JP2014009217A - Anti-cancer drug for breast cancer, gastric cancer, and ovarian cancer - Google Patents
Anti-cancer drug for breast cancer, gastric cancer, and ovarian cancer Download PDFInfo
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本発明は，癌の治療薬ないし薬剤の使用方法に関する。 The present invention relates to a method for using a therapeutic drug or a drug for cancer.
乳癌，胃癌及び卵巣癌は，その発生頻度が加速度的に増加している悪性腫瘍である。乳癌，胃癌及び卵巣癌を合わせた女性の乳癌による死亡数は，日本において四分の一を占めている（非特許文献１）。 Breast cancer, gastric cancer and ovarian cancer are malignant tumors whose incidence is increasing at an accelerating rate. The number of deaths due to breast cancer among women combined with breast cancer, stomach cancer and ovarian cancer accounts for a quarter in Japan (Non-patent Document 1).
乳癌，胃癌及び卵巣癌に対してタキソールをはじめとする抗癌剤が使われているが，十分な治療効果が得られているとはいえない。また，乳癌，胃癌及び卵巣癌における予後因子でもあるEGFRやHER2に対する分子標的治療薬も開発され，臨床試験が行われている（非特許文献２，３，４）。しかし，これら分子標的治療薬の明らかな有効性は，未だ実証されていない。
このように，従来の治療薬では乳癌，胃癌及び卵巣癌について十分な治療効果を得ることができず，有効な治療法は確立されていないのが現状である。
Anticancer drugs such as taxol are used for breast cancer, stomach cancer, and ovarian cancer, but it cannot be said that sufficient therapeutic effects have been obtained. In addition, molecular targeted therapeutic drugs for EGFR and HER2, which are also prognostic factors in breast cancer, gastric cancer, and ovarian cancer, have been developed and clinical trials are being conducted (Non-patent Documents 2, 3, and 4). However, the apparent effectiveness of these molecular targeted therapies has not yet been demonstrated.
As described above, conventional therapeutic agents cannot obtain a sufficient therapeutic effect for breast cancer, gastric cancer and ovarian cancer, and an effective treatment method has not been established.
また，新たな治療薬として，CRM197の開発が進められている（特許文献１，２，３）。CRM197は，乳癌等の悪性腫瘍で高発現する分子であるHB-EGF（heparin binding-epidermal growth factor-like growth factor）をターゲットとした化合物であり，HB-EGFの発現を抑制することにより，抗腫瘍作用を発揮する薬剤である。
In addition, CRM197 is being developed as a new therapeutic agent (Patent Documents 1, 2, and 3). CRM197 is a compound that targets HB-EGF (heparin binding-epidermal growth factor-like growth factor), a molecule that is highly expressed in malignant tumors such as breast cancer, and suppresses the expression of HB-EGF. It is a drug that exerts tumor action.
上記事情を背景として本発明では，乳癌，胃癌及び卵巣癌等を治療するための薬剤ないし薬剤の使用方法の提供を課題とする。 In view of the above circumstances, an object of the present invention is to provide a drug or a method for using a drug for treating breast cancer, stomach cancer, ovarian cancer, and the like.
発明者らは，HB-EGFとPPARγの関連性を見出すことにより，本発明を完成させた。 The inventors have completed the present invention by finding the relationship between HB-EGF and PPARγ.
発明者らは，動脈硬化等の脂質代謝異常に関与する分子であるOxLDL（oxidized low-density lipoprotein）が，その受容体であるCD36に結合することにより，HB-EGFが高発現する一連の経路を発見した。この発見に加え，CD36の発現調節には，PPARγ（peroxisome proliferator-activated receptor γ）が関与することが知られている。 The inventors have developed a series of pathways in which HB-EGF is highly expressed when OxLDL (oxidized low-density lipoprotein), a molecule involved in lipid metabolism abnormalities such as arteriosclerosis, binds to its receptor, CD36. I found In addition to this discovery, it is known that PPARγ (peroxisome proliferator-activated receptor γ) is involved in the regulation of CD36 expression.
これらの知見から，癌において高発現するHB-EGFについても，同様の経路が関与するのではないかと発明者らは考えた。このことから，HB-EGFを抑制する抗がん剤に加え，PPARγに対してアゴニスト活性を有する薬剤を併用して用いることにより，相乗的にHB-EGFを抑制し，顕著な抗癌作用を示すことを発明者らは発見し，本発明を完成させた。 Based on these findings, the inventors thought that a similar pathway might be involved in HB-EGF highly expressed in cancer. Therefore, in addition to the anticancer drug that suppresses HB-EGF, the combined use of drugs with agonist activity against PPARγ synergistically suppresses HB-EGF and has a remarkable anticancer effect. The inventors have discovered that they have completed and completed the present invention.
本発明は，以下の構成からなる。 The present invention has the following configuration.
本発明の第一の構成は，HB-EGF抑制薬と併用投与されて用いられることを特徴とするPPARγ作動薬である。
本発明の第二の構成は，前記HB-EGF抑制薬が，CRM197等の抗HB-EGF抗体フラグメントないし抗HB-EGF抗体のいずれか又は複数から選ばれることを特徴とする請求項１に記載のPPARγ作動薬である。
本発明の第三の構成は，前記PPARγ作動薬が，ピオグリタゾン等のチアゾリジン誘導体から選択されることを特徴とする請求項１又は２に記載のPPARγ作動薬である。
The first configuration of the present invention is a PPARγ agonist characterized by being used in combination with an HB-EGF inhibitor.
According to a second configuration of the present invention, the HB-EGF inhibitor is selected from any one or a plurality of anti-HB-EGF antibody fragments or anti-HB-EGF antibodies such as CRM197. It is a PPARγ agonist.
A third configuration of the present invention is the PPARγ agonist according to claim 1 or 2, wherein the PPARγ agonist is selected from thiazolidine derivatives such as pioglitazone.
本発明の第四の構成は，PPARγ作動薬と併用投与されて用いられることを特徴とするHB-EGF抑制薬である。
本発明の第五の構成は，前記HB-EGF抑制薬が，CRM197等の抗HB-EGF抗体フラグメントないし抗HB-EGF抗体のいずれか又は複数から選ばれることを特徴とする請求項４に記載のHB-EGF抑制薬である。
本発明の第六の構成は，前記PPARγ作動薬が，ピオグリタゾン等のチアゾリジン誘導体から選択されることを特徴とする請求項４又は５に記載のHB-EGF抑制薬である。
A fourth configuration of the present invention is an HB-EGF inhibitor characterized by being used in combination with a PPARγ agonist.
According to a fifth aspect of the present invention, the HB-EGF inhibitor is selected from any one or a plurality of anti-HB-EGF antibody fragments or anti-HB-EGF antibodies such as CRM197. It is an HB-EGF inhibitor.
The sixth constitution of the present invention is the HB-EGF inhibitor according to claim 4 or 5, wherein the PPARγ agonist is selected from thiazolidine derivatives such as pioglitazone.
本発明の第七の構成は，HB-EGF抑制薬とPPARγ作動薬を併用することにより，癌を抑制することを特徴とする薬剤の使用方法である。 The seventh configuration of the present invention is a method for using a drug characterized by suppressing cancer by using an HB-EGF inhibitor and a PPARγ agonist together.
本発明において，PPARγ作動薬とは，直接的または間接的にPPARγに作用することにより，PPARγにアゴニスト活性を有する化合物を有効成分とする薬剤として定義される。
また，本発明において，HB-EGF抑制薬とは，直接的又は間接的にHB-EGFに作用することにより，HB-EGFの発現を抑制する化合物を有効成分とする薬剤として定義される。
In the present invention, a PPARγ agonist is defined as a drug containing a compound having an agonist activity on PPARγ by acting directly or indirectly on PPARγ.
In the present invention, the HB-EGF inhibitor is defined as a drug containing a compound that suppresses the expression of HB-EGF by acting on HB-EGF directly or indirectly.
本発明により，乳癌，胃癌及び卵巣癌を治療するための薬剤および薬剤の使用方法の提供が可能となった。すなわち，HB-EGF抑制薬とPPARγ作動薬を併用して用いることにより，乳癌等のHB-EGFが高発現する癌の，より効果的な治療が期待できる。
According to the present invention, it has become possible to provide a drug for treating breast cancer, gastric cancer and ovarian cancer and a method for using the drug. That is, by using a combination of an HB-EGF inhibitor and a PPARγ agonist, more effective treatment of cancers such as breast cancer that highly express HB-EGF can be expected.
本発明のHB-EGF抑制薬およびPPARγ作動薬等について，説明を行う。 The HB-EGF inhibitor and PPARγ agonist of the present invention will be described.
本発明に用いられるHB-EGF抑制薬は，直接的又は間接的にHB-EGFに作用することにより，HB-EGFの発現を抑制する化合物を有効成分とする薬剤として定義される。
この機能を果たす限り，HB-EGF抑制薬は，特に限定する必要はなく，種々の化合物を有効成分として用いることができる。このようなHB-EGF抑制薬として，例えば，CRM197やこのプロドラッグ体を有効成分とする薬剤などが挙げられる。
The HB-EGF inhibitor used in the present invention is defined as a drug containing a compound that suppresses the expression of HB-EGF by acting on HB-EGF directly or indirectly.
As long as this function is fulfilled, the HB-EGF inhibitor need not be particularly limited, and various compounds can be used as active ingredients. Examples of such HB-EGF inhibitors include CRM197 and drugs containing this prodrug form as an active ingredient.
HB-EGF抑制薬については，有効性および安全性の観点から，HB-EGF抑制薬に応じた適切な使用方法を用いればよい。
CRM197を例に挙げると，１日あたり，0.5〜20mg/body/dayで，腹腔内投与を行うなどすればよい。この場合，月曜日から金曜日の５日間連続投与を行い，土曜日，日曜日の２日間休薬するなどして，投与間隔を調整する。また，投与対象の体重等や，後述するPPAR作動薬との組み合わせにより，適宜，調整することができる。
About the HB-EGF inhibitor, from the viewpoint of efficacy and safety, an appropriate method of use corresponding to the HB-EGF inhibitor may be used.
Taking CRM197 as an example, intraperitoneal administration may be performed at 0.5 to 20 mg / body / day per day. In this case, the administration interval is adjusted by, for example, continuous administration for 5 days from Monday to Friday, and a 2-day withdrawal from Saturday and Sunday. Moreover, it can adjust suitably according to the combination with the PPAR agonist etc. which are mentioned later and the PPAR agonist mentioned later.
本発明に用いられるPPARγ作動薬は，直接的または間接的にPPARγに作用することにより，PPARγにアゴニスト活性を有する化合物を有効成分とする薬剤として定義される。
この機能を果たす限り，PPARγ作動薬は，特に限定する必要はなく，種々の化合物を有効成分として用いることができる。このようなPPARγ作動薬として，例えば，ピオグリタゾン，トログリタゾン，ロジクリタゾンなどのチアゾリジン誘導体やこれらのプロドラッグ体などが挙げられる。
The PPARγ agonist used in the present invention is defined as a drug containing, as an active ingredient, a compound having an agonist activity in PPARγ by acting directly or indirectly on PPARγ.
As long as this function is fulfilled, the PPARγ agonist is not particularly limited, and various compounds can be used as active ingredients. Such PPARγ agonists include, for example, thiazolidine derivatives such as pioglitazone, troglitazone, and rozicritazone, and prodrugs thereof.
PPARγ作動薬については，有効性および安全性の観点から，PPARγ作動薬に応じた適切な使用方法を用いればよい。
ピオグリタゾンを例に挙げると，１日あたり，15〜45mgで，1日1回，経口投与を行えばよい。また，投与対象の体重や，前述のHB-EGF抑制薬との組み合わせにより，適宜，調整することができる。
For PPARγ agonists, an appropriate method of use depending on the PPARγ agonist may be used from the viewpoint of efficacy and safety.
Taking pioglitazone as an example, oral administration may be performed once a day at 15 to 45 mg per day. Moreover, it can adjust suitably according to the body weight of a to-be-administered object, and the combination with the above-mentioned HB-EGF inhibitor.
本発明におけるHB-EGF抑制薬ないしPPARγ作動薬については，これらを併用して用いる。
CRM197とピオグリタゾンを例に挙げると，CRM197を0.5〜20mg/body/dayで月曜から金曜日の５日間腹腔内投与を行い，土日を休薬日とする。この月曜日から日曜日までの投薬スケジュールを１クールとして，２クール行う。一方，ピオグリタゾンについては，投与量を15〜45mg/body/dayとして，同様の投薬スケジュールを４クール行う。
当然のことながら，HB-EGF抑制薬ないしPPARγ作動薬の組み合わせにより，投与量や投与間隔等を適宜調整することができる。
The HB-EGF inhibitor or PPARγ agonist in the present invention is used in combination.
For example, CRM197 and pioglitazone are given intraperitoneally for 5 days from Monday to Friday at 0.5 to 20 mg / body / day, with Saturday and Sunday as the drug holiday. This medication schedule from Monday to Sunday is 1 course and 2 courses are performed. On the other hand, for pioglitazone, the dose is 15 to 45 mg / body / day, and the same dosing schedule is conducted 4 times.
As a matter of course, the dose, the administration interval, etc. can be appropriately adjusted by a combination of an HB-EGF inhibitor or a PPARγ agonist.
以下，本発明について，実施例を用いて詳細に説明するが，当然のことながら，本発明はこの内容に限定されるものではない。
なお，以下では，必要に応じ，下記の略語を用いる。
HB-EGF：heparin binding-epidermal growth factor-like growth factor
PPARγ：peroxisome proliferator-activated receptor γ
LOX1：lectin-like oxidized LDL rexepter-1
OxLDL：oxidized low-density lipoprotein
PTZ：Pioglitazone
CRM197：cross-reacting material 197
Hereinafter, the present invention will be described in detail using examples, but the present invention is naturally not limited to this content.
In the following, the following abbreviations are used as necessary.
HB-EGF: heparin binding-epidermal growth factor-like growth factor
PPARγ: peroxisome proliferator-activated receptor γ
LOX1: lectin-like oxidized LDL rexepter-1
OxLDL: oxidized low-density lipoprotein
PTZ: Pioglitazone
CRM197: cross-reacting material 197
＜＜実験例１．卵巣癌及び良性卵巣腫瘍組織におけるHB-EGF，CD36及びLOX1の発現解析＞＞
＜方法＞
１．Informed consentの得られた卵巣癌患者組織44例及び良性卵巣腫瘍患者組織26例のRNA抽出及びcDNA合成を，TRIzolとSuperScript II reverse transcriptase（Invitrogen Corp.）を用いて行った。
２．HB-EGFと，スカベンジャー受容体であるCD36及びLOX1の発現は，TaqMan probeを用いたReal Time PCR法（Applied Biosystems）で行い，GAPDHを内在性コントロールとして解析した（mRNA Expression index＝それぞれのHB-EGF，CD36もしくはLOX1 mRNAのコピー数/GAPDH mRNAのコピー数×10000）。
３．統計学的解析はMann-Whitney検定を用い，P値は0.05以下を有意差ありとした。
<< Experimental Example 1 Expression analysis of HB-EGF, CD36 and LOX1 in ovarian cancer and benign ovarian tumor tissues >>
<Method>
1. RNA extraction and cDNA synthesis of 44 ovarian cancer patient tissues and 26 benign ovarian tumor patient tissues with informed consent were performed using TRIzol and SuperScript II reverse transcriptase (Invitrogen Corp.).
2. Expression of HB-EGF and scavenger receptors CD36 and LOX1 was performed by Real Time PCR method using TaqMan probe (Applied Biosystems) and analyzed using GAPDH as an endogenous control (mRNA Expression index = each HB- EGF, CD36 or LOX1 mRNA copy number / GAPDH mRNA copy number x 10000).
3. For statistical analysis, Mann-Whitney test was used, and P value was 0.05 or less.
＜結果＞
１．結果を図１に示す。
(1) HB-EGFのmRNA発現量は，卵巣癌患者で288.60±475.99，良性卵巣腫瘍患者で16.55±15.47と，卵巣癌患者で有意に高い値を示していた（p＜0.001）。
(2) また，CD36のmRNA発現量は，卵巣癌患者で89.48±148.03，良性卵巣腫瘍患者で13.40±7.93と，卵巣癌患者で有意に高い値を示していた（p＜0.05）。
(3) 一方，LOX1のmRNA発現量は，卵巣癌患者で10.06±19.02，良性卵巣腫瘍患者で3.07±2.19であり，統計学的に有意差は認められなかった。
(4) 卵巣癌患者におけるCD36のmRNA発現量はLOX1のmRNA発現量と比較し有意に高い値を示していた（p＜0.001）。
<Result>
1. The results are shown in FIG.
(1) The mRNA expression level of HB-EGF was 288.60 ± 475.99 in ovarian cancer patients and 16.55 ± 15.47 in benign ovarian tumor patients, showing significantly higher values in ovarian cancer patients (p <0.001).
(2) The mRNA expression level of CD36 was 89.48 ± 148.03 in ovarian cancer patients and 13.40 ± 7.93 in benign ovarian tumor patients, significantly higher in ovarian cancer patients (p <0.05).
(3) On the other hand, the mRNA expression level of LOX1 was 10.06 ± 19.02 in ovarian cancer patients and 3.07 ± 2.19 in benign ovarian tumor patients, and there was no statistically significant difference.
(4) The expression level of CD36 mRNA in ovarian cancer patients was significantly higher than that of LOX1 (p <0.001).
＜＜実験例２．PTZによるCD36発現抑制効果＞＞
１．卵巣癌細胞株MCASを，6cmの培養皿に5×105個ずつ播種し，PTZを1nM，10nM，100nM，1μM，10μMの濃度でそれぞれ添加し，72時間培養後にRNA抽出及びcDNA合成をTRIzolとSuperScript II reverse transcriptase (Invitrogen Corp.）を用いて行った。
２．CD36の発現は特異的なプライマーを用いたPCR法で行った。
<< Experimental Example 2. Inhibition of CD36 expression by PTZ >>
1. 5 × 10 5 ovarian cancer cell lines MCAS are seeded on a 6 cm culture dish, PTZ is added at a concentration of 1 nM, 10 nM, 100 nM, 1 μM, and 10 μM, respectively. After 72 hours of incubation, RNA extraction and cDNA synthesis are performed with TRIzol. And SuperScript II reverse transcriptase (Invitrogen Corp.).
2. Expression of CD36 was performed by PCR using specific primers.
＜結果＞
１．結果を図２に示す。
２．PTZの濃度が０から100nMの間では，PTZ濃度が増加するにつれ，CD36の発現が増加していた。しかしながら，PTZの濃度が1μMを超えると，CD36の発現はほとんど見られなかった。
３．このことから，PTZの濃度が一定濃度に達すると，CD36の発現が抑制されることが分かった。よって，PPARγアゴニストにより，CD36の発現を抑制しうることが分かった。
<Result>
1. The results are shown in FIG.
2. When the PTZ concentration was between 0 and 100 nM, the expression of CD36 increased as the PTZ concentration increased. However, when the PTZ concentration exceeded 1 μM, CD36 expression was hardly observed.
3. This indicates that the expression of CD36 is suppressed when the PTZ concentration reaches a certain level. Therefore, it was found that the expression of CD36 can be suppressed by a PPARγ agonist.
＜＜実験例３．In vitroにおけるPTZとCRM197の併用による抗腫瘍効果の確認＞＞
１．卵巣癌細胞株MCASを6cmの培養皿に5×105個ずつ播種し，PTZを1μM，CRM197を10μg/mLの濃度でそれぞれ添加し，72時間培養した。
２．アポトーシスの同定は細胞を回収し4％パラホルムアルデヒドと70％エタノールで固定した後，TdT (MEBSTAIN Apoptosis Kit Direct, MBL, Co.)を37℃で1時間反応させ，アポトーシス陽性細胞をフローサイトメトリー (Becton Dickinson, FACScalibur) で解析した。
３．統計学的解析はMann-Whitney検定を用い，P値は 0.05以下を有意差ありとした。
<< Experimental Example 3. Confirmation of antitumor effect by combined use of PTZ and CRM197 in vitro >>
1. 5 × 10 5 ovarian cancer cell lines MCAS were seeded on a 6 cm culture dish, PTZ was added at 1 μM and CRM197 was added at a concentration of 10 μg / mL, and cultured for 72 hours.
2. Apoptosis was identified by collecting cells, fixing with 4% paraformaldehyde and 70% ethanol, and then reacting with TdT (MEBSTAIN Apoptosis Kit Direct, MBL, Co.) for 1 hour at 37 ° C. Becton Dickinson, FACScalibur).
3. For statistical analysis, Mann-Whitney test was used, and P value of 0.05 or less was considered significant.
＜結果＞
１．結果を図３に示す。
(1) PTZでは，アポトーシス陽性細胞が1.02±0.78％と，ほとんど見られなかった。
(2) また，CRM197では，アポトーシス陽性細胞が10.11±1.24％であり，PTZと比較して，有意なアポトーシス誘導効果が認められた。
(3) さらに，PTZとCRM197の併用では，アポトーシス陽性細胞が18.88±3.35％であり，CRM197単独と比較しても，有意なアポトーシス誘導効果が認められた。
２．この結果から，In vitroにおいて，PTZとCRM197を併用することにより，CRM197単独の使用と比較して，より強いアポトーシス誘導効果が見られることが分かった。
<Result>
1. The results are shown in FIG.
(1) In PTZ, apoptosis-positive cells were rarely seen at 1.02 ± 0.78%.
(2) In CRM197, apoptosis-positive cells were 10.11 ± 1.24%, and a significant apoptosis-inducing effect was observed compared to PTZ.
(3) Furthermore, when PTZ and CRM197 were used in combination, apoptosis-positive cells were 18.88 ± 3.35%, and a significant apoptosis-inducing effect was observed compared to CRM197 alone.
2. From these results, it was found that the use of PTZ and CRM197 in vitro has a stronger apoptosis-inducing effect than CRM197 alone.
＜＜実験例４．In vivoにおけるPTZとCRM197の併用による抗腫瘍効果の確認＞＞
１．卵巣癌細胞株MCASをNOD/SCIDマウスの背部皮下に1匹あたり5×106個ずつ播種し，腫瘍形成を認めた後，PTZを40mg/kgで週に5日間連続投与を４週間経口投与，CRM197を1mg/kgで10日間連続腹腔内投与した。
２．腫瘍の長径・短径を測定により腫瘍体積量を算出（長径×長径×短径／２）し，造腫瘍能抑制効果を評価した。
３．統計学的解析はMann-Whitney検定を用い，P値は0.05以下を有意差ありとした。
<< Experimental Example 4. Confirmation of antitumor effect by combined use of PTZ and CRM197 in vivo >>
1. Ovarian cancer cell line MCAS was inoculated subcutaneously at the back of NOD / SCID mice at 5 × 10 6 cells per mouse. After tumor formation was observed, PTZ was administered at 40 mg / kg for 5 consecutive days per week for 4 weeks. , CRM197 was administered intraperitoneally for 10 days at 1 mg / kg.
2. Tumor volume was calculated by measuring the major axis and minor axis of the tumor (major axis × major axis × minor axis / 2), and the tumorigenicity inhibitory effect was evaluated.
3. For statistical analysis, Mann-Whitney test was used, and P value was 0.05 or less.
＜結果＞
１．結果を図４に示す。
(1) control群とPTZ投与群では，腫瘍体積量が経時的に増加した。
(2) 一方，CRM197投与群では，これらcontrol群およびPTZ投与群と比較して，腫瘍体積量の増加が，有意に抑制された。
(3) さらに，PTZ+CRM197投与群では，control群，PTZ投与群，CRM197投与群と比較して，腫瘍体積量の増加が，有意に抑制された。
２．この結果から，In vivoにおいても，PTZとCRM197を併用することにより，CRM197単独の使用と比較して，より強い腫瘍抑制効果が見られることが分かった。
<Result>
1. The results are shown in FIG.
(1) In the control group and the PTZ administration group, the tumor volume increased with time.
(2) On the other hand, the increase in tumor volume was significantly suppressed in the CRM197 administration group compared to the control and PTZ administration groups.
(3) Furthermore, in the PTZ + CRM197 administration group, the increase in tumor volume was significantly suppressed compared to the control group, PTZ administration group, and CRM197 administration group.
2. From these results, it was found that even in vivo, the combined use of PTZ and CRM197 shows a stronger tumor suppressive effect than the use of CRM197 alone.
Claims (7)
PPARγ agonist, used in combination with HB-EGF inhibitor
2. The PPARγ agonist according to claim 1, wherein the HB-EGF inhibitor is selected from one or a plurality of anti-HB-EGF antibody fragments or anti-HB-EGF antibodies such as CRM197.
The PPARγ agonist according to claim 1 or 2, wherein the PPARγ agonist is selected from thiazolidine derivatives such as pioglitazone.
HB-EGF inhibitor characterized by being used in combination with PPARγ agonist
5. The HB-EGF inhibitor according to claim 4, wherein the HB-EGF inhibitor is selected from one or a plurality of anti-HB-EGF antibody fragments or anti-HB-EGF antibodies such as CRM197.
The HB-EGF inhibitor according to claim 4 or 5, wherein the PPARγ agonist is selected from thiazolidine derivatives such as pioglitazone.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2001510462A (en) * | 1996-12-11 | 2001-07-31 | ダナ・フアーバー・キヤンサー・インスチチユート | Methods and pharmaceutical compositions for inhibiting the growth of tumor cells |
| JP2006232761A (en) * | 2005-02-25 | 2006-09-07 | Osaka Univ | Anticancer agent |
| WO2006137398A1 (en) * | 2005-06-21 | 2006-12-28 | The Research Foundation For Microbial Diseases Of Osaka University | Therapeutic agent for cancer |
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