JPS621371B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to antitumor agents. Research on cancer chemotherapy has been conducted in a wide range of fields, but cancer chemotherapy aiming at controlling nucleic acid metabolism began in the late 1940s, and 6-mercaptopurine was first synthesized as a nucleic acid metabolism inhibitor. Next, 5-fluorouracil was discovered. 5-Fluorouracil was synthesized by Dushinsky in 1957, and since its antitumor activity was discovered by Heidelberger et al., it has a broad antitumor spectrum and is particularly effective against adenocarcinoma, so it is currently the most widely used clinically. It is one of the antitumor agents in use. Since 5-fluorouracil is a representative compound of nucleic acid-related antimetabolites,
Research and development of compounds with this basic skeleton is still actively being carried out. The present inventor also conducted intensive studies on the development of antitumor agents with strong antitumor effects and few side effects, and the results were as follows:
At least one 5-fluoropyrimidine selected from 5'-deoxy-5-fluorouridine or 5'-deoxy-5-fluorocytidine, and at least one selected from uracil, thymine, and thymidine. By blending one type of uracil, 5
-We have completed the present invention by finding that the antitumor effects of fluoropyrimidines are significantly enhanced, and that they do not exhibit any toxicity (acute toxicity) even at the maximum dose that is experimentally possible. That is, the present invention provides at least one 5-fluoropyrimidine selected from 5'-deoxy-5-fluorouridine and 5'-deoxy-5-fluorocytidine, and at least one 5-fluoropyrimidine selected from uracil, thymine, and thymidine. The present invention relates to an antitumor agent characterized in that it contains both uracils and one type of uracil. According to the present invention, although uracils themselves have no antitumor effect, the antitumor effect of 5-fluoropyrimidines is significantly enhanced by blending uracils with 5-fluoropyrimidines. Moreover, even when the antitumor agent of the present invention is administered in the maximum amount that is technically possible (total amount of 5-fluoropyrimidines and uracils), acute toxicity does not occur, so the intended purpose was achieved. Therefore, it is extremely desirable as a therapeutic agent for tumors. The 5-fluoropyrimidines used in the present invention, namely 5'-deoxy-5-fluorouridine and 5'-deoxy-5-fluorocytidine, are known compounds, and both are described in JP-A-53-95982. It can be manufactured according to In the antitumor agent of the present invention, the blending ratio of 5-fluoropyrimidines and uracils varies depending on the type of 5-fluoropyrimidines and uracils, but cannot be determined unconditionally, but in general, It is preferable to mix the latter in an amount of 0.5 mol or more. Preferably 0.5 mol or more of the latter per 1 mol of the former, 100
It is best to mix less than mol. In the present invention, 5-fluoropyrimidines and uracils can be administered separately, but it is preferable to mix them in advance and administer them at the same time. As the dosage unit form of the antitumor agent according to the present invention, various forms can be selected depending on the therapeutic purpose, such as oral preparations such as tablets, capsules, and granules, and parenteral preparations such as injections and suppositories. etc. can be mentioned. When forming such a dosage unit form, carriers conventionally known in this field are used, and they are manufactured according to methods commonly used in this field. The amount of 5-fluoropyrimidines to be incorporated into these various dosage unit forms varies depending on the type of 5-fluoropyrimidines and uracils, but cannot be particularly limited.
Generally about 10 to 200 mg for oral preparations and about 200 mg for injections.
50-1000mg, preferably about 50-1000mg for suppositories.
The daily dosage also varies depending on the type of 5-fluoropyrimidines and uracils and cannot be specifically limited, but the usual clinical dosage is:
5-Fluoropyrimidines generally contain about 20 to 1200 mg for oral preparations and about 50 to 2000 mg for injections.
mg, preferably about 50 to 2000 mg for suppositories. Next, typical prescription examples of the antitumor agent of the present invention are listed. Formulation Example 1 5'-Deoxy-5-fluorouridine 100mg Uracil 200mg Lactose 250mg Cornstarch 140mg Hydroxypropyl cellulose 10mg 700mg per package Prepare granules at the above mixing ratio. Prescription Example 2 5'-deoxy-5-fluorouridine 10mg Thymine 250mg Lactose 60mg Magnesium stearate 15mg Talc 5mg Hydroxypropyl methylcellulose 10mg 350mg per tablet Prepare tablets at the above mixing ratio. Formulation Example 3 5'-deoxy-5-fluorouridine 25mg Thymidine 215mg Lactose 100mg Crystalline cellulose 57mg Magnesium stearate 3mg Per capsule 400mg Capsules are prepared at the above blending ratio. Formulation Example 4 5'-Deoxy-5-fluorocytidine 50mg Uracil 350mg Lactose 390mg Cornstarch 200mg Hydroxypropyl cellulose 10mg 1000mg per package Prepare granules at the above mixing ratio. Formulation example 5 5'-deoxy-5-fluorocytidine 150mg Thymine 100mg Lactose 97mg Crystalline cellulose 50mg Magnesium stearate 3mg Per capsule 400mg Capsules are prepared at the above blending ratio. Formulation Example 6 5'-deoxy-5-fluorocytidine 100mg Thymidine 500mg Witepsol W-35 1000mg 1600mg per unit Suppositories are prepared at the above mixing ratio. Next, the antitumor effect of the antitumor agent of the present invention will be shown by experimental examples. Experimental Example The antitumor effect of the antitumor agent of the present invention was investigated using Sarcoma 180. 2×10 ⁶ Sarcoma 180 ascites tumor cells were subcutaneously transplanted into the back of male ICR mice (6 mice per group) weighing 22±2 g. tumor transplant
After 24 hours, 5% of a mixture of 5-fluoropyrimidines and uracils in the proportions shown below.
Dissolve or suspend in gum arabic aqueous solution, once a day
The drug was forcibly administered intragastrically using an oral probe for 7 consecutive days. On the 10th day after tumor implantation, the tumor was removed and its weight was measured, and the tumor suppression rate was calculated from the average tumor weight ratio of the drug administration group and the control group. On the other hand, the average body weight of each group after tumor removal was measured, and the degree of weight gain was determined from the value before tumor implantation, and the weight gain in the drug administration group was compared with that in the control group, which was used as an indicator of toxicity. All drugs were prepared at a dose of 1 ml/100 g body weight, and a 5% gum arabic solution alone was orally administered to the control group. The results are shown in Tables 1-6. Table 1~
3 shows the results when 5'-deoxy-5-fluorouridine was mixed with uracil, thymine, and thymidine, and Tables 4 to 6 show the results when 5'-deoxy-5-fluorocytidine was mixed with uracil, thymine, and thymidine, respectively. The results are shown below. Comparative data without uracils is also shown.

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[Table] From the results of the experimental examples, the antitumor effects of all compounds were significantly enhanced by adding uracil, thymine, and thymidine to 5-fluoropyrimidines. That is, when uracils are blended with 5-fluoropyrimidines, the antitumor effect of the antitumor agent of the present invention increases significantly compared to each individual effect, and as the blending ratio of uracils increases, Furthermore, the antitumor effect is even more significantly increased. Moreover, it has been found that even when these uracils are blended with a trace amount of 5-fluoropyrimidine, an extremely excellent antitumor effect that could not be expected from 5-fluoropyrimidine alone can be obtained. That is, as is clear from Table 1 above, uracil 50
1 mole of 5'-deoxy-5-fluorouridine
When administering 15 mg/Kg of the antitumor agent of the present invention in molar combination, the tumor growth inhibition rate is 69%, but in order to obtain the same inhibition rate by administering 5'-deoxy-5-fluorouridine alone, 120 mg/Kg of the antitumor agent of the present invention is administered. Kg should be administered. Therefore, it is sufficient for the antitumor agent of the present invention to be administered in a dose 1/8 of that of a single agent that does not contain uracil. The excellent effects of the present invention are also shown in Tables 2 to 6.
It can also be seen in Furthermore, the toxicity of the antitumor agent of the present invention was low, and no deaths were observed even when the maximum dose was administered. That is, the LD ₅₀ value determined by the Up and Down method was at least 2000 mg/Kg as a total dose. Furthermore, as is clear from the results in Tables 1 to 6, no suppression of weight gain in the test mice that would suggest toxicity was observed in any of the administration groups. As is clear from the above experimental results, the antitumor agent of the present invention is an ideal antitumor agent that exhibits almost no toxicity and exhibits sufficient antitumor effects.

Claims (1)

[Claims] 1 5′-deoxy-5-fluorouridine and
At least one 5-fluoropyrimidine selected from 5'-deoxy-5-fluorocytidine,
An antitumor agent characterized by containing at least one kind of uracil selected from uracil, thymine, and thymidine. 2. The antitumor agent according to claim 1, which contains 0.5 mol or more of uracil per 1 mol of 5-fluoropyrimidine.