JP2001288107A - Reducing agent for adverse effect accompanied in cancer chemotherapy - Google Patents
Reducing agent for adverse effect accompanied in cancer chemotherapyInfo
- Publication number
- JP2001288107A JP2001288107A JP2000108662A JP2000108662A JP2001288107A JP 2001288107 A JP2001288107 A JP 2001288107A JP 2000108662 A JP2000108662 A JP 2000108662A JP 2000108662 A JP2000108662 A JP 2000108662A JP 2001288107 A JP2001288107 A JP 2001288107A
- Authority
- JP
- Japan
- Prior art keywords
- fatty acid
- side effects
- cancer chemotherapy
- present
- ratio
- 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.)
- Granted
Links
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、癌化学療法に伴う
副作用軽減剤に関する。本発明製剤は、癌化学療法施行
中の患者において多発する食欲不振、下痢、白血球及び
血小板減少、肝機能障害や腎機能障害などの副作用を軽
減し、且つ栄養補給のできる優れた製剤として有用であ
る。The present invention relates to an agent for reducing side effects associated with cancer chemotherapy. The preparation of the present invention is useful as an excellent preparation capable of reducing side effects such as anorexia, diarrhea, leukocyte and thrombocytopenia, hepatic dysfunction and renal dysfunction frequently occurring in patients undergoing cancer chemotherapy, and providing nutritional supplementation. is there.
【０００２】[0002]
【従来の技術】近年の癌化学療法の進歩はめざましいも
のがある。特に、新しい抗悪性腫瘍薬の開発と臨床応
用、多剤併用化学療法、造血幹細胞移植を用いた大量化
学療法などの施行によりさらに向上しつつある。中で
も、造血系悪性腫瘍、乳癌、卵巣癌、精巣腫瘍などにお
いては、化学療法による長期生存や治癒の可能性も出て
きている。癌化学療法は標的となる癌細胞に対する薬剤
の殺細胞効果を期待した治療法である。しかし、化学療
法剤は選択的に癌細胞にのみ作用するものではない。言
い換えれば、正常細胞にも抗悪性腫瘍薬の作用が及ぶの
が、癌化学療法の宿命であり、臨床上の副作用として問
題となっていた。2. Description of the Related Art Recent advances in cancer chemotherapy have been remarkable. In particular, it has been further improved by the development and clinical application of new antineoplastic drugs, multiple drug chemotherapy, and high-dose chemotherapy using hematopoietic stem cell transplantation. In particular, in hematopoietic malignant tumors, breast cancer, ovarian cancer, testicular tumors, etc., the possibility of long-term survival and cure by chemotherapy is emerging. Cancer chemotherapy is a treatment that expects the cell-killing effect of drugs on target cancer cells. However, chemotherapeutic agents do not selectively act only on cancer cells. In other words, the effect of the antineoplastic drug on normal cells is the fate of cancer chemotherapy, and has been a problem as a clinical side effect.
【０００３】近年の癌化学療法の進歩とともに副作用も
高頻度且つ重篤なものが多くなってきた。血液毒性や消
化器症状などの副作用の発生頻度が最も高く、患者に苦
痛を与えるのみならず、患者の治療継続拒否の原因や生
命をも脅かすことにもなる。癌化学療法を側面から支援
して、副作用の緩和すなわち補助療法を充実させること
が、癌に対する治療効果を高めるばかりでなく、Qualit
y of Life(QOL)の面からも重要な課題である。このよう
な観点から、癌化学療法における副作用を軽減させる試
みが数多くなされており、特に近年のG-CSF製剤や5-HT3
受容体拮抗薬の開発が果たした役割は、顆粒球減少や消
化器症状などの様々な副作用症状対策に極めて大きな貢
献をもたらしている。しかし、これらも完全なものとは
言い難い。[0003] With the progress of cancer chemotherapy in recent years, side effects have become more frequent and serious. Side effects such as hematologic toxicity and gastrointestinal symptoms are the most frequent, causing not only pain to the patient but also threatening the patient's refusal to continue treatment and life-threatening. Supporting cancer chemotherapy from the side and reducing side effects, that is, enriching adjuvant therapies, not only enhances the therapeutic effect on cancer, but also Qualit
It is also an important issue from the perspective of y of Life (QOL). From such a viewpoint, many attempts have been made to reduce the side effects of cancer chemotherapy, and in particular, recent G-CSF preparations and 5-HT 3
The role played by the development of receptor antagonists has made an extremely significant contribution to the control of various side effects such as granulocytopenia and gastrointestinal symptoms. However, these are also less than perfect.
【０００４】一方、これと併行して栄養管理によって副
作用を軽減させることが検討されている。特に、栄養補
給の際に大豆たん白質を投与することにより、一部の副
作用を軽減することが報告されている（Funk M.A. et a
l., J.Nutr.,121,1673-1683(1991); Sitren H.S. et a
l., J.P.E.N., 17(S), 32(1993) ）。しかし、この報告
では下痢及び食欲不振を軽減するのみで、血液毒性や消
化器障害、腎障害などの重篤な副作用に対する軽減効果
については認められていない。又、グルタミンの投与に
より、５-フルオロウラシル（5-ＦＵ）やメトトレキセ
ート（ＭＴＸ）などの化学療法剤を投与したラットの死
亡率を改善することが報告されている（大熊利忠、医学
の歩み、164(5),419-422(1993)）が、これも治療効果と
の関係は明らかになっていない。又、癌化学療法剤ＭＴ
Ｘの大量投与で発生する重篤な副作用症状からの救済を
目的として、近年ロイコボリン（ＬＶ）救済療法が施行
されている。骨肉腫、悪性リンパ腫、小児悪性腫瘍等を
中心にＬＶを併用したＭＴＸ大量療法が試みられている
が、ＬＶ救済療法はある種の癌細胞においては抗腫瘍効
果をも減弱していることが指摘されており（金丸龍之介
ほか、医学のあゆみ、164(5)、291-294(1993)）、さら
にこの適応範囲は骨肉腫等に限られている。このように
現在に至るまで、副作用を抑制してさらに抗腫瘍効果を
も減弱しない療法を開発することが課題である。On the other hand, concurrently with this, it has been studied to reduce side effects by nutritional management. In particular, it has been reported that administration of soy protein during nutritional supplementation reduces some side effects (Funk MA et a
l., J. Nutr., 121, 1673-1683 (1991); Sitren HS et a
l., JPEN, 17 (S), 32 (1993)). However, this report only reduces diarrhea and anorexia, and does not recognize a reduction effect on serious side effects such as hematologic toxicity, digestive disorders and renal disorders. It has also been reported that administration of glutamine improves the mortality of rats given chemotherapeutic agents such as 5-fluorouracil (5-FU) and methotrexate (MTX) (Toshitada Okuma, History of Medicine, 164). (5), 419-422 (1993)), but the relationship with this therapeutic effect has not been clarified. Also, a cancer chemotherapeutic agent MT
Recently, leucovorin (LV) rescue therapy has been performed for the purpose of relieving severe side effects caused by large doses of X. MTX high-dose therapy combined with LV has been tried mainly for osteosarcoma, malignant lymphoma, pediatric malignant tumor, etc., but it is pointed out that LV rescue therapy also attenuates the antitumor effect in certain cancer cells (Ryunosuke Kanamaru et al., History of Medicine, 164 (5), 291-294 (1993)), and its indication is limited to osteosarcoma and the like. Thus, to date, the challenge has been to develop a therapy that suppresses side effects and does not attenuate the antitumor effect.
【０００５】[0005]
【発明が解決しようとする課題】上述の状況に鑑み、本
発明者らは癌化学療法剤の副作用を軽減し、且つ癌化学
療法剤の効果を減弱しないような物質を求めて鋭意探索
の結果、少なくとも乳たん白質、大豆たん白質、及び脂
質を含有し、乳たん白質／大豆たん白質の比率が１／２
〜４／１であることを特徴とする栄養組成物の投与が、
癌化学療法に伴う副作用を顕著に軽減する効果を有する
ことを見出した。従って本発明は、乳たん白質、大豆た
ん白質、及び脂質を含有し、両者の比率が乳たん白質／
大豆たん白質の比率が１／２〜４／１である栄養組成物
を有効成分とする、癌化学療法に伴う副作用軽減剤を提
供することを課題とする。SUMMARY OF THE INVENTION In view of the above-mentioned situation, the present inventors have conducted an intensive search for substances that reduce the side effects of cancer chemotherapeutic agents and do not attenuate the effects of cancer chemotherapeutic agents. Containing at least milk protein, soy protein, and lipid, wherein the ratio of milk protein / soy protein is 1/2.
Administration of a nutritional composition characterized by being で あ 4/1,
It has been found that it has an effect of remarkably reducing side effects associated with cancer chemotherapy. Accordingly, the present invention comprises milk protein, soy protein, and lipid, wherein the ratio of both is milk protein /
An object of the present invention is to provide an agent for reducing side effects associated with cancer chemotherapy, comprising a nutritional composition having a soybean protein ratio of 1/2 to 4/1 as an active ingredient.
【０００６】[0006]
【課題を解決するための手段】本発明は、乳たん白質、
大豆たん白質、及び脂質を含有し、乳たん白質／大豆た
ん白質の比率が１／２〜４／１であることを特徴とする
栄養組成物を有効成分とする、癌化学療法に伴う副作用
軽減剤に関する。又、該副作用軽減剤であって、脂質の
組成がω３系脂肪酸３〜20重量％及びω６系脂肪酸10〜
40重量％であり、且つω３系脂肪酸／ω６系脂肪酸の比
率が１／６以上である、癌化学療法に伴う副作用軽減剤
に関する。又、該副作用軽減剤であって、ω３系脂肪酸
がα−リノレン酸、エイコサペンタエン酸、ドコサヘキ
サエン酸よりなる群から選択される少なくとも１種の脂
肪酸であり、ω６系脂肪酸がリノール酸である癌化学療
法に伴う副作用軽減剤に関する。又、該副作用軽減剤で
あって、ω３系脂肪酸／ω６系脂肪酸の比率が３／１〜
１／５である癌化学療法に伴う副作用軽減剤に関する。
本発明製剤は、癌化学療法施行中の患者において栄養補
給を行うとともに、多発する食欲不振、下痢、白血球及
び血小板減少、肝機能障害や腎機能障害などの副作用を
軽減し、その結果癌化学療法の制癌作用を維持もしくは
増強させる。SUMMARY OF THE INVENTION The present invention provides a milk protein,
Reduction of side effects associated with cancer chemotherapy using a nutritional composition containing soy protein and lipid as an active ingredient, wherein the ratio of milk protein / soy protein is 1/2 to 4/1 Agent. The side effect reducing agent, wherein the composition of the lipid is 3 to 20% by weight of the ω3 fatty acid and 10 to 10% by weight of the ω6 fatty acid.
The present invention relates to an agent for reducing side effects associated with cancer chemotherapy, which is 40% by weight and has a ratio of ω3 fatty acid / ω6 fatty acid of 1/6 or more. In addition, the agent for reducing side effects, wherein the ω3 fatty acid is at least one fatty acid selected from the group consisting of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, and the ω6 fatty acid is linoleic acid The present invention relates to an agent for reducing side effects associated with therapy. The side effect reducing agent, wherein the ratio of ω3 fatty acid / ω6 fatty acid is 3/1 to 1
The present invention relates to an agent for reducing side effects associated with cancer chemotherapy, which is 1/5.
The formulation of the present invention provides nutritional support to patients undergoing cancer chemotherapy, and reduces side effects such as frequent anorexia, diarrhea, leukocyte and thrombocytopenia, liver dysfunction and renal dysfunction. Maintain or enhance the anticancer action of
【０００７】[0007]
【発明の実施の形態】本発明の癌化学療法に伴う副作用
軽減剤は、特定のたん白質及び脂質を一定の割合で組み
合わせることを特徴とする。たん白質としては乳たん白
質及び大豆たん白質を含有し、乳たん白質／大豆たん白
質の比率が１／２〜４／１である。尚、この比率が１／
２未満の場合には、必須アミノ酸の欠乏などの栄養学上
の問題が生じ、４／１を超えると下痢の発生や癌化学療
法の副作用軽減が低下してしまう。又、脂質としては、
ω３系脂肪酸３〜２０％（以下、本発明においては、％
は特記しない限り重量％を示す）及びω６系脂肪酸１０
〜４０％を含有し、且つω３系脂肪酸／ω６系脂肪酸の
比率が１／６以上である。上記の比率を得るための脂質
としては、ω３系脂肪酸はα−リノレン酸、エイコサペ
ンタエン酸、ドコサヘキサエン酸より選択することがで
き、ω３系脂肪酸としてはα−リノレン酸、特に好まし
くはα−リノレン酸３〜２０％、及びω６系脂肪酸とし
てはリノール酸、特に好ましくはリノール酸を脂肪組成
中１０〜４０重量％を含有するように組み合わせる。ω
３系脂肪酸／ω６系脂肪酸の比率は１／６以上、好まし
くは３／１〜１／５とする。尚、この比率が１／６未満
の場合には、副作用の抑制効果が低下してしまい、３／
１を超えると必須脂肪酸の不足など栄養学上の問題や副
作用抑制効果が低下してしまう。本発明ではこれらの脂
肪酸組成の栄養組成物を調製するにあたって、動植物油
として例えばシソ油、エゴマ油、アマニ油、キリ油、魚
油、大豆油、ナタネ油等の食用油を用いることができ
る。所望のω３系脂肪酸／ω６系脂肪酸比を得るため
に、これらの動植物油の２種又はそれ以上を組合せて配
合しても良い。又、本発明製剤は、たん白質及び脂質の
以外の栄養成分として、糖質としてデンプン、デキスト
リン、ショ糖、グルコース、ガラクトース、マルトース
等を、その他ミネラルとしてＮａ、Ｋ、Ｃａ、Ｍｇ、
Ｐ、Ｃｌ、Ｆｅ、Ｚｎ、Ｃｕ、Ｍｎ、Ｉ等の有機又は無
機塩を、又、ビタミンとしてビタミン Ａ、Ｄ、Ｅ、Ｋ
などの脂溶性ビタミンや、ビタミンＢ1、Ｂ2、Ｂ6、Ｂ
12、Ｃ、パントテン酸、ナイアシン、ビオチン、葉酸等
の水溶性ビタミンを所望量含有させることができる。BEST MODE FOR CARRYING OUT THE INVENTION The agent for reducing side effects associated with cancer chemotherapy according to the present invention is characterized by combining specific proteins and lipids at a fixed ratio. The protein contains milk protein and soy protein, and the ratio of milk protein / soy protein is 1/2 to 4/1. Note that this ratio is 1 /
If it is less than 2, nutritional problems such as deficiency of essential amino acids occur, and if it exceeds 4/1, the occurrence of diarrhea and reduction of side effects of cancer chemotherapy decrease. Also, as lipids,
3 to 20% of ω3 fatty acid (hereinafter, in the present invention,%
Represents% by weight unless otherwise specified) and ω6 fatty acid 10
-40%, and the ratio of ω3 fatty acid / ω6 fatty acid is 1/6 or more. As a lipid for obtaining the above ratio, the ω3 fatty acid can be selected from α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. Linoleic acid, particularly preferably linoleic acid, is combined so as to contain 10 to 40% by weight in the fat composition. ω
The ratio of the tertiary fatty acid / ω6 fatty acid is 1/6 or more, preferably 3/1 to 1/5. If this ratio is less than 1/6, the effect of suppressing side effects decreases, and 3 /
If it exceeds 1, nutritional problems such as deficiency of essential fatty acids and the effect of suppressing side effects will decrease. In the present invention, in preparing a nutritional composition having these fatty acid compositions, edible oils such as perilla oil, perilla oil, linseed oil, kiri oil, fish oil, soybean oil, and rapeseed oil can be used as animal and vegetable oils. In order to obtain a desired ω3 fatty acid / ω6 fatty acid ratio, two or more of these animal and vegetable oils may be combined and blended. In addition, the formulation of the present invention, as nutrients other than proteins and lipids, starch, dextrin, sucrose, glucose, galactose, maltose and the like as carbohydrates, and other minerals such as Na, K, Ca, Mg,
Organic or inorganic salts such as P, Cl, Fe, Zn, Cu, Mn and I, and vitamins A, D, E and K as vitamins
Fat-soluble vitamins and the like, vitamins B 1, B 2, B 6 , B
12 , C, a desired amount of water-soluble vitamins such as pantothenic acid, niacin, biotin and folic acid can be contained.
【０００８】本発明製剤は、原料を適当な溶媒に溶解、
混合した後、ホモジナイザー等で均質化し、容器に充填
したのちレトルト殺菌等により殺菌することにより、液
状の製剤を得ることができる。又、噴霧乾燥等により、
これを粉末状の製剤とすることもできる。尚、本発明の
有効成分である栄養組成物の調製にあたっては、必要に
応じ、リン脂質、グリセリン脂肪酸エステル、ショ糖脂
肪酸エステル等の乳化剤を配合しても良い。本発明製剤
の投与量は、栄養剤としてのカロリー換算で成人患者で
１日10〜50kcal／体重kgが好ましい。本発明では、癌化
学療法剤は特に限定されないが、腎***率が高く腎機能
障害の発生の頻度が高い薬剤に対し特に効果を有するこ
とが、以下の試験例で確認されている。このような薬剤
として例えばシスプラチン、メトトレキセート、エトポ
シド、ブレオマイシン、ニトロソウレアなどが挙げられ
る。[0008] The preparation of the present invention is prepared by dissolving the raw materials in a suitable solvent,
After mixing, the mixture is homogenized with a homogenizer or the like, filled in a container, and then sterilized by retort sterilization or the like, whereby a liquid preparation can be obtained. Also, by spray drying, etc.
This can be made into a powdery preparation. In preparing the nutritional composition as the active ingredient of the present invention, an emulsifier such as a phospholipid, a glycerin fatty acid ester, or a sucrose fatty acid ester may be added, if necessary. The dosage of the preparation of the present invention is preferably 10 to 50 kcal / kg of body weight per day in adult patients in terms of calories as a nutritional supplement. In the present invention, the cancer chemotherapeutic agent is not particularly limited, but it has been confirmed in the following test examples that the agent is particularly effective for an agent having a high renal excretion rate and a high frequency of occurrence of renal dysfunction. Such drugs include, for example, cisplatin, methotrexate, etoposide, bleomycin, nitrosoureas and the like.
【０００９】[0009]
【実施例】以下の実施例をもって本発明をより詳細に説
明するが、これらは単に例示したのみであり、本発明は
これらによって何ら限定されるものではない。The present invention will be described in more detail with reference to the following examples, which are merely illustrative, and do not limit the present invention in any way.
【００１０】[0010]
【製造例１】本発明液状製剤の製造 表１に示した配合で、液状の本発明製剤を常法に従い調
製した。この栄養組成物の乳たん白質と大豆たん白質と
の比率は２／１であった。又、脂肪酸組成はカプリル酸
36.5% 、α−リノレン酸9.2%、リノール酸25.9％よりな
り、ω３系脂肪酸／ω６系脂肪酸の比率は1/2.82であっ
た。又、又、ミネラル類は、Ｎａ、Ｋ、Ｃａ、Ｍｇ、
Ｐ、Ｃｌ、Ｆｅなどの有機又は無機塩混合物、ビタミン
類は、ビタミンＡ、Ｄ、Ｅ、ビタミンＢ1、Ｂ2、Ｂ6、
Ｂ12、Ｃ、ナイアシン、パントテン酸などの混合物を、
国民栄養所要量に合致した量を用いた。Production Example 1 Production of Liquid Preparation of the Present Invention A liquid preparation of the present invention having the formulation shown in Table 1 was prepared according to a conventional method. The ratio of milk protein to soy protein in this nutritional composition was 2/1. The fatty acid composition is caprylic acid
It consisted of 36.5%, α-linolenic acid 9.2% and linoleic acid 25.9%, and the ratio of ω3 fatty acid / ω6 fatty acid was 1 / 2.82. Also, minerals are Na, K, Ca, Mg,
Mixtures of organic or inorganic salts such as P, Cl, and Fe, vitamins are vitamins A, D, E, vitamins B 1 , B 2 , B 6 ,
A mixture of B 12 , C, niacin, pantothenic acid, etc.
The amount used was in accordance with the national nutrition requirement.
【００１１】[0011]
【表１】 [Table 1]
【００１２】[0012]
【製造例２】本発明液状製剤の製造・２ 製造例１と同様にして、乳たん白質／大豆たん白質の比
率を２／１に、ω３系脂肪酸／ω６系脂肪酸の比率を１
／５に調整したものを製造した。尚、ミネラル類及びビ
タミン類の組成は製造例１と同様にした。Production Example 2 Production of the liquid preparation of the present invention 2 In the same manner as in Production Example 1, the ratio of milk protein / soy protein was 2/1 and the ratio of ω3 fatty acid / ω6 fatty acid was 1
/ 5 was manufactured. The compositions of the minerals and vitamins were the same as in Production Example 1.
【００１３】[0013]
【製造例３】本発明液状製剤の製造・３ 製造例１と同様にして、乳たん白質／大豆たん白質の比
率を１／２に、ω３系脂肪酸／ω６系脂肪酸の比率を３
／１に調整したものを製造した。尚、ミネラル類及びビ
タミン類の組成は製造例１と同様にした。Production Example 3 Production of the liquid preparation of the present invention 3 In the same manner as in Production Example 1, the ratio of milk protein / soy protein was reduced to 1/2, and the ratio of ω3 fatty acid / ω6 fatty acid was reduced to 3.
/ 1 was manufactured. The compositions of the minerals and vitamins were the same as in Production Example 1.
【００１４】[0014]
【製造例４】本発明粉状製剤の製造 表２に示した配合で、粉状の本発明製剤を常法に従い調
製した。この脂質の脂肪酸組成は、α−リノレン酸3.2
％、リノール酸25.7％ 、エイコサペンタエン酸7.7％、
ドコサヘキサエン酸4.5％よりなり、ω３系脂肪酸／ω
６系脂肪酸は1/1.67であった。又、乳たん白質と大豆た
ん白質との比率は1/3.00であった。尚、ミネラル類及び
ビタミン類の組成は製造例１と同様にした。Production Example 4 Production of Powdered Preparation of the Present Invention A powdered preparation of the present invention was prepared according to a conventional method, using the formulation shown in Table 2. The fatty acid composition of this lipid is α-linolenic acid 3.2
%, Linoleic acid 25.7%, eicosapentaenoic acid 7.7%,
Consists of docosahexaenoic acid 4.5%, ω3 fatty acid / ω
Sixth fatty acid was 1 / 1.67. The ratio of milk protein to soy protein was 1 / 3.00. The compositions of the minerals and vitamins were the same as in Production Example 1.
【００１５】[0015]
【表２】 [Table 2]
【００１６】[0016]
【試験例１】癌化学療法剤投与による副作用抑制効果 本発明製剤（製造例１〜３）を被験栄養剤Ａ、Ｂ、及び
Ｃとし、又、対照栄養剤を栄養剤Ｄ及びＥとして、実験
に用いた。実験に用いた各栄養剤の乳たん白質／大豆た
ん白質の比率及びω３系脂肪酸／ω６系脂肪酸の比率
を、表３に示す。又、栄養剤Ｄ及びＥの配合成分組成
を、表４に示す。ラットは６週齢のSD-IGS系雄性ラット
（体重200-220g）30匹を用い、１週間予備飼育した。予
備飼育終了直後及び予備飼育終了後４日目に、癌化学療
法剤としてメトトレキセート（ＭＴＸ；日本レダリー
社）を軽いエーテル麻酔下に腹腔内投与し（初日；20mg
/kg、４日目；10mg/kg）、被験栄養剤及び対照栄養剤を
６日間、自由摂取させた。栄養剤投与期間中は、体重、
エネルギー摂取量の測定、及び便性状を観察し、実験最
終日に採血解剖した。血液学的検査として白血球数、血
小板数を、小腸及び胸腺萎縮に対する影響として小腸重
量、胸腺重量、及び粘膜中ジアミンオキシダーゼ（ＤＡ
Ｏ）活性を、及び腎機能検査として血中尿素態窒素濃
度、血中クレアチニン濃度をそれぞれ測定した。体重変
化を図１に、エネルギー摂取量の結果を図２に、便性状
の結果を表５に、血液学的検査の結果を表６に、小腸及
び胸腺萎縮に対する影響の結果を表７に、及び腎機能検
査の結果を表８に、それぞれ示す。この結果、本発明栄
養剤Ａ、Ｂ、及びＣは栄養剤Ｄ及びＥに比べ、癌化学療
法剤の副作用である下痢を抑制し、免疫能に影響する白
血球及び血小板の減少を抑制した。又、栄養素吸収障害
あるいはバクテリアルトランスロケーションに影響する
小腸の萎縮、及び免疫能に影響する胸腺の萎縮を抑制
し、又、腎機能を改善した。これらの結果より、本発明
製剤は癌化学療法剤による副作用に対し、優れた改善傾
向が認められ、従って本発明製剤は、癌化学療法剤の副
作用を軽減する優れた製剤として有用であることが明ら
かとなった。又、本試験と同様に、栄養剤Ａの乳たん白
質を大豆たん白に置換した、大豆たん白質のみをたん白
質源とした栄養剤を用いて、上記と同様の試験を行った
が、公知の先行技術を追認するのみであった。即ち、下
痢及び食欲不振に対してはある程度の効果は認められた
ものの、血球系、消化管系、あるいは腎機能に対する副
作用に対し、効果が認められなかった。さらに、癌化学
療法剤としてシスプラチンを用いて上記と同様の試験を
行ったが、本試験例のメトトレキセートを用いた場合と
同様の結果が得られた。特に腎機能の低下を抑制するこ
とから、本発明製剤は癌化学療法剤、特に腎***率の高
いものの副作用を軽減する優れた製剤として有用である
ことが明らかとなった。[Test Example 1] Effect of suppressing the side effects by administration of cancer chemotherapeutic agents Experiments were performed using the preparations of the present invention (Production Examples 1 to 3) as test nutrients A, B, and C, and control nutrients as nutrients D and E. It was used for. Table 3 shows the ratio of milk protein / soy protein and the ratio of ω3 fatty acid / ω6 fatty acid of each nutrient used in the experiment. Table 4 shows the composition of nutrients D and E. As the rats, 30 SD-IGS male rats (body weight 200 to 220 g) of 6 weeks old were preliminarily reared for one week. Immediately after the completion of the preliminary breeding and 4 days after the completion of the preliminary breeding, methotrexate (MTX; Nippon Redley Co., Ltd.) was intraperitoneally administered as a cancer chemotherapeutic agent under light ether anesthesia (first day; 20 mg).
/ kg, day 4; 10 mg / kg), and the test nutritional supplement and the control nutritional supplement were freely taken for 6 days. During nutritional administration period, body weight,
Measurement of energy intake and stool properties were observed, and blood dissection was performed on the last day of the experiment. Leukocyte count and platelet count as hematological tests, and small intestine weight, thymus weight, and diamine oxidase (DA
O) Activity and blood urea nitrogen concentration and blood creatinine concentration were measured as renal function tests. FIG. 1 shows changes in body weight, FIG. 2 shows the results of energy intake, Table 5 shows the results of stool properties, Table 6 shows the results of hematological tests, and Table 7 shows the results of the effects on small intestine and thymus atrophy. Table 8 shows the results of the renal function test. As a result, the nutrients A, B, and C of the present invention suppressed diarrhea, which is a side effect of the cancer chemotherapeutic agent, and suppressed the reduction of white blood cells and platelets that affect immune ability, as compared with nutrients D and E. In addition, atrophy of the small intestine, which affects nutrient absorption disorders or bacterial translocation, and thymus atrophy, which affects immunity, were suppressed, and renal function was improved. From these results, the formulation of the present invention shows an excellent tendency to improve the side effects of the cancer chemotherapeutic agent, and therefore, the formulation of the present invention is useful as an excellent formulation for reducing the side effects of the cancer chemotherapeutic agent. It became clear. Also, in the same manner as in this test, a test similar to the above was performed using a nutrient obtained by replacing the milk protein of nutrient A with soy protein and using only soy protein as a protein source. Only confirm the prior art. That is, although a certain effect was observed on diarrhea and anorexia, no effect was observed on side effects on the blood cell system, digestive tract system, or renal function. Further, the same test as described above was performed using cisplatin as a cancer chemotherapeutic agent, and the same results were obtained as when the methotrexate of this test example was used. In particular, it has been shown that the preparation of the present invention is useful as a cancer chemotherapeutic agent, particularly as an excellent preparation which has a high renal excretion rate and which reduces side effects, because it suppresses a decrease in renal function.
【００１７】[0017]
【表３】 [Table 3]
【００１８】[0018]
【表４】 [Table 4]
【００１９】[0019]
【表５】 [Table 5]
【００２０】[0020]
【表６】 [Table 6]
【００２１】[0021]
【表７】 [Table 7]
【００２２】[0022]
【表８】 [Table 8]
【００２３】[0023]
【試験例２】カテーテル留置及び癌化学療法剤投与に対
する効果 試験例１と同様の栄養剤を用いて試験を行った。ラット
は試験例１と同様のものを用い、予備飼育終了後に胃内
カテーテル留置を施し、さらに留置術施行後７日間の術
後回復期間を設け、回復期間終了後、表９に示す量で各
種栄養剤をポンプにて６日間の飼育期間中定量的に投与
した。又、回復期間終了直後及び回復期間終了後４日目
に癌化学療法剤ＭＴＸを試験例１と同様に投与した。
又、栄養剤投与期間中は、毎日死亡個体の有無を観察し
た。試験例１の結果と同様に、対照である栄養剤Ｄ及び
ＥではＭＴＸ投与に伴う重篤な副作用が発生したが、本
発明栄養剤Ａ、Ｂ、及びＣでは、ＭＴＸ投与による副作
用が軽減されていた。又、栄養剤Ｄ及びＥについては、
投与期間中に死に至る例が見られたが、本発明製剤投与
群ではそのような例は見られなかった。従って本発明製
剤は、癌化学療法剤の副作用を軽減する優れた製剤とし
て有用であることが明らかとなった。[Test Example 2] For catheter placement and cancer chemotherapeutic drug administration
A test was performed using the same nutrient as in Test Example 1. Rats were used in the same manner as in Test Example 1, and an intragastric catheter was placed after the completion of preliminary breeding, and a postoperative recovery period was provided for 7 days after the indwelling operation was performed. Nutrients were pumped in quantitatively during the 6-day breeding period. Immediately after the end of the recovery period and four days after the end of the recovery period, the cancer chemotherapeutic agent MTX was administered in the same manner as in Test Example 1.
During the nutritional administration period, the presence or absence of dead individuals was observed every day. Similar to the results of Test Example 1, the nutrients D and E, which are the controls, caused serious side effects associated with MTX administration, whereas the nutritional supplements A, B, and C of the present invention reduced the side effects caused by MTX administration. I was For nutrients D and E,
Some cases resulted in death during the administration period, but no such cases were observed in the group administered with the preparation of the present invention. Therefore, it was revealed that the preparation of the present invention is useful as an excellent preparation for reducing the side effects of cancer chemotherapeutic agents.
【００２４】[0024]
【表９】 [Table 9]
【００２５】[0025]
【試験例３】平均生存日数及び延命率に対する効果 CDF1系雄性マウス(CRJ社)５週齢を用い、１週間の予備
飼育後、体重が均等になるように１群６匹で群分けを行
った。 本発明製剤である栄養剤Ａ、Ｂ、及びＣ、及び
対照としてマウス用標準飼料を用いて飼育した。群分け
後、白血病細胞であるＬ-1210細胞(ATCC CCL219）を移
植し、癌化学療法剤ＭＴＸを腫瘍移植翌日及び５日目
に、０，１０，２０，４０，及び８０mg/kgの量で腹腔
内に投与した。被験栄養剤Ａ、Ｂ、及びＣ、及び標準飼
料を投与したマウスの死亡個体の有無を毎日観察した。
さらに、同様にＬ−１２１０細胞を移植しＭＴＸを投与
した後、標準飼料を投与したマウスを対照として平均生
存日数及び延命率を求めた。結果を表１０に示す。この
結果、本発明製剤の投与によって、平均生存日数及び延
命率が有意に延長された。またＭＴＸ投与期間中に死亡
する動物は、本発明製剤投与群には認められなかった。
以上の結果より、本発明製剤はＭＴＸの抗腫瘍効果を増
強し、副作用を軽減することが明らかとなった。[Test Example 3] Effects on average survival days and survival rate Using CDF1 male mice (CRJ), 5 weeks old, after pre-breeding for 1 week, groups were divided into 6 groups per group so that the body weight would be even. Was. Nutrients A, B, and C, which are the preparations of the present invention, and a standard diet for mice were raised as a control. After the grouping, L-1210 cells (ATCC CCL219), which are leukemia cells, were transplanted, and the cancer chemotherapeutic agent, MTX, was administered at the doses of 0, 10, 20, 40, and 80 mg / kg on the day after and 5 days after tumor implantation. Administered intraperitoneally. The presence or absence of dead animals of the mice to which the test nutrients A, B, and C were administered and the standard diet were observed daily.
Furthermore, similarly, after transplanting L-1210 cells and administering MTX, the average number of days of survival and the survival rate were determined using the mice to which the standard diet was administered as a control. Table 10 shows the results. As a result, the administration of the preparation of the present invention significantly increased the average survival days and the survival rate. No animal that died during the period of MTX administration was found in the group administered with the preparation of the present invention.
From the above results, it has been clarified that the preparation of the present invention enhances the antitumor effect of MTX and reduces side effects.
【００２６】[0026]
【表１０】 [Table 10]
【００２７】[0027]
【発明の効果】本発明により、癌化学療法剤の副作用に
対する優れた製剤が提供される。本発明製剤は、癌化学
療法施行中の患者において多発する食欲不振、下痢、白
血球及び血小板減少、腎機能障害などの副作用を軽減す
る優れた製剤として有用である。Industrial Applicability According to the present invention, an excellent preparation for the side effect of a cancer chemotherapeutic agent is provided. The formulation of the present invention is useful as an excellent formulation for reducing side effects such as anorexia, diarrhea, leukocyte and thrombocytopenia, and renal dysfunction frequently occurring in patients undergoing cancer chemotherapy.
【図面の簡単な説明】[Brief description of the drawings]
【図１】 試験例１における、各栄養剤投与群の体重増
加率（％）を示す。FIG. 1 shows the rate of weight gain (%) of each nutritional supplement administration group in Test Example 1.
●：被験栄養剤Ａ ▲：被験栄養剤Ｂ ◆：被験栄養剤Ｃ ×：栄養剤Ｄ ○：栄養剤Ｅ ●: Test nutrient A ▲: Test nutrient B ◆: Test nutrient C ×: Nutrient D ○: Nutrient E
【図２】 試験例１における、各栄養剤投与群のエネル
ギー摂取量（Kcal）を示す。FIG. 2 shows the energy intake (Kcal) of each nutrient administration group in Test Example 1.
●：被験栄養剤Ａ ▲：被験栄養剤Ｂ ◆：被験栄養剤Ｃ ×：栄養剤Ｄ ○：栄養剤Ｅ ●: Test nutrient A ▲: Test nutrient B ◆: Test nutrient C ×: Nutrient D ○: Nutrient E
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｐ 13/12 Ａ６１Ｋ 37/02 37/22 Ｆターム(参考） 4C084 AA02 AA24 BA46 CA15 CA38 MA02 MA16 MA43 ZA511 ZA661 ZA731 ZA751 ZA811 4C206 AA01 AA02 DA05 MA03 MA36 MA63 ZA51 ZA66 ZA73 ZA75 ZA81 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) A61P 13/12 A61K 37/02 37/22 F-term (Reference) 4C084 AA02 AA24 BA46 CA15 CA38 MA02 MA16 MA43 ZA511 ZA661 ZA731 ZA751 ZA811 4C206 AA01 AA02 DA05 MA03 MA36 MA63 ZA51 ZA66 ZA73 ZA75 ZA81
Claims (4)
含有し、乳たん白質／大豆たん白質の比率が１／２〜４
／１であることを特徴とする栄養組成物を有効成分とす
る、癌化学療法に伴う副作用軽減剤。Claims: 1. A milk protein, a soy protein, and a lipid, wherein the ratio of milk protein / soy protein is 1/2 to 4
/ 1. An agent for reducing side effects associated with cancer chemotherapy, comprising a nutritional composition as an active ingredient.
及びω６系脂肪酸10〜40重量％であり、且つω３系脂肪
酸／ω６系脂肪酸の比率が１／６以上である、請求項１
記載の癌化学療法に伴う副作用軽減剤。2. The composition of a lipid having an ω3 fatty acid content of 3 to 20% by weight.
And 10 to 40% by weight of the ω6 fatty acid and the ω3 fatty acid / ω6 fatty acid is 1/6 or more.
The agent for reducing side effects associated with the cancer chemotherapy described above.
サペンタエン酸、ドコサヘキサエン酸よりなる群から選
択される少なくとも１種の脂肪酸であり、ω６系脂肪酸
がリノール酸である、請求項２記載の癌化学療法に伴う
副作用軽減剤。3. The cancer according to claim 2, wherein the ω3 fatty acid is at least one fatty acid selected from the group consisting of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, and the ω6 fatty acid is linoleic acid. Agent for reducing side effects associated with chemotherapy.
／１〜１／５である、請求項２又は３記載の癌化学療法
に伴う副作用軽減剤。4. The ratio of ω3 fatty acid / ω6 fatty acid is 3
The agent for reducing side effects associated with cancer chemotherapy according to claim 2 or 3, wherein the ratio is from 1/1 to 1/5.
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| JP2000108662A JP4625156B2 (en) | 2000-04-10 | 2000-04-10 | Side effect reducing agent associated with cancer chemotherapy |
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| JP2000108662A JP4625156B2 (en) | 2000-04-10 | 2000-04-10 | Side effect reducing agent associated with cancer chemotherapy |
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| JP2007519609A (en) * | 2003-09-17 | 2007-07-19 | アイコス コーポレイション | Use of CHK1 inhibitors to control cell proliferation |
| JP2007530542A (en) * | 2004-03-26 | 2007-11-01 | アボット・ラボラトリーズ | HMB composition and use thereof |
| JP2008039415A (en) * | 2006-08-01 | 2008-02-21 | Genome Soyaku Kenkyusho:Kk | Method for evaluating and screening substance having activity for alleviating side effect of a medicine and side effect alleviating agent containing substance identified by these methods as effective component |
| WO2010064714A1 (en) * | 2008-12-05 | 2010-06-10 | 味の素株式会社 | Nutrient composition |
| US8778992B2 (en) | 2005-12-19 | 2014-07-15 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate to treat allergies and asthma |
| US8916217B2 (en) | 2010-01-29 | 2014-12-23 | Abbott Laboratories | Aseptically packaged nutritional liquids comprising HMB |
| US9241508B2 (en) | 2010-01-29 | 2016-01-26 | Abbott Laboratories | Nutritional emulsions comprising calcium HMB |
| US9521859B2 (en) | 2010-06-10 | 2016-12-20 | Normanella T. Dewille | Substantially clear nutritional liquids comprising calcium HMB and soluble protein |
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| US8785495B2 (en) | 2004-03-26 | 2014-07-22 | Abbott Laboratories | Compositions including beta-hydroxy-beta-methylbutyrate |
| US8609725B2 (en) | 2004-03-26 | 2013-12-17 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate for reducing tumor growth rate |
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| JP2007530542A (en) * | 2004-03-26 | 2007-11-01 | アボット・ラボラトリーズ | HMB composition and use thereof |
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| JP2012229227A (en) * | 2004-03-26 | 2012-11-22 | Abbott Lab | Hmb composition and use thereof |
| US8796333B2 (en) | 2005-12-19 | 2014-08-05 | Abbott Laboratories | Method of using β-hydroxy-β-methylbutyrate to treat a condition |
| US8778992B2 (en) | 2005-12-19 | 2014-07-15 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate to treat allergies and asthma |
| JP2008039415A (en) * | 2006-08-01 | 2008-02-21 | Genome Soyaku Kenkyusho:Kk | Method for evaluating and screening substance having activity for alleviating side effect of a medicine and side effect alleviating agent containing substance identified by these methods as effective component |
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| JP5950292B2 (en) * | 2008-12-05 | 2016-07-13 | 味の素株式会社 | Nutritional composition |
| US9629386B2 (en) | 2008-12-05 | 2017-04-25 | Ajinomoto Co., Inc. | Nutrition composition |
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