and is then reduced to Hcy, forming the methionine cycle (or one-carbon cycle). When tetrahydrofolate carries a one-carbon unit, it forms 10-formyltetrahydrofolate, 5,10-methylenetetrahydrofolate, and 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is primarily transported to the liver for storage, serving as a methyl donor and the active form of folic acid.

[0004] One-carbon metabolism is a complex, self-circulating system involved in numerous important biological functions, such as providing the metabolites necessary for DNA synthesis and repair (maintaining DNA integrity) and methylating DNA. This modification is the material basis for normal DNA function, and this process is regulated by gene expression. Abnormalities in any of these processes can affect DNA methylation, potentially inducing tissue cancer. Methionine is the primary methyl donor for DNA, and 5-MTHF plays a crucial role as an essential cofactor and methyl donor in the remethylation of homocysteine ​​to methionine. Chronic 5-MTHF deficiency can hinder DNA methylation, leading to a range of pathophysiological changes.

[0005] Regarding the role of 5-MTHF in regulating lung cancer risk in one-carbon metabolism, the results of various studies to date are inconsistent. For example, a Finnish study tested the association between selected B vitamins (folate, vitamin B6, and vitamin B12) and lung cancer incidence and found that no significant correlation was found between serum folate, vitamin B12, or homocysteine ​​levels and lung cancer risk (Terryl J. Hartman KW, Rachael Stolzenberg-Solomon, Jarmo Virtamo, Jacob Selhub, Michael J. Barrett, Demetrius Albanes. Association of the B-vitamins pyridoxal 5'-phosphate (B(6)), B(12), and folate with lung cancer risk in older men. American Journal of Epidemiology. 2001; 7: 688-694.). The Southern United States Community Cohort Study recorded 1,064 lung cancer events among 68,236 participants aged 40-79 years and found no association between folate levels or folate intake and lung cancer risk (Takata Y, Shu XO, Buchowski MS, et al. Food intake of folate, folic acid and other Bvitamins with lung cancer risk in a low-income population in the Southeastern United States. European Journal of Nutrition. 2019; 59(2): 671-683).

[0006] Currently, folic acid is available in three dosage forms: 0.4mg, 1mg, and 5mg. The 0.4mg dosage is primarily indicated for preventing neural tube defects in the fetus, followed by anemia, severe pregnancy reactions, spontaneous abortion, or other birth defects in pregnant women. The 1mg and 5mg dosages are indicated for treating megaloblastic anemia caused by folic acid deficiency. Therefore, using 5-MTHF for the treatment or prevention of lung cancer represents a new indication. Currently, no applications or market approvals have been made for 5-MTHF. Furthermore, its applicable population and efficacy are closely related to the user's genetic background (A1298C gene polymorphism). Therefore, improvements in pharmacogenomics are urgently needed for this product. Summary of the Invention

[0007] The inventors discovered in scientific research that while total blood folate levels are not significantly correlated with lung cancer risk, 5-methyltetrahydrofolate levels are significantly correlated with lung cancer risk. Therefore, the present invention aims to provide a composition with proven efficacy in the prevention and treatment of lung cancer. This composition offers the beneficial effects of definite efficacy and low risk of side effects, embodying the advantages of pharmacogenomics or precision medicine applications, and thus represents a significant technological advancement.

[0008] In order to achieve the purpose of the present invention, the following technical solutions are adopted:

[0009] A composition for preventing and treating lung cancer comprises an effective dose of 5-methyltetrahydrofolate or a salt thereof.

[0010] In the present invention, the lung cancer includes small cell lung cancer and non-small cell lung cancer.

[0011] In the present invention, the dosage of 5-methyltetrahydrofolate is 200-5000 μg, preferably 400-2000 μg, and more preferably 800-1600 μg.

[0012] In the present invention, the 5-methyltetrahydrofolate can be selected from pharmaceutically acceptable salts, 5-methyltetrahydrofolate metal salts or amino acid salts or glucosamine salts. 5-methyltetrahydrofolate metal salts include 5-methyltetrahydrofolate calcium salt, 5-methyltetrahydrofolate sodium salt, 5-methyltetrahydrofolate lithium salt, 5-methyltetrahydrofolate magnesium salt, 5-methyltetrahydrofolate barium salt, 5-methyltetrahydrofolate potassium salt, 5-methyltetrahydrofolate ammonium salt and 5-methyltetrahydrofolate zinc salt; 5-methyltetrahydrofolate amino acid salts include valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, threonine, lysine, ornithine, histidine, cysteine, theanine, and methionine; preferably 5-methyltetrahydrofolate calcium salt or 5-methyltetrahydrofolate glucosamine salt.

[0013] The term "effective dose" refers to a dose administered to an individual for the purpose of effectively preventing, controlling or treating a disease. It should be understood that the effective dose provided by the present invention is not a limitation of the present invention, but a preference for the present invention. Generally, within the preferred range of the dose, the ingredient can reduce the risk of an individual developing a disease or produce an effective therapeutic effect on the diseased individual. A diseased individual refers to an independent living being suffering from a disease. In the present invention, a living being particularly refers to a human being. It should be understood that in the prior art, a pharmaceutical dose or a pharmaceutical dose range for humans can be converted to that for mammals, such as rats, mice, etc., to obtain a pharmaceutical dose or dose range suitable for the corresponding animal.

[0014] The present invention may also contain a pharmaceutically or food-acceptable carrier to prepare oral products containing the active ingredient, including ordinary tablets, ordinary capsules, granules, oral liquids, films or patches, etc. The composition according to the present invention can be prepared into medicines, foods, health products, health foods, etc. containing 5-MTHF.

[0015] Another object of the present invention is to provide a use of an effective dose of 5-MTHF or a composition containing an effective dose of 5-MTHF in preparing a product for reducing the risk of lung cancer. In such use, the composition contains 200 to 5000 μg, preferably 200 to 1600 μg, and more preferably 800 to 1600 μg, of 5-methyltetrahydrofolate.

[0016] Another object of the present invention is to provide a use of an effective dose of 5-MTHF or a composition containing an effective dose of 5-MTHF in preparing a drug product for improving the efficacy of a drug for treating lung cancer. In such use, the composition contains 200 to 5000 μg, preferably 200 to 1600 μg, and more preferably 200 to 1000 μg, of 5-methyltetrahydrofolate.

[0017] In the present invention, the aforementioned drugs for treating lung cancer include a variety of drugs: first, chemotherapy drugs: commonly used ones include paclitaxel, docetaxel, vinorelbine, gemcitabine, pemetrexed, etoposide, carboplatin, cisplatin, and lobaplatin; second, targeted drugs: commonly used ones include Iressa and Truvac; and third, immunotherapy: commonly used immunotherapy drugs include bevacizumab and nimotuzumab. These drugs for treating lung cancer may also be active ingredients, compositions, or finished products of traditional Chinese medicine, such as Kanglixin capsules and Lentinan.

[0018] In the present invention, the lung cancer includes small cell lung cancer and non-small cell lung cancer.

[0019] In the above-mentioned use provided by the present invention, the composition is particularly suitable for people with a history of smoking or currently smoking, and more preferably for male people with a history of smoking or currently smoking.

[0020] In the above-mentioned use provided by the present invention, the composition is particularly suitable for people aged less than 65 years old.

[0021] Among the above uses provided by the present invention, the above use is particularly suitable for people whose serum 5-MTHF concentration is less than 6.4 ng / ml.

[0022] In the above-mentioned use provided by the present invention, the composition is particularly suitable for people with serum homocysteine ​​concentration ≥10 μmol / L.

[0023] In the above-mentioned uses provided by the present invention, the composition is more suitable for people with any of the above combined symptoms, such as people with a history of smoking or current smoking and aged <65 years, male people with a history of smoking or current smoking and aged <65 years, people with a history of smoking or current smoking and a serum 5-MTHF concentration <6.4 ng / ml, people with a history of smoking <65 years and a serum homocysteine ​​concentration ≥10 μmol / L, male people with a history of smoking or current smoking and a serum homocysteine ​​concentration ≥10 μmol / L, male people with a history of smoking or current smoking and aged <65 years and a serum homocysteine ​​concentration ≥10 μmol / L, etc.

[0024] The present invention has the advantages of providing a composition comprising an effective dose of 5-MTHF and a carrier. The composition provided by the present invention has the beneficial effect of significantly reducing the risk of or treating lung cancer, particularly in people with specific genetic characteristics, with a lower risk of side effects, embodying the advantages of precision medicine and thus being a more optimal composition for preventing and treating lung cancer.

[0025] The present invention will be further described below with reference to specific embodiments, which is not intended to limit the present invention. Any equivalent replacements in the art made according to the contents of the present invention shall fall within the scope of protection of the present invention. DETAILED DESCRIPTION

[0026] Example 1: Nested case-control study of 5-methyltetrahydrofolate levels and lung cancer incidence

[0027] The present invention team conducted a nested case-control study in the Chinese Type H Hypertension Registry Study (CHHRS). The CHHRS was initiated in 2016 to investigate the prevalence of type H hypertension in China and its associated risk factors. Participants were patients with essential hypertension aged ≥18 years, defined as sitting systolic blood pressure ≥140 mmHg and / or sitting diastolic blood pressure ≥90 mmHg at the screening visit. There were no pre-specified exclusion criteria except for patients who were unable to participate in the follow-up or could not provide informed consent according to the study protocol. Participants were planned to be followed up every 3 months for a maximum of 3 years. At each visit, a physical examination was performed, SBP, DBP and resting heart rate were measured, and medication use, adverse events and clinical outcomes, including newly diagnosed diseases such as specific types of cancer, were recorded. The study was approved by the Ethics Committee of the Institute of Biomedical Sciences, Anhui Medical University.

[0028] Result analysis:

[0029] Table 1. Baseline characteristics of subjects in the case-control study in Lianyungang City

[0030]

[0031]

[0032] BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; CHD: coronary heart disease. LOD: upper limit of detection; DHFR: dihydrofolate reductase; UMFA: unmetabolized folate; MTHFR: methylenetetrahydrofolate reductase. P<0.001. Continuous variables are expressed as means and standard deviations, and categorical variables are expressed as numbers (percentages). Characteristics of case and control subjects were compared using the nonparametric Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables. P values ​​were calculated using two-sided tests.

[0033] Table 1 lists the baseline characteristics of the study participants by case-control status. The mean age of the participants was 66.5 years. Overall, 58.4% of the participants were male. Compared with the control group, the lung cancer participants were more likely to have a history of coronary heart disease and a family history of diabetes at baseline. Serum 5-MTHF, UMFA, and vitamin B 12 Table 1 shows the DHFR and MTHFR genotype frequencies for cases and controls, as well as the concentrations of homocysteine ​​and 5-MTHF. The mean concentration of 5-MTHF was lower in the case group than in the control group (8.96 vs 10.98 ng / mL, P = 0.001). Only 6 (2.19%) of the participants had serum UMFA values ​​above the limit of detection (LOD), with the same proportion in both cases and controls. 12 The mean concentrations of DHFR and MTHFR were similar in cases and controls. Serum homocysteine ​​was higher in cases than in controls, but the difference was not statistically significant (P = 0.125). There was no statistically significant difference in DHFR and MTHFR genotype frequencies between cases and controls.

[0034] Table 2. Serum 5-methyltetrahydrofolate (5-MTHF) and vitamin B6 in Lianyungang, China 12 Correlation between homocysteine ​​and the risk of lung cancer 1

[0035]

[0036]

[0037]

[0038] 1. A conditional logistic regression model was used. The adjusted model included the following covariates: smoking status, body mass index, pulse, history of coronary heart disease, history of dyslipidemia, family history of hypertension, and family history of diabetes. IQR: interquartile range; OR: odds ratio; CI: confidence interval. 2. A logistic regression model was adjusted for the following covariates: age, sex, smoking status, body mass index, pulse, history of coronary heart disease, history of dyslipidemia, family history of hypertension, and family history of diabetes.

[0039] Table 3 Relationship between serum 5-methyltetrahydrofolate (5-MTHF) and the risk of lung cancer stratified by smoking status

[0040]

[0041] 1 OR: odds ratio; confidence interval; IQR: interquartile range; 5-MTHF: 5-methyltetrahydrofolate.

[0042] 2 The logistic regression model was adjusted for the following covariates: age, sex, body mass index, pulse, history of coronary heart disease, history of dyslipidemia, and family history of hypertension.

[0043] Table 4. Relationship between serum 5-methyltetrahydrofolate (5-MTHF) and age-stratified risk of lung cancer 1 .

[0044]

[0045]

[0046] 1 OR: odds ratio; confidence interval; IQR: interquartile range; 5-MTHF: 5-methyltetrahydrofolate.

[0047] 2 The logistic regression model was adjusted for the following covariates: sex, smoking status, body mass index, pulse, history of coronary heart disease, history of dyslipidemia, and family history of hypertension.

[0048] For 5-MTHF, the association with lung cancer remained significant after adjustment for confounders, regardless of whether 5-MTHF was considered a continuous [per interquartile range (IQR) increment] or categorical variable (tertiles) (Table 2). 12 After adjusting for lung cancer risk factors, the association remained nonsignificant. For homocysteine, a significant trend toward increased lung cancer risk with increasing concentration (per IQR increment) was observed in the unadjusted analysis. After adjusting for covariates, the association weakened and was borderline significant (P = 0.083).

[0049] As shown in Table 3, the association between serum 5-MTHF levels and lung cancer risk varied by smoking status (never smokers compared with former and current smokers). A significant trend toward a decreased risk with increasing 5-MTHF concentrations was observed in subjects with a history of smoking or current smoking, whereas a decreased association was observed in subjects who had never smoked. A trend toward a decreased risk of lung cancer with increasing 5-MTHF concentrations was observed in men but not in women, likely due to significant differences in smoking prevalence and 5-MTHF levels between men and women. Heterogeneity by age is also shown in Table 4, with a protective association observed in subjects <65 years of age but no association in subjects ≥65 years of age.

[0050] From the analysis of the above case-control trial results, it can be found that the concentration of 5-MTHF in the human body is negatively correlated with the incidence of lung cancer, proving that supplementing with 5-methyltetrahydrofolate has a significant effect on reducing the risk of lung cancer. Further analysis and research have shown that not all people have the effect of reducing lung cancer by supplementing with 5-MTHFR. Compared with never smokers, male smokers compared with female smokers; those <65 years old compared with those ≥65 years old; serum 5-MTHF concentration <6.4ng / ml compared with ≥6.4ng / ml; serum homocysteine ​​concentration ≥10μmol / L compared with <10μmol / L, those who use 5-MTHFR to reduce the incidence of lung cancer have a significantly better effect. These results have not been mentioned in previous literature reports and are significantly different from the previous understanding of the role of folic acid in lung cancer in this field. They are unexpected results. It suggests that supplementation with 5-methyltetrahydrofolate has an unexpectedly better effect on reducing the risk of HCV infection in specific populations: (1) individuals with a history of smoking or current smoking, especially males; (2) individuals aged <65 years; (3) individuals with serum folate concentrations <6.4 ng / ml; and (4) individuals with serum homocysteine ​​concentrations ≥10 μmol / L.

[0051] Example 2: Preventive effect of the drug of the present invention on lung cancer model rats

[0052] In this experiment, lung cancer was induced in rats by combining crocidolite with benzopyrene (B(a)P), and the compound provided by the present invention was given for treatment to observe its effect on the incidence and mortality of lung cancer in rats.

[0053] Experimental Animals: Male Wistar rats weighing 200-250 g were purchased from Beijing Weitonglihua Laboratory Animal Company and were enrolled in the experiment after passing a one-week inspection. The 5-MTHF and folic acid groups were gavaged for 4 weeks according to the dosages in Table 5. The other groups had free access to water and food during this experimental period.

[0054] Crocidolite for dust staining was prepared by the laboratory of the present invention team, and B(a)P was purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd.

[0055] A mixture of 20 mg of crocidolite and 50 mg of B(a)P / ml was prepared. After four weeks of oral gavage administration to the 5-MTHF and folic acid groups, rats (except the control group) were injected with 0.1 ml of the dust and B(a)P solution once a month for three consecutive months to establish a combined dust-exposed and smoking lung cancer model. During model establishment, rats in the 5-MTH and folic acid groups continued to be gavage-treated for one month. Surviving rats in the control, model, 5-MTHF, and folic acid groups were then sacrificed, and the number of lung tumors, survival time, and mortality were recorded.

[0056] Table 5: Preventive effect of the pharmaceutical composition provided by the present invention on the incidence of lung cancer in rats induced by crocidolite combined with benzo(a)pyrene

[0057]

[0058]

[0059] The above experimental results show that after establishing a rat lung cancer model induced by crocidolite combined with benzo(a)pyrene, the tumor incidence and mortality rates of the rats increased significantly, indicating a successful model. Compared to the model group, the folic acid groups 1-3 significantly reduced the tumor incidence and mortality of rats with lung cancer. However, compared to the same dose of 5-MTHF, 5-MTHF showed an unexpectedly superior effect in preventing both the occurrence and mortality of lung cancer. Compared to the folic acid groups 1-2, the folic acid group 3 did not further reduce the tumor incidence and mortality with increasing dose. Within the dose range of 0.04-0.16 mg / kg, the tumor incidence and mortality rates further decreased with increasing dose of 5-MTHF, demonstrating a dose-response relationship. Increasing the dose of 5-MTHF to 0.2 mg / kg showed no further preventive effect. In summary, within the experimental dose range of rats, 5-MTHF (0.04-0.5 mg / kg) showed a highly significant effect in reducing the incidence and mortality of lung cancer, and its effect was significantly superior to that of folic acid.

[0060] Example 3. Effect of the composition of the present invention on lung cancer mice

[0061] 3-4 week old SPF-grade C57BL / 6 mice, half male and half female, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. All mice were adaptively fed for 1 week with free access to water and food.

[0062] Mouse Lewis lung cancer cells were purchased from Shanghai Meiyan Biotechnology Co., Ltd. Mouse transforming growth factor (TGF-β), interleukin (IL-2), and interferon (IFN-γ) enzyme-linked immunosorbent assay (ELISIA) kits were purchased from Shanghai Meiyan Biotechnology Co., Ltd.

[0063] Mouse Lewis lung cancer cells were cultured in a 37°C 5% CO2 cell culture incubator. When the cell confluence reached 80%, 0.25% trypsin was added for digestion. After digestion was terminated, the cells were repeatedly pipetted with PBS buffer to disperse into a single suspension. The cells were counted and the cells were arranged into 1×10 7 / ml cell suspension.

[0064] Tumor-bearing mouse models were established in C57BL / 6 mice, and 1×10 7 A suspension of mouse Lewis lung cancer cells (100 cells / ml) was prepared. Seven days after modeling, the mice were observed subcutaneously; if a rice-sized mass appeared, the model was considered successful. The mice with successful modeling were randomly divided into a model group, a cisplatin group, a 5-MTHF1 group, a 5-MTHF2 group, a cisplatin + 5-MTHF1 group, and a cisplatin + 5-MTHF2 group. The cisplatin group received an intraperitoneal injection of 4 mg / kg cisplatin; the model group received an equal volume of saline by gavage. The cisplatin group received medication once daily, while the other groups received medication once daily for 20 consecutive days.

[0065] After the mice were killed by cervical dislocation, the tumors were removed and weighed. The tumor weight of each group was recorded and the average value was calculated. The tumor growth inhibition rate was calculated according to the formula: Tumor growth inhibition rate (%) = (1-average tumor weight of treatment group / average tumor weight of model group) × 100%.

[0066] ELISA was used to measure TGF-β, IL-2, and IFN-γ concentrations in mouse peripheral blood. Submandibular venous blood was collected from the mice and allowed to stand at room temperature for 2 hours before serum separation. The serum was centrifuged at 3000 rpm, 8 cm centrifuge radius, and centrifuged for 15 minutes according to the ELISA instructions.

[0067] The interactions between the components in the composition were calculated using the Jin Zheng mean Q value method:

[0068] Jin Zhengjun's Q value method is used to calculate the interaction between composites: Q = E a+b / (E a +E b -E a ×E b ), where E a+b is the average value of the data when components A and B are combined, E a and E bare the average values ​​of the data when component A and component B are used alone. In the formula, the numerator represents the "measured combined effect", the denominator represents the "expected combined effect", and Q is the ratio of the two. Q < 0.85 is antagonistic, 0.85 ≤ Q < 1.15 is additive, and Q ≥ 1.15 is synergistic. In order to meet the analysis of the pharmacological effect relationship, the measured value is converted into an effect that can intuitively reflect the strength of the pharmacological effect. The calculation formula is: E i =(1-P i / P 模型组 )×100%,P i is the measured value of each group, P 模型组 is the measured value of the model group.

[0069] Table 6 Sensitization effect of the composition of the present invention on lung cancer mice

[0070]

[0071]

[0072] Compared with the model control group, # P<0.01, ## P<0.05

[0073] See Table 5. Compared with the model control group, the cisplatin group was able to inhibit tumor growth, reduce TGF-β levels, and increase IL-2 and IFN-γ levels. Compared with the model group, the 5-MTHF1 group had less ability to inhibit tumor growth, reduce TGF-β, and increase IL-2, but significantly increased IFN-γ levels. The 5-MTHF2 group had less ability to inhibit tumor growth, but significantly reduced TGF-β and increased IL-2 and IFN-γ levels. The cisplatin + 5-MTHF1 group and the cisplatin + 5-MTHF2 group not only significantly inhibited tumor growth but also significantly reduced TGF-β and increased IL-2 and IFN-γ levels. Because cisplatin has a significant tumor-suppressing effect and 5-MTHF has a relatively low tumor-suppressing effect, we used the Gold mean coefficient to analyze the combined effect of the two. Since the gold mean coefficients of the cisplatin + 5-MTHF1 group and the cisplatin + 5-MTHF2 group for the above-mentioned detection indicators were greater than 1.15 compared with the corresponding cisplatin group and 5-MTHF group, cisplatin and low-dose 5-MTHF had a synergistic effect in inhibiting tumor growth, indicating that 5-MTHF had a sensitizing effect on the anti-tumor effect of cisplatin.

Claims

1. Use of a composition comprising an effective dose of 5-methyltetrahydrofolate or a salt thereof in the preparation of a medicament for reducing the risk of lung cancer.

2. The use according to claim 1, characterized in that: The composition contains 200-5000 μg of 5-methyltetrahydrofolate.

3. The use according to claim 2, characterized in that: The composition contains 200-1600 μg of 5-methyltetrahydrofolate.

4. The use according to claim 3, characterized in that: The composition contains 800-1600 μg of 5-methyltetrahydrofolate.

5. The use according to claim 1, characterized in that: The salt of 5-methyltetrahydrofolate is a metal salt, an amino acid salt or a glucosamine salt of 5-methyltetrahydrofolate. The metal salt of 5-methyltetrahydrofolate is a calcium salt of 5-methyltetrahydrofolate, a sodium salt of 5-methyltetrahydrofolate, a lithium salt of 5-methyltetrahydrofolate, a magnesium salt of 5-methyltetrahydrofolate, a barium salt of 5-methyltetrahydrofolate, a potassium salt of 5-methyltetrahydrofolate, an ammonium salt of 5-methyltetrahydrofolate and a zinc salt of 5-methyltetrahydrofolate. The amino acid salt of 5-methyltetrahydrofolate is a salt of valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, threonine, lysine, ornithine, histidine, cysteine, theanine and methionine.

6. The use according to claim 5, characterized in that: The salt of 5-methyltetrahydrofolic acid is 5-methyltetrahydrofolic acid calcium salt or 5-methyltetrahydrofolic acid glucosamine.

7. The use according to claim 1, characterized in that: The lung cancer includes small cell lung cancer and non-small cell lung cancer.

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