JPS6348245B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel antitumor agents, more specifically, 1-
The present invention relates to an antitumor agent comprising a combination of (2-tetrahydrofuryl)-5-fluorouracil and L-cysteine. 1-(2-tetrahydrofuryl)-5-fluorouracil (hereinafter abbreviated as FT) is a derivative of 5-fluorouracil (hereinafter abbreviated as 5-FU) that has an antitumor effect. Since FT has weaker toxicity and side effects than 5-FU, it is often used clinically as an antitumor agent from the viewpoint of safety, but its antitumor effect is slightly weaker than that of 5-FU. Therefore, it is desired to increase the antitumor effect of FT without adversely affecting toxicity and side effects, and many studies have been conducted to date. The antitumor effect of FT is due to the fact that FT ingested into the body is gradually converted into 5-FU, an antimetabolite, mainly by drug-metabolizing enzymes in the liver, and this 5-FU is mainly responsible for the function of RNA in tumor cells. failure and
It is thought to be expressed by inhibiting DNA synthesis. Therefore, in order to increase the antitumor effect of FT,
Promote the conversion of FT to 5-FU in vivo, prevent the conversion of FT to inert substances other than 5-FU, and reduce the amount of 5-FU produced.
It is possible to suppress the decomposition of FU and maintain it in the body at high concentration for a long time. In order to achieve this purpose, attempts have been made to use FT and other drugs in combination, for example, Fujita ("Cancer and Chemotherapy" Vol. 3, No. 6, p. 1082;
(November 1976), Saito et al. ("Cancer and Chemotherapy" Vol. 6,
No. 2, p. 245, March 1979) and Koshizuka ("Cancer Clinical" Vol. 24, No. 2, p. 127, February 1978), the effect of the combination of FT with glutathione and phenobarbital. has been reported. However, glutathione and phenobarbital enhance the action of drug-metabolizing enzymes in the liver, resulting in a high blood concentration of 5-FU, but as the 5-FU concentration increases,
The disadvantage is that the FT concentration decreases and the effect does not last for a long time. Therefore, as a result of intensive research on enhancing the antitumor effect of FT, the present inventor found that when FT and L-cysteine were used together, the plasma and liver concentrations of FT and 5-FU significantly increased, resulting in an antitumor effect. They found that the effect was increased and completed the present invention. Therefore, the present invention provides an antitumor agent comprising a combination of FT and L-cysteine. By combination with L-cysteine in the present invention
The results of testing for increases in plasma and liver concentrations of FT and 5-FU and antitumor effects are as follows. (1) Effect of increasing FT and 5-FU concentrations in plasma and liver Test method: FT and physiological saline dissolved in 1M sodium carbonate aqueous solution were administered to male Wistar rats (10 rats per group) weighing approximately 200 g that had been fasted for 12 hours. L dissolved in liquid
-Cysteine was administered according to the method described in Table-1. After a predetermined period of time had elapsed after administration, the concentrations of FT and 5-FU in the plasma and liver of each group were measured. FT and 5-FU measurement method Add 0.5 ml of ethanol under ice-cooling to 1 ml of plasma or 1 ml of 25% liver homogenate (0.25 M, phosphate buffer (PH6.0)) and mix well.
Centrifuge at 3000 rpm for 10 minutes and collect 0.5 ml of supernatant. Add to this 0.25M phosphate buffer (PH6.0)
Add 0.5 ml and mix well, add 8 ml of ethyl acetate, and shake vigorously for 10 minutes. Next, 3000r.p.
Centrifuge for 10 minutes at m., remove 8 ml of the ethyl acetate layer, and dry under reduced pressure. To the residue, add 0.1 ml of a methanol solution (30 μg/ml for plasma, 150 μg/ml for liver homogenate) of the internal standard substance orotic acid (hereinafter abbreviated as OA) and 0.1 ml of a diazomethane ether solution, and leave at room temperature. Leave it for about 20 minutes. After drying under reduced pressure, add 0.1ml of acetone and add 1μl of it.
is injected into NP-GLC to determine the peak height ratio of the 5-FU methyl derivative and the peak area ratio of the FT methyl derivative to the internal standard OA methyl derivative, and determine the 5-FU and FT concentrations from the standard calibration curve. NP-GLC measurement conditions Testing model: Hewllet Packard Co&Ltd
5710A Detector: NP detector Packing material: 1% PEG-HT Uniport HP (80~
100mesh) Column: Glass column length 2m, inner diameter 3mm Temperature: Column 175℃ Sample vaporization chamber 300℃ Detector 300℃ Flow rate: Carrier gas (He) 20ml/min H ₂ 3ml/min Air 60ml/min

[Table] Results Table 2 shows the average values of FT and 5-FU concentrations in plasma.
Table 3 shows that in the liver.

【table】

[Table] (2) Antitumor effect Test method: 5 x 10 ⁶ Sarcomer 180 tumor cells, weighing approx.
It was inoculated subcutaneously in the axillary region of 25 g of male DDY mice (10 mice per group). 24 hours after tumor cell inoculation, 1M−
FT dissolved in an aqueous sodium carbonate solution and L-cysteine dissolved in a physiological saline solution were administered according to the method described in Table 4. Tumors were excised on the 15th day after tumor cell inoculation, and their weights were measured to determine the average tumor weight ratio (T/C) between drug administration group T and control group C.

【table】

[Table] Results The tumor weight and T/C in each drug administration group are shown in Table 5.

[Table] As is clear from the above results, when FT and L-cysteine are administered together, the
The concentrations of FT and 5-FU increased significantly (Tables 2 and 3), and the antitumor effect of FT was enhanced (Tables 2 and 3).
5). The antitumor agent of the present invention is preferably combined in a molar ratio of L-cysteine to FT1 of 0.3 or more. As for the dosage form, FT is preferably an oral preparation such as a tablet, capsule, granule, or powder, and L-cysteine is preferably an oral preparation or an injection as described above. FT and L-cysteine can be administered by the same or different routes, simultaneously or at intervals. Furthermore, better results can be obtained if L-cysteine is additionally administered a certain time after the administration of FT and L-cysteine. The dosage is
FT 15-500mg/Kg/day, L-cysteine 3
It is preferable that the amount is more than mg/Kg/day. Next, examples of the present invention will be described. Example 1 Fine granules: After kneading a mixture consisting of 500 g of FT, 400 g of L-cysteine, and 90 g of corn starch with 120 g of a 5% hydroxypropyl cellulose aqueous solution,
Pelletize using a conventional method and dry at 60° for 1 hour. Mix 4 g of magnesium stearate with 996 g of the material that passed through the 32-mesh sieve to make fine granules. This fine granule agent 1
g contains 500 mg of FT and 400 mg of L-cysteine. Example 2 Capsules: Using the fine granules obtained in (1) above, hard capsules with a content weight of 500 mg per capsule are prepared using Japanese Pharmacopoeia hard capsules (size 0). One capsule contains 250mg of FT and 200mg of L-cysteine. Example 3 Granules: 500g FT, 193g corn starch, lactose
140 g of 5% hydroxypropyl cellulose aqueous solution is added to the 300 g mixture and kneaded. After granulation by a conventional method, it is dried at 60°C for 1 hour. After sieving, 16 mesh to 48 mesh granules are taken and used as FT granules. L-cysteine 200g, corn starch
A mixture consisting of 80 g and 220 g of D-mannitol.
Knead with 50% ethanol solution. After granulating in a conventional manner, the mixture is dried at 60°C for 1 hour, and sieved to obtain 16 to 48 mesh granules, which are used as L-cysteine granules. 1 part by weight of FT granules and 15 parts by weight of L-cysteine granules are mixed to form a granule containing 50 mg of FT and 600 mg of L-cysteine in 1600 mg. Example 4 Tablet: A mixture of 500 g of FT, 100 g of L-cysteine, 146 g of crystalline cellulose, and 50 g of carboxymethyl cellulose calcium is kneaded with a 50% ethanol solution, granulated by a conventional method, and dried at 60° C. for 1 hour. granules
4 g of magnesium stearate was mixed with 1496 g, and tablets with a weight of 400 mg and a diameter of 11.0 mm were prepared by a conventional method. One tablet contains 250 mg of FT and 50 mg of L-cysteine. Example 5 (Combination) The following injections and granules were combined into one package. Injection (intramuscular injection) Make an 8% sterile purified aqueous solution of L-cysteine,
After passing through a membrane filter, fill 3 ml of the solution into an ampoule or vial and seal it with nitrogen gas.
(Contains 240 mg of L-cysteine.) Granules (oral) FT granules obtained in Example 3 (500 mg/g as FT)
use.

[Claims]

1. A preparation for intracorporeal administration characterized by containing sulfamethoxazole, trimethoprim and phospholipid as essential components.