JPS6154007B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to amino acid infusions for cancer. Conventionally, it has been used as a nutritional supplement to maintain and improve physical strength by supplying nutrients parenterally and enterally to patients who cannot take nutrients orally and/or enterally, such as post-operative patients. Amino acid infusions of various compositions are known and widely used. Because these known amino acid infusions are originally intended as nutritional infusions, their basic composition uniformly imitates the amino acid composition that is a nutritional source necessary for the human body, such as human milk, chicken eggs, and human serum albumin. Therefore, all eight essential amino acids are included as necessary ingredients. In the process of conducting research on amino acid infusions especially for cancer patients, the present inventors happened to find that an amino acid infusion that did not contain methionine compared to conventionally known amino acid infusions did not substantially inhibit the original effects of nutritional replenishment fluids. Surprisingly, it was found that conventional amino acid infusions exert cancer cell reduction and anticancer effects that were completely unexpected. In other words, when a known amino acid infusion is applied to a cancer patient, it exerts its own effect of maintaining physical strength through nutritional supplementation, but at the same time, the above-mentioned nutritional source also provides nutrients to the cancer cells in the body.
It only helps the cancer cells proliferate and therefore slows down the patient's weight loss rate, without any improvement in symptoms or weight gain. On the other hand, when using an infusion with methionine removed from the infusion, the original effects of the infusion are expressed, and due to the absence of methionine, the proliferation of cancer cells in the body is selectively suppressed, resulting in improvement in weight gain and symptoms. It was found that the effect was expressed. The gist thereof is an amino acid infusion for cancer that is composed of at least the following amino acids and is characterized by having the following composition (g/100g of total amino acids) in terms of free amino acids. Amino acid composition range (g/
100g) L-leucine 9.36-18.26 L-valine 4.23-12.76 L-isoleucine 4.95-12.76 L-lysine 6.48-22.11 L-phenylalanine 6.93-12.98 L-threonine 4.14-8.47 L-tryptophan 1.26-4.29 L-arginine 7.47 ~12.43 L-histidine 3.24-6.93 Glycine 10.08-19.80 According to a preferred embodiment of the amino acid infusion for cancer of the present invention, the infusion has the following composition range per 100 g of total amino acids. Amino acid composition range (g/
100g) L-leucine 9.88-17.43 L-valine 4.47-12.18 L-isoleucine 5.23-12.18 L-lysine 6.84-21.11 L-phenylalanine 7.32-12.39 L-threonine 4.37-8.09 L-tryptophan 1.33-4.10 L-arginine 7.89 ~11.87 L-histidine 3.42-6.62 Glycine 10.64-18.90 Furthermore, according to a more preferred embodiment of the amino acid infusion for cancer of the present invention, the infusion contains 100 g of total amino acids.
It has a composition within the following g range. Amino acid composition range (g/
100g) L-leucine 15.77-17.43 L-valine 7.70-8.51 L-isoleucine 6.94-7.67 L-lysine 19.10-21.11 L-phenylalanine 11.12-12.29 L-threonine 6.94-7.67 L-tryptophan 2.28-2.52 L-Arginine 8.55 ~9.45 L-histidine 3.42-4.20 Glycine 13.11-14.49 The amino acid infusion of the present invention is completely different from conventionally known amino acid infusions of this type in that it does not contain methionine, and based on this, it is different from conventional amino acid infusions and Therapy using this amino acid infusion has a totally unexpected cancer cell reduction effect and a remarkable survival and anticancer effect on cancer patients.Moreover, the amino acid infusion's original nutritional supplementation has a substantial effect on maintaining and improving physical strength. not be damaged by This effect is particularly pronounced when the amino acid infusion of the present invention is used in combination with known anticancer agents, and in this case an effective cancer treatment method can be provided. The main feature of the amino acid infusion of the present invention is that it does not contain methionine, and the other amino acid compositions are almost the same as those of various known amino acid infusions. Essential amino acids leucine, valine,
In addition to isoleucine, lysine, phenylalanine, threonine, and tryptophan, it has a composition that contains non-essential amino acids such as arginine, histidine, and glycine, which are included in ordinary amino acid infusions. This composition range is approximately the same as the blending range of the above-mentioned 10 components in various known amino acid infusions (composition range excluding methionine and other amino acid components). These amino acids can also be used in the form of pharmacologically acceptable salts, such as hydrochloride, according to conventional methods, and in this case, the blending ratio is determined so as to fall within the above range in terms of free amino acids. Furthermore, in addition to amino acids, the infusion solution of the present invention may contain various ingredients that have been conventionally known to be added to this type of infusion solution, such as carbohydrates, sugars, vitamins, fats, electrolytes, etc. good. The amino acid infusion of the present invention obtained in this way may be used parenterally or enterally by intravenous injection, drip, etc., according to conventional methods, and the dosage may be the same as that of ordinary amino acid infusions. good. Generally, the amount per person per day is about 500 to 1,500 ml, and may be increased or decreased as appropriate depending on the condition of the patient to whom it is applied, the timing of application, etc. Examples of the composition of the amino acid infusion of the present invention are shown below as examples, but the present invention is not limited thereto. Example 1 [Table] Example 2 [Table] Pure crystals of each amino acid in an amount having the composition described in Examples 1 and 2 above were added to distilled water for injection, stirred and dissolved, and then sulfite was added as a stabilizer. Add 0.2 g of sodium hydrogen and adjust the pH to approximately 6.0 using acetic acid as a pH regulator. Next, the resulting amino acid aqueous solution was filtered aseptically, filled into an infusion container, replaced with nitrogen, the container was closed, and the container was placed in an autoclave at 110°C.
Sterilize for 40 minutes to obtain the amino acid infusion for cancer of the present invention. Hereinafter, the amino acid infusion having the composition of Example 1 will be referred to as "AO-30", and the amino acid infusion having the composition of Example 2 will be referred to as "AO-90". In addition, AO-90 is AO-30
This corresponds to a concentration approximately three times that of the previous one. Next, experimental examples and clinical examples using the amino acid infusion for cancer of the present invention will be shown. Experimental Example Donryu and Wistar rats weighing 150-160 g are used in this experiment. Prior to creating tumor-bearing animals, a catheter for continuous infusion without restraint is placed according to the following surgical procedure, and the adjustment period is 3 days after surgery. Under Nembutal anesthesia, a small incision was made in the neck skin of the rat to expose the jugular vein up to the point where it branches to the subclavian vein. A catheter was inserted through the jugular vein and fixed when the tip reached the superior vena cava. , the contralateral side passes subcutaneously and emerges dorsally. A harness is then placed, and the catheter is passed through the harness and protective coil and connected to the continuous infusion pump via a swivel. For this procedure, we used an unrestrained continuous injector "BIO-CANNULA" manufactured by Bio-Medica Co., Ltd. During the subsequent 3-day adjustment period, panamine (hereinafter referred to as PA) with the following composition was used.
) was administered continuously at a rate of 1.5 ml/hr, and protein-free food with the following composition and water were allowed to be taken ad libitum. PA composition Leucine 410mg/100ml Valine 200 Isoleucine 180 Lysine HC 620 Phenylalanine 290 Threonine 180 Tryptophan 60 Arginine HC 270 Histidine HC. 2H ₂ O 130 Methionine 240 Glycine 340 Protein-free α-starch 47.83g Seuclose 23.92g Multivitamin Note ¹ 1.0g Mixed salt Note ² 5.0g Corn oil 5.0g Cellulose 2.0g "Chiyokola A" Note ³ 0.05ml Choline C 0.20ml In addition, the above-mentioned complex vitamin Note ¹ ] and mixed salt Note ² ] have the following compositions, and "Chiyokola A" Note
³ ] is a vitamin A palmitate ester manufactured by Eisai Co., Ltd., containing 30,000 international units/ml of vitamin A (20 mg/ml of retinol palmitate). Complex vitamin composition Thiamine HC 0.059% Riboflavin 0.059 Nicotinic acid 0.294% Calcium pantothenate 0.235 Pyridoxyl HC 0.029 Menadione 0.006 Biotin 0.001 Folic acid 0.002 Vitamin B ₁₂ 0.0002 Inositol 1.176 Ascorbic acid 0.588 Lac Tate 97.551 Mixed acid composition CaCO ₃ 29.29% CaHPO ₄・2H ₂ O 0.43 KH ₂ PO ₄ 34.31 NaC 25.06 MgSO ₄・7H ₂ O 9.98% Fe (C ₅ H ₅ O ₇ )・6H ₂ O 0.623 CuSO ₄・5H ₂ O 0.156 MnSO ₄・H ₂ O 0.121 ZnC ₂ 0.02 (NH ₄ ) ₆ Mo ₇ O ₄・4H ₂ O 0.0025 KI 0.0005 1 Solid tumor suppression experiment After the adjustment period, Tasarcoma cells 2.7×10 ⁷ cells/ml and AH130 9×10 ⁶ cells/ml were injected into Donriyu rats.
Tumor-bearing animals were prepared by subcutaneously inoculating Wistar rats with 1×10 ⁷ Walker sarcoma cells/ml and 0.2 ml of rhodamine sarcoma tumor tissue porridge subcutaneously in the left inguinal region. The amino acid infusion of the present invention (AO-30) was administered to non-cancer animals and tumor-bearing animals for each type of tumor as shown in Table 1 below as experimental groups.
Single administration group (A-1 and A-4), combination group of AO-30 and mitomycin-C (hereinafter referred to as MMC) (A-2 and A-5), combination group of AO-30, MMC and food ( A-3 and A-6), and as controls, PA alone administration group (P-1 and P-4), PA and MMC combination group (P-2 and P-5), PA, MMC
and food combination groups (P-3 and P-6), 12 groups each. Each group consists of 6 experimental animals. A.O.
-30 and PA were administered continuously at a rate of 1.5 ml/hr.
MMC is administered intraperitoneally at 0.1 mg/Kg/day 24 hours after tumor inoculation. The diet used was the protein-free diet mentioned above. [Table] For Ta sarcoma and AH130 after inoculation of each tumor
The tumor is excised on the 12th day, and on the 15th day for Walker's sarcoma and rhodamine sarcoma, and its weight is measured. The results are shown in Tables 2 to 5 for each sarcoma.
In addition, each table shows the average tumor weight C of the tumor-bearing animal (P-4) to which only PA was administered, and the weight of each tumor-bearing animal group (P-5, P-6, A-4 to
The results of calculating the average tumor weight T, ie, T/C in A-6) are also listed. Valid if this T/C ratio is <0.50,
0.50 to 0.70 is determined to be somewhat valid, and >0.70 is determined to be invalid. [Table] From Table 2 above, the tumor weight when the present invention amino acid infusion AO-30 was administered alone (A-4 group) was about
It decreased by more than 1/3, and it is clear that AO-30 has the effect of suppressing the proliferation of cancer cells. In addition, the T/C ratio in the above A-4 group was 0.64, which indicates that the efficacy is the same as or even better than that of conventional MMC administration (P-5 group) and MMC and food combination group (P-6 group). It turns out that it is acceptable. Furthermore, the above AO
Group A-5 and AO-30, which used a combination of -30 and MMC;
In group A-6, which received both MMC and food, the T/C ratio was 0.42, showing effectiveness, and AO-30 and MMC
It is clear that the combined effect of each of these is enhanced. [Table] From Table 3 above, the present invention amino acid infusion AO-30
(A-4 group), PA use (P-4 group)
The tumor weight was reduced to about 1/3 compared to the AO-30 group), and it had the effect of suppressing cancer cell proliferation.The AO-30 was effective when used alone, and when used in combination with MMC or MMC and food, its effectiveness was confirmed. It is clear that the performance is further enhanced. [Table] The effectiveness of the amino acid infusion of the present invention can be confirmed from the above table as well as in Tables 2 and 3. [Table] Similar to Tables 2 to 4, Table 5 clearly demonstrates the effectiveness of the amino acid infusion of the present invention. It is clear that, unlike the amino acid infusions they contain, they all exert a remarkable effect on inhibiting the proliferation of various cancer cells. 2. Life extension effect experiment: Tasarcoma cells (1.7×10 ⁵
cells/ml), AH130 1.1×10 ⁶ cells/ml, and Walker sarcoma cells 1.0×10 ⁵ cells/ml in Wistar rats.
Tumor-bearing animals are created by intraperitoneally administering ml of each. In this experiment, AO-30 (PA in control experiment)
is administered in combination with glucose, electrolytes, and vitamins, resulting in so-called total parenteral nutrition (hereinafter referred to as TPN method).
Nutritional management was carried out by The composition of the infusion is shown in the table below. [Table] As shown in Table 6 below, the experimental groups are the TPN group (A-1') in which AO-30 was administered to tumor-bearing animals, and the AO-30
and MMC combination group (A-2′), PA administration as control
TPN group (P-1') and PA and MMC combination group (P-
2'), a total of four groups are provided. Each group consists of 10 experimental animals. MMC is administered intraperitoneally at 0.1 mg/Kg/day. [Table] Observe the survival status of experimental animals for 30 days after inoculating each tumor cell, and calculate the mean survival days (hereinafter referred to as MST) using the following formula. MST=Σ(t.f)/n n: Number of animals observed f: Number of animals that died on day t t: Number of days of survival after tumor inoculation The efficacy was evaluated in the TPN group (P -1'), the average survival days (T) of each tumor-bearing animal group, that is, the T/C ratio, is calculated, and the T/C ratio is >1.25.
is determined to be valid, and <1.25 is determined to be invalid. The results are shown in Table 7 below for each cancer cell. [Table] From Table 7 above, the infusion of the present invention was found to have a survival effect 1.3 to 1.5 times more effective than infusion using PA for any cancer cells, and this was found to be 1.3 to 1.5 times more effective when used in combination with MMC (A- 2' group), it is clear that MMC's survival-prolonging effect is further enhanced. As a cancer cell
When using AH130, the survival rate at 30 days after tumor inoculation in experimental groups P-2' and A-2' was 40% and 60%, respectively.
%, and when Walker's sarcoma was used, the experimental group P-2' was 20%, whereas the experimental group A-2' was 20%.
That of 2′ actually showed 50%. From the above results, the methionine-free amino acid infusion of the present invention can be administered alone for a certain period of time to treat Ta's sarcoma, Walker's sarcoma, etc.
It shows a remarkable tumor growth inhibitory effect on AH130 and rhodamine sarcoma, and this effect is further enhanced when used in combination with anticancer agents such as MMC. In addition, the amino acid infusion of the present invention is continuously administered using the TPN method as the only nitrogen source.
It has been shown that this anticancer drug exhibits an excellent survival effect on Tian sarcoma, AF130, and Walker's sarcoma, and furthermore, the effect of this anticancer drug is enhanced when used in combination with MMC administration. 3 Tumor Suppression Experiment The same procedure as in Experiment 1 was conducted using the amino acid infusion AO-90 prepared in Example 2. That is, male rats weighing approximately 250 g were used in this experiment. 1 x 10 ⁶ Sato lung cancer cells were subcutaneously transplanted into the back of the tumor, and 7 to 9 days later, when the tumor diameter reached approximately 15 mm, cannulation was performed into the superior vena cava, and 50% glucose solution and amino acid infusion were performed under unrestrained conditions. , electrolyte solution,
High-calorie infusions containing vitamin supplements were administered. Depending on the amino acid infusion used, rats were given the following 1 group 7
The animals were divided into four groups. Group A: Amino acid infusion prescribed by FAO/WHO (commercial product, manufactured by Otsuka Pharmaceutical Factory, 12% milk amine injection)
Administration group, B: Amino acid infusion administration group in which 50 mg/dl of tyrosine was added to the AO-90 of the present invention, C: Administration group of the AO-90 of the present invention D: DI-47 (phenylalanine and tyrosine were excluded from the FAO prescription) Amino acid infusion, prescribed in "Modern Igaku" Vol. 28, No. 5, p. 936, Table 3 (1971) administration group. The amino acid infusion dose for each group was all 10g/Kg/
The glucose dose was 53g/Kg/day. After the start of high-calorie infusion, the major axis and minor axis of the tumor were measured every two days, and the estimated tumor weight was calculated using the following formula. Estimated tumor weight = long axis x (breadth axis) ² x 1/2 The results are shown in Figure 1. In FIG. 1, the vertical axis shows the estimated tumor weight (g), and the horizontal axis shows the number of days (days) after amino acid infusion administration. In addition, on the 8th day after the start of the high-calorie infusion, the test rats were sacrificed, the tumors were removed, and their weights were measured.
The results were as shown in Table 8 below. Table 8: Test group actual tumor weight (g) A 25.43±6.87 B 15.15±5.25 C 4.56±3.89 D 19.73±5.14 From Figure 1 and Table 8 above, Groups B and C (amino acid infusion administration group of the present invention) A significantly significant tumor growth inhibiting effect was observed in comparison with the control group A (FAO/WHO prescribed amino acid infusion administration group). On the other hand, in the comparative group D (prescription excluding phenylalanine and tyrosine from the FAO prescription), although a slight tumor growth suppressive effect was observed,
It should be noted that this was not as noticeable as in Group A, which served as a control. Clinical case 1 This case developed cancerous peritonitis approximately 2 years after total gastric dissection.
This study was performed on a 54-year-old male patient who was extremely weak and had severe vomiting due to cancerous stenosis of the intestinal tract. Amino acid infusion AO-30, which does not contain methineon, prepared in Example 1 of the present invention was used for this patient.
While performing the TPN method, MMC, 5-
Fluorouracil (5FU) and neocarzinostatin (NCS) were administered. After 4 weeks, the patient recovered to a state where he could take the drug and was discharged from the hospital. Clinical case 2 The patient in this case is a 39-year-old male.
The patient was readmitted to the hospital one year after gastric excision due to liver metastases with jaundice. Hepatomegaly, abdominal wall vein distention, ascites, and lower body edema developed, which became serious. Same as the first case
As a result of administering the amino acid infusion of the present invention using the TPN method and administering 5FU, NCS, etc., the hepatomegaly and venous distension disappeared after 5 weeks, and other symptoms were mild.
The patient died from gastrointestinal bleeding. Autopsy revealed extensive necrosis of the cancerous focus histologically. Clinical Case 3 The patient in this case was a 43-year-old man who was diagnosed with Borrmann type 4 (Borr type 4) gastric cancer by gastric fluoroscopy. During the waiting period for surgery, it became impossible to eat due to pyloric stenosis, clinical case 1.
The amino acid infusion of the present invention (AO
-90) and 5FU250 as an anticancer drug.
mg/day and NCS 2 mg/day were simultaneously administered for 16 days.
As an amino acid infusion for the TPN method, one having the following composition was intravenously administered at 2400 ml/day. Amino acid infusion composition 10% glucose ^*1 1000ml 50% glucose ^*1 300ml AO-90 ^*2 500ml Potassium chloride ^*1 40ml Calcium gluconate ^*3 20ml Calcium bicarbonate ^*1 40ml "Intrafat" ^*4 500ml Vitamins: TTFD ^*5 50mg VB ₂ 50mg VB ₁₂ ^*6 1mg VC 1000mg VK ₁ 30mg VK ₂ 10mg FAD ^*7 10mg Total calorie content Approx. 2000Cal Total solution volume Approx. 2400ml *1...Made by Otsuka Pharmaceutical Co., Ltd.* ₂ ... 9% amino acid infusion *3... Manufactured by Dainippon Pharmaceutical Co., Ltd. *4... Manufactured by Daigo Nutrient Chemical Co., Ltd. *5... Thiamin tetrahydrofurfuryl disulfide *6... As hydroxycobalamin *7... Flavin-Adenine Di Nucleotide At first, we performed a gastric resection, but there was significant metastasis to the pancreatic vagina and retroperitoneum, presenting with cancerous peritonitis. The histological image on the 18th day after starting the TPN method showed a differentiated adenocarcinoma that had fallen into necrosis, and was judged to be highly effective Ef ₃ according to the esophageal cancer handling regulations.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the results of tumor suppression experiment 3 (time-dependent changes in tumor weight under administration of the infusion) to clarify the effects of the amino acid infusion for cancer of the present invention.

Claims (1)

[Scope of Claims] 1. An amino acid infusion for cancer comprising at least the following amino acids, characterized in that it has the following composition (g/100g of total amino acids) in terms of free amino acids. Amino acid composition range (g/
100g) L-leucine 9.36-18.26 L-valine 4.23-12.76 L-isoleucine 4.95-12.76 L-lysine 6.48-22.11 L-phenylalanine 6.93-12.98 L-threonine 4.14-8.47 L-tryptophan 1.26-4.29 L-arginine 7.47 ~12.43 L-histidine 3.24~6.93 Glycine 10.08~19.80 2 An amino acid infusion for cancer consisting of at least the following amino acids, and having the following composition (g/100g of total amino acids) in terms of free amino acids: Claim 1 Amino acid infusion for cancer as described in section. Amino acid composition range (g/
100g) L-leucine 9.88-17.43 L-valine 4.47-12.18 L-isoleucine 5.23-12.18 L-lysine 6.84-21.11 L-phenylalanine 7.32-12.39 L-threonine 4.37-8.09 L-tryptophan 1.33-4.10 L-arginine 7.89 ~11.87. L-Histidine 3.42-6.62 Glycine 10.64-18.90 3 An amino acid infusion for cancer consisting of at least the following amino acids, which has the following composition (g/100g of total amino acids) in terms of free amino acids: Amino acid infusion for cancer as described. Amino acid composition range (g/
100g) L-leucine 15.77-17.43 L-valine 7.70-8.51 L-isoleucine 6.94-7.67 L-lysine 19.10-21.11 L-phenylalanine 11.12-12.29 L-threonine 6.94-7.67 L-tryptophan 2.28-2.52 L-Arginine 8.55 ~9.45 L-Histidine 3.42~4.20 Glycine 13.11~14.49