JP2002282000A - Method for discrimating therapy resistance of cancer cell - Google Patents
Method for discrimating therapy resistance of cancer cellInfo
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- JP2002282000A JP2002282000A JP2001094489A JP2001094489A JP2002282000A JP 2002282000 A JP2002282000 A JP 2002282000A JP 2001094489 A JP2001094489 A JP 2001094489A JP 2001094489 A JP2001094489 A JP 2001094489A JP 2002282000 A JP2002282000 A JP 2002282000A
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- cancer
- treatment
- cancer cell
- resistance
- coagulation
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、実験用細胞として
の癌のキャラクタライズなど、癌のキャラクタライズに
有用な、癌細胞の治療に対する抵抗性の鑑別法に関す
る。The present invention relates to a method for identifying resistance to cancer cell therapy, which is useful for characterizing cancer, such as characterization of cancer as an experimental cell.
【０００２】[0002]
【従来の技術】癌は現在においても治療が困難な疾患で
あり、その治療の困難性の一因に癌そのものの多様性が
挙げられる。即ち、ある特定の療法がある癌腫には有効
であるが、別の癌腫には全く無効であったりすることは
日常茶飯事であり、癌腫に適した治療法を見出すことは
極めて困難なことであった。取り分け、この様な癌腫の
キャラクタライズで重要なことは、酸素分圧の低い、治
療抵抗性のある癌部位がどの程度存在するか、言い換え
れば、その癌腫がどの程度の治療抵抗性を有するかを知
ることである。しかしながら、この様なことを知る手だ
ては開発されておらず、単にｐ５３遺伝子のステイタス
で論じられているのみであるのが現状であった。2. Description of the Related Art Cancer is a disease that is still difficult to treat even today, and one of the difficulties in the treatment is the diversity of the cancer itself. In other words, it is a daily occurrence that a particular therapy is effective for one carcinoma, but completely ineffective for another carcinoma, and it is extremely difficult to find a suitable treatment for carcinoma. Was. In particular, what is important in the characterization of such carcinomas is how many cancer sites that have low oxygen tension and are resistant to treatment, in other words, how resistant the carcinoma is to treatment. Is to know. However, a means to know such a thing has not been developed, and at present, it is only discussed in the status of the p53 gene.
【０００３】治療抵抗性を有する癌の問題は、一方では
研究の分野においても暗雲を投げかけている。即ち、従
来においては、放射線抵抗性の低酸素細胞のような治療
抵抗性の癌細胞のモデルとして、培養条件を低酸素条件
としたものが使用されてきた。しかしながら、この様な
治療抵抗性実験モデルが現実の治療の場に於ける治療抵
抗性癌細胞をうまくトレースしているかどうかと言う問
題となると、治療実績からすれば問題ありと言わざるを
得ないことが少なくなかった。即ち、前記実験モデルで
治療抵抗性癌細胞に有効であると認められた医薬が実際
の治療の現場においては、それほどの効果を示さないこ
とが少なくなかったからである。即ち、実験的にアキュ
ートにもたらされる低酸素状況とは異なった治療抵抗性
因子が存在していることが推測される。しかしながら、
この様な因子については全く何の知見も存在しないのが
現状であった。The problem of refractory cancer, on the other hand, has also cast a dark cloud in the field of research. That is, conventionally, as a model of a treatment-resistant cancer cell such as a radiation-resistant hypoxic cell, a model in which the culture condition is a hypoxic condition has been used. However, the problem of whether such a treatment-resistant experimental model successfully traces the treatment-resistant cancer cells in the actual treatment setting has to be said to be problematic based on the treatment results. There were many things. That is, in many cases, medicines that have been found to be effective for treatment-resistant cancer cells in the experimental model do not show much effect in actual treatment sites. That is, it is presumed that there is a treatment resistance factor different from the hypoxia condition that is experimentally brought about. However,
At present, there is no knowledge about such factors.
【０００４】[0004]
【発明が解決しようとする課題】本発明は、この様な状
況下為されたものであり、癌治療や癌実験モデルのキャ
ラクタリゼーションに有用な、癌細胞の治療抵抗性の因
子を解明し、実際に適合した癌の治療抵抗性の鑑別法を
提供することを課題とする。DISCLOSURE OF THE INVENTION The present invention has been made under such circumstances, and has elucidated a factor of cancer cell treatment resistance which is useful for cancer treatment and characterization of a cancer experimental model. It is an object of the present invention to provide a method for identifying treatment resistance of cancer which is actually adapted.
【０００５】[0005]
【課題の解決手段】この様な状況に鑑みて、本発明者ら
は癌治療や癌実験モデルのキャラクタリゼーションに有
用な、癌細胞の治療抵抗性の因子を解明し、実際に適合
した癌の治療抵抗性の鑑別法を求めて鋭意研究努力を重
ねた結果、患者よりバイオプシーにより採取した癌細胞
或いは実験動物より得られた癌細胞に於いて、前記癌細
胞の凝固線溶系因子の発現状況を指標とすることによ
り、かかる治療抵抗性を鑑別しうることを見出し、発明
を完成させるに至った。即ち、本発明は以下に示す技術
に関するものである。 （１）癌細胞の治療に対する抵抗性を鑑別する方法であ
って、前記癌細胞の凝固線溶系因子の発現状況を指標と
することを特徴とする、癌細胞の治療に対する抵抗性の
鑑別法。 （２）凝固線溶系因子が、プラスミノーゲンアクチベー
ター及び／又はプラスミノーゲンアクチベターのインヒ
ビターであることを特徴とする、（１）に記載の癌細胞
の治療に対する抵抗性の鑑別法。 （３）治療が放射線治療であることを特徴とする、
（１）又は（２）に記載の癌細胞の治療に対する抵抗性
の鑑別法。 （４）癌細胞が動物より得られた自然発生癌及び／又は
癌患者よりバイオプシーで得られた癌由来のものである
ことを特徴とする、（１）〜（３）何れか１項に記載の
鑑別法。 以下、本発明について実施の形態を中心に更に詳細に説
明を加える。In view of such circumstances, the present inventors have elucidated the factors of cancer cell treatment resistance that are useful for cancer treatment and the characterization of cancer experimental models, and have identified cancer cells that have actually been matched. As a result of intensive research efforts in search of a method for identifying treatment resistance, the expression status of the coagulation / fibrinolytic factors of the cancer cells in cancer cells obtained by biopsy from a patient or in cancer cells obtained from experimental animals was determined. It has been found that such treatment resistance can be distinguished by using it as an index, and the present invention has been completed. That is, the present invention relates to the following technology. (1) A method for discriminating the resistance of a cancer cell to a treatment, wherein the method comprises using the expression status of a coagulation / fibrinolytic factor of the cancer cell as an index. (2) The method for identifying resistance to cancer cell treatment according to (1), wherein the coagulation / fibrinolysis factor is a plasminogen activator and / or an inhibitor of plasminogen activator. (3) the treatment is radiation treatment,
The method for identifying resistance to cancer cell treatment according to (1) or (2). (4) The cancer cell according to any one of (1) to (3), wherein the cancer cell is derived from a naturally occurring cancer obtained from an animal and / or a cancer obtained by biopsy from a cancer patient. Differentiation method. Hereinafter, the present invention will be described in more detail focusing on embodiments.
【０００６】本発明の癌細胞の治療に対する抵抗性の鑑
別法は、当該癌細胞の凝固線溶系因子の発現状況を指標
とする。一般的に癌細胞に於ける治療困難性の度合い
は、癌細胞内の酸素分圧の低さに比例していると言われ
ている。このことは、癌放射線療法において、放射線に
抵抗性のある癌細胞が存在し、この様な放射線抵抗性細
胞に高圧酸素下放射線を照射したり、２−二トロイミダ
ゾール誘導体のような電子供与性物質の存在下放射線照
射を行うと、かかる放射線抵抗性癌の治療効果を向上し
うることよりも裏付けられる。しかしながら、この様な
酸素分圧と治療困難性の因果関係を定量的に求めた例は
今のところ無い。本発明者らは、この因果関係を確かめ
るために、酸素分圧と治療困難性の関係を調査した。酸
素分圧は、癌内に電極を設置し、測定し、治療困難性は
２０グレイの放射線照射による、癌の腫瘍再増殖延長期
間を指標とした。結果を図１に示す。これより、酸素分
圧が低いほど増殖抑制は小さいことがわかる。更に、こ
の様な酸素分圧の差は癌腫固有の値であることもわか
る。この様な知見をもとに、本発明者らは癌腫により酸
素分圧の差ができる現象の原因を追及した結果、その原
因が癌腫による凝固線溶系の因子の発現の差であること
を見出した。即ち、凝固系が強い癌においては、血栓の
形成により低酸素条件になりやすく、この様な血栓の生
成に起因する低酸素状態が治療抵抗性の原因となってい
ることが明らかになった。本発明の癌細胞の治療に対す
る抵抗性の鑑別法は、この知見に基づいており、凝固線
溶系因子の発現状況を指標とする。本発明で指標として
用いることのできる因子としては、プラスミノ−ゲン、
プラスミン、プラスミノーゲンアクチベーター等の線溶
系因子、プラスミノーゲンアクチベーターのインヒビタ
ーなどの凝固系因子などが例示できる。これらは更に細
分化されたものを用いても良く、例えば線溶系では、ｕ
−ＰＡ、ｕ−ＰＡＲ、ｔ−ＰＡ等が例示できるし、凝固
系であれば、ＰＡＩ−１、ＰＡＩ−２などが例示でき
る。これらの発現状況は、通常知られている方法に従っ
て知ることができる。例えば、プライマーとともにＰＣ
Ｒ反応をかけてそのバンドの濃さを指標にしたり、ウェ
スタンブロットのバンドの濃さなどを指標とすることも
できる。これらの内、好ましいものはＰＣＲによるバン
ドの濃さを指標とする方法である。これらの凝固線溶系
因子のアミノ酸配列或いはそのＲＮＡの塩基配列につい
ては公知の部分が多く、これらの情報をもとにプライマ
ーを設計し、ＰＣＲ反応にかければよい。又、この様な
ＰＣＲ反応を行うためのサンプルとしては、動物の自然
発生癌、癌の患者さんより採取したバイオプシーの標本
の何れもが使用できる。これらのサンプルは培養細胞で
あっても良い。これは、治療抵抗性の因子である、凝固
線溶系因子は、癌細胞に特有のものであって、培養条件
や移植条件などの環境的因子によって変化をあまり受け
ないものだからである。この様な因子の内、プラスミノ
−ゲン、プラスミン、プラスミノーゲンアクチベーター
等の線溶系因子の発現が高い癌細胞或いは癌腫ほど、血
栓が形成しにくく、治療困難性が低く、プラスミノーゲ
ンアクチベーターのインヒビターなどの凝固系因子の発
現が高い癌細胞或いは癌腫は、癌血管内で血栓が生じや
すく、酸素分圧が低くなるので治療困難性が高いと鑑別
される。この様な鑑別結果は、癌のキャラクタライズや
治療指針策定に有意義である。例えば、動物から得られ
た自然発生癌が、治療に対してどの程度抵抗性があるの
か、或いは、治療抵抗性癌のモデルとなる癌か否かの判
断の指標とすることもできる。又、本発明の鑑別法で治
療困難と判断された癌細胞を用いて抗ガン剤のスクリー
ニングを行うことにより、治療困難性の高い癌に有効な
抗ガン剤を開発することができる。又、バイオプシーで
患者さんから得た癌細胞が凝固線溶系において凝固系の
高いものであれば、治療抵抗性が高いと鑑別され、放射
線増感剤を用いた放射線治療や、放射線と化学療法剤の
組み合わせ療法等の療法を早期より行うなどの治療の指
針を策定することができる。[0006] The method of the present invention for determining the resistance of a cancer cell to treatment uses the expression status of a coagulation / fibrinolytic factor in the cancer cell as an index. Generally, it is said that the degree of difficulty in treating cancer cells is proportional to the low oxygen partial pressure in the cancer cells. This means that in cancer radiotherapy, there are cancer cells that are resistant to radiation, and such radiation-resistant cells are irradiated with radiation under high-pressure oxygen, or are exposed to an electron-donating substance such as a 2-ditolimidazole derivative. Irradiation in the presence of a substance is supported by the ability to improve the therapeutic effect of such radiation-resistant cancer. However, there is no example in which such a causal relationship between the oxygen partial pressure and the difficulty in treatment is quantitatively determined. In order to confirm this causal relationship, the present inventors investigated the relationship between oxygen partial pressure and the difficulty of treatment. The oxygen partial pressure was measured by placing an electrode in the cancer, and the difficulty of treatment was determined by using a 20-gray irradiation for prolonging the tumor regrowth of the cancer. The results are shown in FIG. This indicates that the lower the oxygen partial pressure, the lower the growth suppression. Further, it is understood that such a difference in oxygen partial pressure is a value unique to carcinoma. Based on such findings, the present inventors have investigated the cause of the phenomenon that the difference in oxygen partial pressure is caused by carcinoma and found that the cause is the difference in expression of coagulation and fibrinolytic factors by carcinoma. Was. That is, it has been revealed that in a cancer having a strong coagulation system, a hypoxia condition is easily caused by the formation of a thrombus, and the hypoxia caused by the formation of such a thrombus causes a treatment resistance. The method of the present invention for identifying the resistance of a cancer cell to treatment is based on this finding, and uses the expression status of a coagulation / fibrinolytic factor as an index. Factors that can be used as indicators in the present invention include plasminogen,
Examples include fibrinolytic factors such as plasmin and plasminogen activator, and coagulation factors such as inhibitors of plasminogen activator. These may be further subdivided. For example, in the fibrinolytic system, u
-PA, u-PAR, t-PA, etc., and PAI-1, PAI-2, etc., for coagulation type. The expression status can be determined according to a generally known method. For example, PC with primer
R-reaction can be used as an index, and the intensity of the band can be used as an index, or the intensity of a Western blot band can be used as an index. Among these, a preferred method is to use the band density by PCR as an index. There are many known amino acid sequences of these coagulation / fibrinolysis factors or the nucleotide sequences of their RNAs, and it is sufficient to design primers based on such information and perform PCR reactions. In addition, as a sample for performing such a PCR reaction, any of a naturally occurring cancer of an animal and a biopsy specimen collected from a cancer patient can be used. These samples may be cultured cells. This is because the coagulation-fibrinolytic factor, which is a treatment-resistant factor, is specific to cancer cells and is not significantly changed by environmental factors such as culture conditions and transplantation conditions. Among such factors, cancer cells or carcinomas with higher expression of fibrinolytic factors such as plasminogen, plasmin and plasminogen activator are less likely to form thrombi, have lower therapeutic difficulty, and have lower plasminogen activator activity. Cancer cells or carcinomas with high expression of coagulation factors such as inhibitors of the above are distinguished as having high therapeutic difficulty because thrombus easily forms in cancer blood vessels and low oxygen partial pressure. Such a discrimination result is significant for characterizing cancer and formulating a treatment guideline. For example, it can also be used as an index for determining how resistant a spontaneous cancer obtained from an animal is to treatment or as a model for a treatment-resistant cancer. In addition, by screening an anticancer drug using cancer cells determined to be difficult to treat by the identification method of the present invention, an effective anticancer drug can be developed for cancers that are difficult to treat. In addition, if cancer cells obtained from a patient by biopsy have a high coagulation system in the coagulation / fibrinolysis system, it is discriminated as having high treatment resistance, and radiotherapy using a radiosensitizer or radiation and chemotherapeutic agents It is possible to formulate a therapeutic guideline such as performing therapy such as combination therapy from an early stage.
【０００７】[0007]
【実施例】以下に実施例を挙げて本発明について更に詳
細に説明を加えるが、本発明がこれら実施例にのみ限定
されないことは言うまでもない。EXAMPLES The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples.
【０００８】＜実施例１＞図１に示した癌腫（癌株）ご
との酸素分圧−腫瘍再増殖延長期間（tumor regrowth d
elay time）平面へのプロットより、酸素分圧が低く、
治療抵抗性の高い癌としてＵ８７ＭＧ株を選択し、酸素
分圧が高く、治療抵抗性が低い癌としてＡ７株を選択
し、これらのＰＡＩ−１のｍ−ＲＮＡの発現量をＲＴ−
ＰＣＲによって求めた。プライマーとしては配列式１
（センスプライマー）と配列式２（アンチセンスプライ
マー）に示される合成オリゴヌクレオチドを用いた。電
気泳動し、バンドを感光させた。写真画像を画像として
取込、バンド位置の輝度より、ＧＡＰＤＨのバンドの輝
度に対する比を求めた。結果を表１に示す。これより凝
固系であるＰＡ１の発現は、Ｕ８７ＭＧ株が優位にＡ７
より高いことがわかる。又、この電気泳動の結果を図２
に示す。Example 1 Oxygen partial pressure-tumor regrowth d for each carcinoma (cancer strain) shown in FIG.
elay time) plotted on a plane, the oxygen partial pressure is lower,
The U87MG strain was selected as a cancer with high treatment resistance, the A7 strain was selected as a cancer with high oxygen partial pressure and low treatment resistance, and the expression levels of these PAI-1 m-RNAs were determined by RT-
Determined by PCR. As a primer, sequence formula 1
(Sense primer) and a synthetic oligonucleotide represented by sequence formula 2 (antisense primer) were used. The band was exposed by electrophoresis. A photographic image was captured as an image, and the ratio of the GAPDH band luminance to the band position luminance was determined from the band position luminance. Table 1 shows the results. From this, the expression of PA1 which is a coagulation system was predominantly in A87MG strain,
It turns out that it is higher. FIG. 2 shows the results of the electrophoresis.
Shown in
【０００９】[0009]
【表１】 [Table 1]
【００１０】＜実施例２＞実施例１と同様に、配列式
３、４に示される合成オリゴヌクレオチドをプライマー
として用い、ＰＡＩ−２についてもＰＣＲ反応により確
かめた。結果を表２と図３に示す。これより凝固系であ
るＰＡＩ−１の発現は、Ｕ８７ＭＧ株が優位にＡ７より
高いことがわかる。<Example 2> In the same manner as in Example 1, PAI-2 was also confirmed by PCR using the synthetic oligonucleotides represented by Sequence Formulas 3 and 4 as primers. The results are shown in Table 2 and FIG. This shows that the expression of PAI-1 which is a coagulation system is significantly higher in the U87MG strain than in A7.
【００１１】[0011]
【表２】 [Table 2]
【００１２】＜実施例３＞Ａ７株細胞に於ける、その他
の凝固線溶系因子についてもＰＣＲによって調べた。結
果を図４に示す。これより、Ａ７株細胞においては、線
溶系因子の発現が著しく、凝固系因子の発現はあまりな
いことがわかる。この結果は図１の結果の低酸素性条件
の原因が血栓形成によるものであることを裏付けるもの
である。Example 3 Other coagulation / fibrinolytic factors in the A7 cell line were also examined by PCR. FIG. 4 shows the results. This indicates that in the A7 cell line, the expression of the fibrinolytic system factor is remarkable, and the expression of the coagulation system factor is not much. This result confirms that the hypoxic condition in the result of FIG. 1 is caused by thrombus formation.
【００１３】[0013]
【発明の効果】本発明によれば、癌治療や癌実験モデル
のキャラクタリゼーションに有用な、癌細胞の治療抵抗
性の因子を解明し、実際に適合した癌の治療抵抗性の鑑
別法を提供することができる。According to the present invention, it is possible to elucidate factors of cancer cell treatment resistance useful for characterization of cancer treatments and cancer experimental models, and to provide a method for actually matching cancer treatment resistance. can do.
【００１４】[0014]
【配列表】SEQENCE LISTING <110>NAKATSUGAWA, Shigekazu <120>癌細胞の治療抵抗性の鑑別法 <130>Ｐ２００１０２９ <160>4[Sequence List] SEQENCE LISTING <110> NAKATSUGAWA, Shigekazu <120> Method for identifying the resistance of cancer cells to treatment <130> P200129 <160> 4
【００１５】<210>1 <211>20 <212>DNA <213>Artificial Sequence <400>１ agcta tggga ttcaa gattg 1 5 10 15<210> 1 <211> 20 <212> DNA <213> Artificial Sequence <400> 1 agcta tggga ttcaa gattg 1 5 10 15
【００１６】<210>2 <211>20 <212>DNA <213>Artificial Sequence <400>2 ttcca ggatg tcgta gtaat 1 5 10 15<210> 2 <211> 20 <212> DNA <213> Artificial Sequence <400> 2 ttcca ggatg tcgta gtaat 1 5 10 15
【００１７】<210>2 <211>20 <212>DNA <213>Artificial Sequence <400>3 taagc tgttt ggtga gaagt 1 5 10 15<210> 2 <211> 20 <212> DNA <213> Artificial Sequence <400> 3 taagc tgttt ggtga gaagt 1 5 10 15
【００１８】<210>2 <211>20 <212>DNA <213>Artificial Sequence <400>4 tacat catct gtaca ggtgt 1 5 10 15<210> 2 <211> 20 <212> DNA <213> Artificial Sequence <400> 4 tacat catct gtaca ggtgt 1 5 10 15
【図１】 癌腫による酸素分圧と腫瘍再増殖延長期間の
関係を示す図である。FIG. 1 is a graph showing the relationship between the oxygen partial pressure due to carcinoma and the prolonged period of tumor regrowth.
【図２】 実施例１のＰＣＲの結果を示す図である。
（図面代用写真）FIG. 2 is a diagram showing the results of PCR in Example 1.
(Drawing substitute photo)
【図３】 実施例２のＰＣＲの結果を示す図である。
（図面代用写真）FIG. 3 is a diagram showing the results of PCR in Example 2.
(Drawing substitute photo)
【図４】 実施例３のＡ７株の細胞の凝固線溶系因子の
ＰＣＲの結果を示す図である。（図面代用写真）FIG. 4 is a diagram showing the results of PCR of a coagulation / fibrinolysis factor of the cells of the A7 strain of Example 3. (Drawing substitute photo)
Claims (4)
方法であって、前記癌細胞の凝固線溶系因子の発現状況
を指標とすることを特徴とする、癌細胞の治療に対する
抵抗性の鑑別法。1. A method for determining the resistance of a cancer cell to treatment, which comprises using the expression status of a coagulation / fibrinolytic factor of the cancer cell as an index, wherein the method comprises the steps of: Law.
クチベーター及び／又はプラスミノーゲンアクチベター
のインヒビターであることを特徴とする、請求項１に記
載の癌細胞の治療に対する抵抗性の鑑別法。2. The method according to claim 1, wherein the coagulation / fibrinolytic factor is a plasminogen activator and / or an inhibitor of a plasminogen activator. .
る、請求項１又は２に記載の癌細胞の治療に対する抵抗
性の鑑別法。3. The method according to claim 1, wherein the treatment is radiation treatment.
び／又は癌患者よりバイオプシーで得られた癌由来のも
のであることを特徴とする、請求項１〜３何れか１項に
記載の鑑別法。4. The method according to claim 1, wherein the cancer cells are derived from a naturally occurring cancer obtained from an animal and / or a cancer obtained by biopsy from a cancer patient. Differentiation method.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8942781B2 (en) | 2008-04-09 | 2015-01-27 | Universite Pierre Et Marie Curie (Paris 6) | Medical system comprising a percutaneous probe |
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2001
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8942781B2 (en) | 2008-04-09 | 2015-01-27 | Universite Pierre Et Marie Curie (Paris 6) | Medical system comprising a percutaneous probe |
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