JP810H - Antitumor agent composition - Google Patents
Antitumor agent compositionInfo
- Publication number
- JP810H JP810H JP810H JP 810 H JP810 H JP 810H JP 810 H JP810 H JP 810H
- Authority
- JP
- Japan
- Prior art keywords
- fluorouracil
- present
- tetrahydrofuryl
- antitumor agent
- uracil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims description 16
- 239000000203 mixture Substances 0.000 title description 5
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 28
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 15
- 229960002949 Fluorouracil Drugs 0.000 claims description 15
- 229940035893 Uracil Drugs 0.000 claims description 14
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 claims description 11
- -1 2-tetrahydrofuryl Chemical group 0.000 claims description 4
- 230000000259 anti-tumor Effects 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 8
- 230000001225 therapeutic Effects 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- 231100000486 side effect Toxicity 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- 210000004881 tumor cells Anatomy 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 210000002356 Skeleton Anatomy 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- 230000000607 poisoning Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Description
【発明の詳細な説明】
本発明は１−（２−テトラヒドロフリル）−５−フルオ
ロウラシルとウラシルとを有効成分として含有する抗腫
瘍剤に関するものである。
抗腫瘍剤の研究開発は従来から活発に行なわれており、
臨床的にも種々の優れた抗腫瘍剤が悪性腫瘍の化学療法
に導入されている。その成績は年々改善されつつある
が、多くの場合一時的であり腫瘍の増殖を完全に抑制
し、患者を長期生存せしめるには必ずしも満足する効果
は得られていない。例えば現在、臨床上繁用されている
５−フルオロウラシルはその抗腫瘍効果は強いのである
が毒性及び副作用も著しく大きく、従つて実際の治療の
場においては効果発現と同時に副作用の発現も避け得な
い。また１−（２−テトラヒドロフリル）−５−フルオ
ロウラシルについては比較的毒性及び副作用は少ない
が、その抗腫瘍効果も若干劣るといわれている。また、
従来から用いられている抗腫瘍剤と種々の他の抗腫瘍剤
との組み合わせによる多剤併用により抗腫瘍効果の増強
及び副作用の軽減を目的とした試みも数多く行なわれて
いるが、いずれも悪性腫瘍の化学療法剤として決定的な
ものでない。本発明は１−（２−テトラヒドロフリル）
−５−フルオロウラシルとウラシルとを含有する抗腫瘍
剤に関するものである。
５−フルオロウラシルを骨格とする化合物は生体内にお
いて５−フルオロウラシルに変換され、これが抗腫瘍効
果を発現すると言われているが、十分な抗腫瘍効果を発
現し得ないのは変換された５−フルオロウラシルが速や
かに代謝されて不活性化されることによるものと考えら
れる。従つて生体内で変換された５−フルオロウラシル
が不活性化されないように処置を講ずる必要があるが、
腫瘍組織内に存在する５−フルオロウラシルの不活性化
を抑制し他の正常な組織内に存在する５−フルオロウラ
シルの不活性化を抑制しないようにすることが望まれ
る。
本発明者は斯かる現状に鑑み５−フルオロウラシル類の
抗腫瘍効果を高めた抗腫瘍剤を得るべく鋭意研究を重ね
て来た。その結果５−フルオロウラシル類１モルに抗腫
瘍効果をまつたく有さないウラシルを０．０２〜２モル
配合したときに所期の目的を達成し得ることを見い出
し、先に特許出願（特願昭５２−３９３４１）した。
本発明者は前記発明について最適条件を追及するため更
に研究を重ねた結果、５−フルオロウラシル類１モルに
対してウラシルを２モルを越えて１０モル以下配合した
時にさらに治療係数の増大することを見い出し、本発明
を完成するに至つた。
本発明は、１−（２−テトラヒドロフリル）−５−フル
オロウラシル及び該１−（２−テトラヒドロフリル）−
５−フルオロウラシル１モルに対して２．５モル以上１
０モル以下のウラシルを含有することを特徴とする抗腫
瘍剤に係る。
本発明に依れば、ウラシル自体には抗腫瘍効果は認めら
れないが、これと１−（２−テトラヒドロフリル）−５
−フルオロウラシルとを併用することによつて抗腫瘍効
果が著しく増大し、治療係数は後記第１表に示すように
約３．８〜４．１倍に増大する。本発明の抗腫瘍剤を用
いると、腫瘍内における５−フルオロウラシルの濃度が
著しく高まるが、その他の組織例えば血清における５−
フルオロウラシルの濃度はほとんど高まらず、従つて腫
瘍の治療剤としては理想的なものである。
本発明で使用される１−（２−テトラヒドロフリル）−
５−フルオロウラシルは公知の化合物であり、公知の方
法に従つて製造される。この１−（２−テトラヒドロフ
リル）−５−フルオロウラシルは特公昭４９−１０５１
０号に記載されている。
本発明の抗腫瘍剤に於て１−（２−テトラヒドロフリ
ル）−５−フルオロウラシルとウラシルとの使用割合
は、一般には前者１モルに対して後者を２．５モル以上
１０モル以下用いるのがよい。
本発明では１−（２−テトラヒドロフリル）−５−フル
オロウラシルとウラシルとをそれぞれ別個に投与するこ
ともできるが、両者を予め配合しておきこれらを同時に
投与するのが好ましい。本発明に係る抗腫瘍剤の投与単
位形態としては各種の形態を治療目的に応じて選択で
き、例えば錠剤、カプセル剤、顆粒剤等の経口用剤、注
射剤、坐剤等の非経口用剤等を挙げることができる。斯
かる投与単位形態に形成するに際しては、担体としてこ
の分野で従来公知のものが使用され、この分野で慣用さ
れている手段に従つて製造される。斯かる種々の投与単
位形態中に配合されるべき１−（２−テトラヒドロフリ
ル）−５−フルオロウラシルの量については、実際の臨
床用量及び基礎的効力実験から推定される臨床用量は１
日当り、一般的には０．５〜５０mg／kgであるのが望ま
しい。
次に本発明の抗腫瘍剤の代表的な処方例を掲げる。
処方例１
１−（２−テトラヒドロフリル）−
５−フルオロウラシル ５０mg
ウラシル ２００mg
乳糖 ３４０mg
コーンスターチ ４００mgヒドロキシプロピルセルロース １０mg
１包当り１０００mg
上記配合割合で顆粒剤を調製する。
処方例２
１−（２−テトラヒドロフリル）−
５−フルオロウラシル １００mg
ウラシル １５０mg
炭酸ナトリウム ４４０mg
水酸化ナトリウム ６０mg注射用蒸留水 適量
１アンプル当り１０ml
上記配合割合で注射剤を調製する。
次に本発明抗腫瘍剤のマウスにおける急性毒性、抗腫瘍
効果及び治療係数を示す。
(1)急性毒性試験
体重２２±１ｇのＩＣＲ系雄性マウスを１群５匹として
実験に使用した。使用薬剤は下記第１表に示す割合で１
−（２−テトラヒドロフリル）−５−フルオロウラシル
とウラシルとを配合し、５％アラビアゴム溶液にて懸濁
し、経口ゾンデにて強制的に投与した。投与量は１ml／
１００ｇとなるように調製した。試験開始より３週間に
わたつて一般中毒症状、体重および死亡の有無を連日観
察した。ＬＤ50値の算出は３週間後にＵｐ ａｎｄ Ｄ
ｏｗｎ法により行なつた。その結果は第１表の通りであ
る。
(2)抗腫瘍試験
ザルコーマ１８０腫瘍細胞２×１０６個をＩＣＲ系雄性
マウス（１群６匹）の背部皮下に接種した。腫瘍細胞接
種２４時間後から下記第１表に示す割合で１−（２−テ
トラヒドロフリル）−５−フルオロウラシルとウラシル
とを配合したものを５％アラビアゴム溶液に懸濁し、１
日１回連続７日間経口投与した。投与量は各薬剤とも５
doseを設け、１ml／１００ｇとなるように調製した。腫
瘍細胞接種後１０日目に腫瘍を摘出し、その重量を測定
して薬剤投与群（Ｔ）と対照群（Ｃ）との平均腫瘍重量
比（Ｔ／Ｃ）を求め、投与量と効果（Ｔ／Ｃ）の用量−
反応曲線から５０％腫瘍抑制を示す用量（ＥＤ50）を求
めた。その結果は第１表の通りである。
(3)治療係数
前記試験で得られた薬剤処置群のＬＤ50値とＥＤ50値の
比（ＬＤ50／ＥＤ50）をもつて治療係数とした。結果を
第１表に示す。
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antitumor agent containing 1- (2-tetrahydrofuryl) -5-fluorouracil and uracil as active ingredients. Research and development of antitumor agents have been actively carried out for a long time.
Clinically, various excellent antitumor agents have been introduced into chemotherapy for malignant tumors. The results are improving year by year, but in most cases it is temporary and completely suppresses the growth of tumors, and it has not necessarily been satisfactory in achieving long-term survival of patients. For example, 5-fluorouracil, which is clinically widely used at present, has a strong antitumor effect, but its toxicity and side effects are also extremely large. Therefore, in the actual therapeutic field, it is inevitable that both side effects occur and side effects occur. . Further, 1- (2-tetrahydrofuryl) -5-fluorouracil has relatively little toxicity and side effects, but it is said that its antitumor effect is slightly inferior. Also,
Many attempts have been made to enhance the antitumor effect and reduce the side effects by combining multiple drugs by combining the conventionally used antitumor agent with various other antitumor agents, but all of them are malignant. Not a definitive tumor chemotherapeutic agent. The present invention is 1- (2-tetrahydrofuryl)
The present invention relates to an antitumor agent containing 5-fluorouracil and uracil. It is said that a compound having 5-fluorouracil as a skeleton is converted into 5-fluorouracil in vivo, and this exhibits an antitumor effect. However, the compound that cannot exhibit a sufficient antitumor effect is converted 5-fluorouracil. It is thought that this is due to rapid metabolism and inactivation. Therefore, it is necessary to take measures so that the 5-fluorouracil converted in vivo is not inactivated.
It is desirable to suppress the inactivation of 5-fluorouracil present in tumor tissue but not the inactivation of 5-fluorouracil present in other normal tissues. In view of the present situation, the present inventor has earnestly studied to obtain an antitumor agent having an enhanced antitumor effect of 5-fluorouracils. As a result, it was found that when 1 mol of 5-fluorouracils was blended with 0.02 to 2 mol of uracil having no antitumor effect, the intended purpose could be achieved, and a patent application was previously filed (Japanese Patent Application No. 52-39341). The present inventor has conducted further studies to pursue the optimum conditions for the above invention, and as a result, it has been found that the therapeutic index is further increased when uracil is blended in an amount of more than 2 mol and 10 mol or less per 1 mol of 5-fluorouracils. They have found the present invention and completed the present invention. The present invention provides 1- (2-tetrahydrofuryl) -5-fluorouracil and the 1- (2-tetrahydrofuryl)-
2.5 mol or more per 1 mol of 5-fluorouracil 1
The present invention relates to an antitumor agent characterized by containing 0 mol or less of uracil. According to the present invention, uracil itself does not have an antitumor effect, but uracil and 1- (2-tetrahydrofuryl) -5
-The combination use with fluorouracil markedly increases the antitumor effect, and the therapeutic index is increased by about 3.8 to 4.1 times as shown in Table 1 below. When the antitumor agent of the present invention is used, the concentration of 5-fluorouracil in the tumor is significantly increased, but the concentration of 5-fluorouracil in other tissues such as 5-
Concentrations of fluorouracil increase little and are therefore ideal as therapeutic agents for tumors. 1- (2-tetrahydrofuryl) -used in the present invention
5-Fluorouracil is a known compound and can be produced according to known methods. This 1- (2-tetrahydrofuryl) -5-fluorouracil is disclosed in Japanese Examined Patent Publication No. Sho 49-1051.
No. 0. In the antitumor agent of the present invention, the ratio of 1- (2-tetrahydrofuryl) -5-fluorouracil to uracil is generally 1 mol of the former and 2.5 mol or more and 10 mol or less of the latter. Good. In the present invention, 1- (2-tetrahydrofuryl) -5-fluorouracil and uracil can be separately administered, but it is preferable to premix them and administer them simultaneously. As the dosage unit form of the antitumor agent according to the present invention, various forms can be selected according to the therapeutic purpose, and examples thereof include oral preparations such as tablets, capsules and granules, parenteral preparations such as injections and suppositories. Etc. can be mentioned. When forming such a dosage unit form, a carrier conventionally known in this field is used, and it is manufactured according to the means commonly used in this field. Regarding the amount of 1- (2-tetrahydrofuryl) -5-fluorouracil to be incorporated in such various dosage unit forms, the actual clinical dose and the clinical dose estimated from basic efficacy experiments are 1
Generally, it is desirable to be 0.5 to 50 mg / kg per day. Next, typical prescription examples of the antitumor agent of the present invention are listed. Formulation Example 1 1- (2-Tetrahydrofuryl) -5-fluorouracil 50 mg Uracil 200 mg Lactose 340 mg Corn starch 400 mg Hydroxypropyl cellulose 10 mg 1000 mg per packet Prepare granules at the above blending ratio. Formulation Example 2 1- (2-Tetrahydrofuryl) -5-fluorouracil 100 mg Uracil 150 mg Sodium carbonate 440 mg Sodium hydroxide 60 mg Distilled water for injection Appropriate amount 10 ml per ampoule An injection is prepared at the above mixing ratio. Next, the acute toxicity, antitumor effect and therapeutic index of the antitumor agent of the present invention in mice are shown. (1) Acute toxicity test Male ICR mice with a body weight of 22 ± 1 g were used in the experiment in groups of 5 mice. The drug used is 1 at the ratio shown in Table 1 below.
-(2-Tetrahydrofuryl) -5-fluorouracil and uracil were blended, suspended in a 5% gum arabic solution, and forcibly administered by an oral sonde. The dose is 1 ml /
It was adjusted to 100 g. For 3 weeks from the start of the test, general poisoning symptoms, body weight and the presence or absence of death were observed daily. The LD 50 value was calculated up and D after 3 weeks.
It was performed by the own method. The results are shown in Table 1. (2) Antitumor test 2 × 10 6 Sarcoma 180 tumor cells were subcutaneously inoculated on the back of ICR male mice (6 mice per group). Twenty-four hours after tumor cell inoculation, a mixture of 1- (2-tetrahydrofuryl) -5-fluorouracil and uracil in the proportions shown in Table 1 below was suspended in a 5% gum arabic solution, and 1
Oral administration was carried out once a day for 7 consecutive days. Dosage is 5 for each drug
A dose was prepared and the dose was adjusted to 1 ml / 100 g. Ten days after tumor cell inoculation, the tumor was excised, and the weight was measured to obtain the average tumor weight ratio (T / C) between the drug administration group (T) and the control group (C), and the dose and effect ( T / C) dose-
The dose showing 50% tumor suppression (ED 50 ) was determined from the response curve. The results are shown in Table 1. (3) Therapeutic index The therapeutic index was obtained by using the ratio of the LD 50 value and the ED 50 value (LD 50 / ED 50 ) of the drug-treated group obtained in the above test. The results are shown in Table 1.
Claims (1)
ルオロウラシル及び該１−（２−テトラヒドロフリル）
−５−フルオロウラシル１モルに対して２．５モル以上
１０モル以下のウラシルを含有することを特徴とする抗
腫瘍剤。Claims for correction: Claims: 1- (2-tetrahydrofuryl) -5-fluorouracil and the 1- (2-tetrahydrofuryl)
An antitumor agent, which comprises 2.5 mol or more and 10 mol or less of uracil with respect to 1 mol of 5-fluorouracil.
Family
ID=
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