JP2021195309A - Agents for treating pancreatic cancer - Google Patents
Agents for treating pancreatic cancer Download PDFInfo
- Publication number
- JP2021195309A JP2021195309A JP2020100937A JP2020100937A JP2021195309A JP 2021195309 A JP2021195309 A JP 2021195309A JP 2020100937 A JP2020100937 A JP 2020100937A JP 2020100937 A JP2020100937 A JP 2020100937A JP 2021195309 A JP2021195309 A JP 2021195309A
- Authority
- JP
- Japan
- Prior art keywords
- pancreatic cancer
- gemcitabine
- paclitaxel
- sirolimus
- therapeutic agent
- 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
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Abstract
Description
本発明は、膵癌を有効に治療するための薬剤に関するものである。 The present invention relates to a drug for effectively treating pancreatic cancer.
日本における膵癌による死亡数は増加の一途を辿っており、国立がん研究センターのがん登録・統計によれば、２０１８年には年間４万人が罹患し、３５，０００人が死亡しており、臓器別死亡者数では第４位となっている。Ｓｔａｇｅ ＩＶ期の５年生存率は１．４％であり、Ｓｔａｇｅ ＩＩＩ期でも６．４％、全Ｓｔａｇｅでは９％と、膵癌の予後は非常に悪い。その理由の一つとして、膵臓周囲の後腹膜などへの直接浸潤や、肝臓・肺・リンパ節への転移を有する症例が多いため、手術適応となる症例が全体の約３０％に過ぎないことが挙げられる。また、分子標的薬など有効性の高い新規治療薬の開発が遅れていることも、膵癌の予後が悪い理由の一つである。 The number of deaths from pancreatic cancer in Japan is steadily increasing, and according to the Cancer Registration and Statistics of the National Cancer Center, 40,000 people will be affected annually and 35,000 will die in 2018. It ranks fourth in the number of deaths by organ. The 5-year survival rate for Stage IV is 1.4%, 6.4% for Stage III, and 9% for all Stages, and the prognosis for pancreatic cancer is very poor. One of the reasons is that there are many cases with direct infiltration into the retroperitoneum around the pancreas and metastasis to the liver, lungs, and lymph nodes, so only about 30% of the cases are indicated for surgery. Can be mentioned. In addition, the delay in the development of highly effective new therapeutic agents such as molecular-targeted drugs is also one of the reasons for the poor prognosis of pancreatic cancer.
膵癌に対する化学療法は、切除不能例に対する治療と、術後補助療法の２つに分類できる。切除不能例に対する治療では、オキサリプラチン＋イリノテカン＋フルオロウラシル＋レボホリナートカルシウムを用いるＦＯＬＦＩＲＩＮＯＸ療法と、ゲムシタビン（ＧＥＭ）＋ナブパクリタキセル併用療法が第一選択である。手術の補助療法としては、ＴＳ−１（テガフール・ギメラシル・オテラシルカリウム配合剤）による単独治療が第一選択となっている。 Chemotherapy for pancreatic cancer can be divided into two categories: treatment for unresectable cases and adjuvant therapy. For treatment of unresectable cases, FOLFIRINOX therapy with oxaliplatin + irinotecan + fluorouracil + levofolinate calcium and gemcitabine (GEM) + nabpaclitaxel combination therapy are the first choice. As an adjuvant therapy for surgery, monotherapy with TS-1 (tegafur / gimeracil / oteracil potassium combination drug) is the first choice.
膵癌取り扱い規約によれば、遠隔転移は無いが切除不能である局所進行膵癌の一次化学療法としては、ゲムシタビンの単独療法、ＴＳ１の単独療法、ＦＯＬＦＩＲＩＮＯＸ療法、およびゲムシタビン＋ナブパクリタキセル併用療法が弱い推奨レベルＣで提案されており、遠隔転移のある進行膵癌に推奨される一次化学療法としては、ＦＯＬＦＩＲＩＮＯＸ療法、およびゲムシタビン＋ナブパクリタキセル併用療法が強い推奨レベルＡで推奨されている。しかしながら、ゲムシタビン単独療法の生存期間の中央値５．７ヶ月を基準とすると、ＴＳ１単独療法では９．７ヶ月（ハザード比０．９６）、ＦＯＬＦＩＲＩＮＯＸ療法では１１．１ヶ月（ハザード比０．５７）、ゲムシタビン＋ナブパクリタキセル併用療法では８．７ヶ月（ハザード比０．７２）と、比較的長い。生存期間の延長の観点ではＦＯＬＦＩＲＩＮＯＸ療法が最も優れているが、発熱性好中球減少症をはじめとした強い血液毒性が日本人で多く認められることを考慮すると、益のアウトカムと害のアウトカムは伯仲している。結論として、現状ではゲムシタビン＋ナブパクリタキセル併用療法とＦＯＬＦＩＲＩＮＯＸ療法の間に優劣はつけられない。 According to the Pancreatic Cancer Handling Regulations, gemcitabine monotherapy, TS1 monotherapy, FOLFIRINOX therapy, and gemcitabine + nabpaclitaxel combination therapy are weakly recommended as first-line chemotherapy for locally advanced pancreatic cancer that has no distant metastasis but is unresectable. FOLFIRINOX therapy and gemcitabine plus nabpaclitaxel combination therapy are recommended at strongly recommended level A as the first-line chemotherapy proposed in C and recommended for advanced pancreatic cancer with distant metastasis. However, based on the median survival of 5.7 months for gemcitabine monotherapy, TS1 monotherapy is 9.7 months (hazard ratio 0.96) and FOLFIRINOX therapy is 11.1 months (hazard ratio 0.57). , Gemcitabine + nab-paclitaxel combination therapy is 8.7 months (hazard ratio 0.72), which is relatively long. FOLFIRINOX therapy is the best in terms of prolonging survival, but given that strong hematological toxicity, including febrile neutropenia, is common in Japanese, the outcomes of benefit and harm are I am in a relationship. In conclusion, at present, there is no superiority or inferiority between gemcitabine + nab-paclitaxel combination therapy and FOLFIRINOX therapy.
消化器癌の中でも、胃癌・大腸癌・肝臓癌に対する新規治療薬の治験が欧米を中心にして行われているが、膵癌に対する治験は少ない。ゲムシタビン＋ナブパクリタキセル併用療法とＦＯＬＦＩＲＩＮＯＸ療法との間に優劣はつけられない問題を解決するために、副作用の頻度を増やすことなく有効性に優れた新たな療法を早急に臨床の現場に実用化することが重要である。 Among gastrointestinal cancers, clinical trials of new therapeutic agents for gastric cancer, colorectal cancer, and liver cancer are being conducted mainly in Europe and the United States, but clinical trials for pancreatic cancer are few. In order to solve the problem that there is no difference between gemcitabine + nab-paclitaxel combination therapy and FOLFIRINOX therapy, a new highly effective therapy will be immediately put into practical use in clinical practice without increasing the frequency of side effects. This is very important.
上記の通り、膵癌の予後が悪い理由として、膵癌細胞の浸潤転移性が高いことが挙げられる。そこで本発明者は、膵癌細胞において、ヒトインスリン様成長因子２ｍＲＮＡ結合タンパク質３（ＩＧＦ２ＢＰ３）がｍＲＮＡと複合体を形成し、カイネシンモータータンパク質であるＫＩＦ２０Ａにより膵癌細胞の運動性や浸潤性に必須である葉状仮足まで運搬され、ｍＲＮＡの局所翻訳に関与することを見出し、ＩＧＦ２ＢＰ３の一部のペプチドを膵癌細胞浸潤転移抑制ワクチンとして開発している（特許文献１）。また、本発明者は、ＩＧＦ２ＢＰ３に対するｓｉＲＮＡを膵癌細胞浸潤転移阻害剤として開発している（特許文献２）。更に本発明者は、ＥＲＫ１／２阻害薬および／またはｍＴＯＲ阻害剤を有効成分として含有する膵癌細胞の浸潤転移抑制剤を開発している（特許文献３）。また、本発明者らは、低分子二本鎖ＲＮＡ（ｓｉＲＮＡ）を用いてｍＴＯＲの発現を抑制することにより、膵癌細胞の後腹膜浸潤、腹膜播種、および肺への転移が抑制されることを明らかにしている（非特許文献１）。
As described above, the reason why the prognosis of pancreatic cancer is poor is that the infiltration metastasis of pancreatic cancer cells is high. Therefore, the present inventor forms a complex with human insulin-
上述したように、予後の悪い膵癌を有効に治療可能な手段が切望されている。そこで本発明は、膵癌を有効に治療するための薬剤を提供することを目的とする。 As described above, there is an urgent need for a means capable of effectively treating pancreatic cancer having a poor prognosis. Therefore, an object of the present invention is to provide a drug for effectively treating pancreatic cancer.
本発明者は、上記課題を解決するために鋭意研究を重ねた。その結果、特定の有効成分を組み合わせることにより、膵癌を有効に治療できることを見出して、本発明を完成した。
以下、本発明を示す。
The present inventor has conducted extensive research to solve the above problems. As a result, they have found that pancreatic cancer can be effectively treated by combining specific active ingredients, and completed the present invention.
Hereinafter, the present invention will be shown.
［１］ シロリムス、およびゲムシタビンまたはＴＳ−１を有効成分として含有することを特徴とする膵癌治療剤。
［２］ 上記ゲムシタビンを含有し、更にパクリタキセルを有効成分として含有する上記［１］に記載の膵癌治療剤。
［３］ 上記パクリタキセルがナブパクリタキセルである上記［２］に記載の膵癌治療剤。
［４］ シロリムスを含む経口製剤、およびゲムシタビンを含む注射用製剤またはＴＳ−１を含む経口製剤を含有する上記［１］〜［３］のいずれかに記載の膵癌治療剤。
［５］ 上記ゲムシタビンを含む注射用製剤を含有し、更にパクリタキセルを含む注射用製剤を含有する上記［４］に記載の膵癌治療剤。
[1] A pancreatic cancer therapeutic agent containing sirolimus and gemcitabine or TS-1 as an active ingredient.
[2] The pancreatic cancer therapeutic agent according to the above [1], which contains the above-mentioned gemcitabine and further contains paclitaxel as an active ingredient.
[3] The pancreatic cancer therapeutic agent according to the above [2], wherein the paclitaxel is nab-paclitaxel.
[4] The pancreatic cancer therapeutic agent according to any one of the above [1] to [3], which comprises an oral preparation containing sirolimus, an injectable preparation containing gemcitabine, or an oral preparation containing TS-1.
[5] The pancreatic cancer therapeutic agent according to the above [4], which contains the above-mentioned injectable preparation containing gemcitabine and further contains the above-mentioned injectable preparation containing paclitaxel.
本発明に係る膵癌治療剤は、膵癌細胞の運動性と浸潤性を効果的に抑制し、結果として膵癌細胞の浸潤転移を効果的に抑制することができる。よって、例えば膵癌の手術による除去後、除去しきれなかった膵癌細胞を腹腔内に封じ込めることが可能になると考えられる。また、膵癌細胞の増殖も抑制することができる。実際、本発明に係る膵癌治療剤が、既存の治療剤に比べて膵癌細胞の増殖を有意に抑制することができるのみならず、膵癌細胞を壊死させ得ることが動物実験にて実証されている。よって本発明は、膵癌に対する実用的で新たな治療手段として非常に有用である。 The pancreatic cancer therapeutic agent according to the present invention can effectively suppress the motility and infiltration of pancreatic cancer cells, and as a result, can effectively suppress the infiltration metastasis of pancreatic cancer cells. Therefore, for example, after removal of pancreatic cancer by surgery, it is considered possible to contain pancreatic cancer cells that could not be completely removed in the abdominal cavity. It can also suppress the growth of pancreatic cancer cells. In fact, it has been demonstrated in animal experiments that the therapeutic agent for pancreatic cancer according to the present invention can not only significantly suppress the growth of pancreatic cancer cells as compared with existing therapeutic agents, but also can necrotize pancreatic cancer cells. .. Therefore, the present invention is very useful as a practical and new therapeutic means for pancreatic cancer.
本発明に係る膵癌治療剤は、シロリムス、およびゲムシタビンまたはＴＳ−１を有効成分として含有する。なお、本開示において「有効成分として含有する」とは、成分がその効果を示すに十分な量で含まれることを意味する。 The pancreatic cancer therapeutic agent according to the present invention contains sirolimus and gemcitabine or TS-1 as active ingredients. In the present disclosure, "containing as an active ingredient" means that the ingredient is contained in an amount sufficient to exhibit its effect.
シロリムスは下記構造を有する化合物であり、その化学名は（１Ｒ，９Ｓ，１２Ｓ，１５Ｒ，１６Ｅ，１８Ｒ，１９Ｒ，２１Ｒ，２３Ｓ，２４Ｅ，２６Ｅ，２８Ｅ，３０Ｓ，３２Ｓ，３５Ｒ）−１，１８−ジヒドロキシ−１２｛−（１Ｒ）−２［−（１Ｓ，３Ｒ，４Ｒ）−４−ヒドロキシ−３−メトキシシクロヘキシル］−１−メチルエチル｝−１９，３０−ジメトキシ−１５，１７，２１，２３，２９，３５−ヘキサメチル−１１，３６−ジオキサ−４−アザトリシクロ［３０．３．１．０４，９］ヘキサトリアコンタ−１６，２４，２６，２８−テトラエン−２，３，１０，１４，２０−ペンタオンである。シロリムスは、細胞の***、増殖、生存などを調節する哺乳類ラパマイシン標的タンパク質（ｍＴＯＲ：ｍａｍｍａｌｉａｎ ｔａｒｇｅｔ ｏｆ ｒａｐａｍｙｃｉｎ）の作用を阻害し、免疫抑制作用も有し、日本ではリンパ脈管筋腫症の治療剤の有効成分として承認されている。 Silolimus is a compound having the following structure, and its chemical names are (1R, 9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28E, 30S, 32S, 35R) -1,18-. Dihydroxy-12 {-(1R) -2 [-(1S, 3R, 4R) -4-hydroxy-3-methoxycyclohexyl] -1-methylethyl} -19,30-dimethoxy-15,17,21,23 29,35-Hexamethyl-11,36-dioxa-4-azatricyclo [30.3.1.04,9] Hexatriaconta-16,24,26,28-Tetraene-2,3,10,14,20- It is pentaon. Sirolimus inhibits the action of mammalian target protein (mTOR: mammarin target of rapamycin) that regulates cell division, proliferation, survival, etc., and also has an immunosuppressive action. In Japan, it is a therapeutic agent for lymphangioleiomyomatosis. Approved as an active ingredient.
シロリムスの投与量は、患者の重篤度、体重、症状、性別、年齢などに応じて適宜調整すればよいが、例えば、１日あたり１ｍｇ以上、１０ｍｇ以下とすることができる。当該投与量は、２ｍｇ／日以上が好ましく、また、８ｍｇ／日以下が好ましく、６ｍｇ／日以下または４ｍｇ／日以下がより好ましい。かかる観点から、１製剤、例えば１錠剤あたりのシロリムスの含有量は０．５ｍｇ以上、２ｍｇ以下とすることが好ましく、１±０．０１ｍｇとすることがより好ましい。投与頻度も同様に適宜調整すればよく、例えば３日に１回から１日に２回とすることができ、１日に１回が好ましい。また、休薬日や休薬期間を設けてもよい。 The dose of sirolimus may be appropriately adjusted according to the severity, weight, symptom, gender, age, etc. of the patient, and may be, for example, 1 mg or more and 10 mg or less per day. The dose is preferably 2 mg / day or more, preferably 8 mg / day or less, and more preferably 6 mg / day or less or 4 mg / day or less. From this viewpoint, the content of sirolimus per preparation, for example, one tablet is preferably 0.5 mg or more and 2 mg or less, and more preferably 1 ± 0.01 mg. The administration frequency may be appropriately adjusted in the same manner, and may be, for example, once every three days to twice a day, preferably once a day. In addition, a drug holiday or a drug holiday may be provided.
ゲムシタビンは下記構造を有する化合物であり、その化学名は（＋）−２’−デオキシ−２’，２’−ジフルオロシチジン一塩酸塩、または２’−デオキシ−２’，２’−ジフルオロ−シチジン一塩酸塩である。ゲムシタビンは、細胞内に取り込まれた後にリン酸化され、ＤＮＡ合成を阻害することにより抗腫瘍効果を発揮する。 Gemcitabine is a compound having the following structure, and its chemical name is (+)-2'-deoxy-2', 2'-difluorocystidine monohydrochloride, or 2'-deoxy-2', 2'-difluoro-cytidine. It is a monohydrochloride. Gemcitabine exerts an antitumor effect by being taken up into cells and then phosphorylated and inhibiting DNA synthesis.
ゲムシタビンの投与量は、患者の重篤度、症状、体重、性別、年齢などに応じて適宜調整すればよいが、例えば、患者の体表面積あたりの投与量として、１日あたり５００ｍｇ／ｍ2以上、２０００ｍｇ／ｍ2以下とすることができ、通常は１０００±１０ｍｇ／ｍ2、手術不能の場合には１２５０±１２．５ｍｇ／ｍ2が好ましい。かかる観点から、１製剤、例えば１注射用製剤あたりのゲムシタビンの含有量は１００ｍｇ以上、２ｇ以下とすることが好ましく、２００±２ｍｇや１０００±１０ｍｇとすることがより好ましい。投与頻度も同様に適宜調整すればよく、例えば０．５回／週以上、２回／週以下とすることができ、１回／週が好ましい。また、２週間以上、４週間以下投与した後、１週間休薬してもよく、かかるサイクルを繰り返してもよい。 The dose of gemcitabine may be appropriately adjusted according to the severity, symptoms, weight, sex, age, etc. of the patient. For example, the dose per body surface area of the patient is 500 mg / m 2 or more per day. , 2000 mg / m 2 or less, usually 1000 ± 10 mg / m 2 , preferably 1250 ± 12.5 mg / m 2 in the case of inoperability. From this viewpoint, the content of gemcitabine per preparation, for example, the preparation for injection, is preferably 100 mg or more and 2 g or less, and more preferably 200 ± 2 mg or 1000 ± 10 mg. The administration frequency may be appropriately adjusted in the same manner, and may be, for example, 0.5 times / week or more and 2 times / week or less, preferably once / week. Further, after administration for 2 weeks or more and 4 weeks or less, the drug may be withdrawn for 1 week, or the cycle may be repeated.
ＴＳ−１は、テガフール、ギメラシルおよびオテラシルカリウムを含有する製剤である。テガフールは下記構造を有する化合物であり、その化学名は５−フルオロ−１−［（２ＲＳ）−テトラヒドロフラン−２−イル］ウラシルである。ギメラシルは下記構造を有する化合物であり、その化学名は５−クロロ−２，４−ジヒドロキシピリジンである。オテラシルカリウムは下記構造を有する化合物であり、その化学名は１，２，３，４−テトラヒドロ−２，４−ジオキソ−１，３，５−トリアジン−６−カルボン酸モノカリウム塩である。 TS-1 is a preparation containing tegafur, gimeracil and oteracil potassium. Tegafur is a compound having the following structure, and its chemical name is 5-fluoro-1-[(2RS) -tetrahydrofuran-2-yl] uracil. Gimeracil is a compound having the following structure, and its chemical name is 5-chloro-2,4-dihydroxypyridine. Oteracil potassium is a compound having the following structure, and its chemical name is 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylic acid monopotassium salt.
ＴＳ−１の抗腫瘍効果は、テガフール由来の５−フルオロウラシルに基づく。ギメラシルは、主に肝に多く分布する５−ＦＵ異化代謝酵素ＤＰＤを選択的に阻害することによって、テガフールから生ずる５−フルオロウラシルの濃度低下を抑制する。その結果、腫瘍内における５−フルオロウラシルのリン酸化代謝物である５−フルオロヌクレオチドが高濃度で持続し、抗腫瘍効果が増強される。オテラシルカリウムは、消化管組織においてオロト酸ホスホリボシルトランスフェラーゼを選択的に拮抗阻害して、５−フルオロウラシルから５−フルオロヌクレオチドへの生成を選択的に抑制することにより、消化器毒性を軽減すると考えられる。 The antitumor effect of TS-1 is based on 5-fluorouracil derived from tegafur. Gimeracil suppresses the decrease in the concentration of 5-fluorouracil generated from tegafur by selectively inhibiting the 5-FU catabolic enzyme DPD, which is mainly distributed in the liver. As a result, 5-fluoronucleotide, which is a phosphorylated metabolite of 5-fluorouracil in the tumor, is maintained at a high concentration, and the antitumor effect is enhanced. Oteracil potassium is thought to reduce gastrointestinal toxicity by selectively antagonisticizing orotic acid phosphoribosyltransferase in the gastrointestinal tissue and selectively suppressing the production of 5-fluorouracil to 5-fluoronucleotide. Be done.
ＴＳ−１製剤におけるテガフール、ギメラシルおよびオテラシルカリウムの割合は適宜調整すればよいが、例えば、テガフールに対するギメラシルの割合を０．２質量倍以上、０．４質量倍とすることができ、０．３±０．００３質量倍とすることが好ましく、テガフールに対するオテラシルカリウムの割合を０．５質量倍以上、１．５質量倍以下とすることができ、１±０．０１質量倍とすることが好ましい。 The ratios of tegafur, gimeracil and oteracil potassium in the TS-1 preparation may be appropriately adjusted. For example, the ratio of gimeracil to tegafur can be 0.2% by mass or more and 0.4% by mass. The ratio of oteracil potassium to tegafur can be preferably 0.5 mass times or more and 1.5 mass times or less, and 1 ± 0.01 mass times. Is preferable.
ＴＳ−１の投与量は、患者の重篤度、症状、体重、性別、年齢などに応じて適宜調整すればよいが、例えば、ＴＳ−１に含まれるテガフールの量として、１回あたり２０ｍｇ以上、８０ｍｇ以下とすることができ、４０ｍｇ以上、７５ｍｇ以下が好ましい。かかる観点から、１製剤、例えばＴＳ−１製剤あたりのテガフールの含有量は１０ｍｇ以上、５０ｍｇ以下とすることが好ましく、２０±０．２ｍｇや２５±０．２５ｍｇとすることがより好ましい。投与頻度も同様に適宜調整すればよく、例えば１回／日以上、４回／日週以下とすることができ、２回／日が好ましい。また、２０日以上、４０日以下、好ましくは２８±１日投与した後、１０日以上、２０日間、好ましくは１４±１日休薬してもよく、かかるサイクルを繰り返してもよい。 The dose of TS-1 may be appropriately adjusted according to the severity, symptoms, weight, gender, age, etc. of the patient. For example, the amount of tegafur contained in TS-1 is 20 mg or more at one time. , 80 mg or less, preferably 40 mg or more and 75 mg or less. From this viewpoint, the content of tegafur per preparation, for example, TS-1 preparation, is preferably 10 mg or more and 50 mg or less, and more preferably 20 ± 0.2 mg or 25 ± 0.25 mg. The administration frequency may be appropriately adjusted in the same manner, and may be, for example, once / day or more, four times / day or less, preferably twice / day. Further, after administration for 20 days or more and 40 days or less, preferably 28 ± 1 day, the drug may be withdrawn for 10 days or more, 20 days, preferably 14 ± 1 day, and such a cycle may be repeated.
本発明においてゲムシタビンを用いる場合には、パクリタキセルを併用することが好ましい。パクリタキセルは下記構造を有する化合物であり、その化学名は（−）−（１Ｓ，２Ｓ，３Ｒ，４Ｓ，５Ｒ，７Ｓ，８Ｓ，１０Ｒ，１３Ｓ）−４，１０−ジアセトキシ−２−ベンゾイルオキシ−５，２０−エポキシ−１，７−ジヒドロキシ−９−オキソタクス−１１−エン−１３−イル（２Ｒ，３Ｓ）−３−ベンゾイルアミノ−２−ヒドロキシ−３−フェニルプロピオン酸である。パクリタキセルは、微小管タンパク質の重合を促進して微小管の安定化と過剰形成を引き起こし、紡錘体の機能を障害することにより細胞***を阻害して、抗腫瘍活性を発揮する。 When gemcitabine is used in the present invention, it is preferable to use paclitaxel in combination. Paclitaxel is a compound having the following structure, and its chemical name is (-)-(1S, 2S, 3R, 4S, 5R, 7S, 8S, 10R, 13S) -4,10-diacetoxy-2-benzoyloxy-5. , 20-Epoxy-1,7-Dihydroxy-9-oxotax-11-en-13-yl (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenylpropionic acid. Paclitaxel promotes the polymerization of microtubule proteins to stabilize and hyperform microtubules, and impairs the function of the mitotic spindle to inhibit cell division and exert antitumor activity.
パクリタキセルの投与量は、患者の重篤度、症状、体重、性別、年齢などに応じて適宜調整すればよいが、例えば、患者の体表面積あたりの投与量として、１日あたり５０ｍｇ／ｍ2以上、２００ｍｇ／ｍ2以下とすることができ、１２５±１．２５ｍｇ／ｍ2が好ましい。かかる観点から、１製剤、例えば１注射用製剤あたりのパクリタキセルの含有量は５０ｍｇ以上、２００ｍｇ以下とすることが好ましく、１００±１ｍｇとすることがより好ましい。投与頻度も同様に適宜調整すればよく、例えば０．５回／週以上、２回／週以下とすることができ、１回／週が好ましい。また、２週間以上、５週間以下投与した後、１週間休薬してもよく、かかるサイクルを繰り返してもよい。 The dose of paclitaxel may be appropriately adjusted according to the severity, symptoms, body weight, sex, age, etc. of the patient. For example, the dose per body surface area of the patient is 50 mg / m 2 or more per day. , 200 mg / m 2 or less, preferably 125 ± 1.25 mg / m 2. From this point of view, the content of paclitaxel per preparation, for example, the preparation for injection, is preferably 50 mg or more, 200 mg or less, and more preferably 100 ± 1 mg. The administration frequency may be appropriately adjusted in the same manner, and may be, for example, 0.5 times / week or more and 2 times / week or less, preferably once / week. Further, after administration for 2 weeks or more and 5 weeks or less, the drug may be withdrawn for 1 week, or the cycle may be repeated.
パクリタキセルとしては、ナブパクリタキセルを用いてもよい。ナブパクリタキセルは、血清アルブミンにパクリタキセルを結合させナノ粒子化したものであり、パクリタキセル自体の水溶性は比較的低いのに対して、溶媒として水を用いることができる。血清アルブミンの含有量は適宜調整すればよいが、例えば、パクリタキセルに対する血清アルブミンの割合を５質量倍以上、１０質量倍以下とすることができ、８±０．１質量倍とすることが好ましい。ナブパクリタキセルの平均粒子径としては、１３０±１０ｎｍとすることができる。 As the paclitaxel, nab-paclitaxel may be used. Nab-paclitaxel is obtained by binding paclitaxel to serum albumin to form nanoparticles, and while paclitaxel itself has a relatively low water solubility, water can be used as a solvent. The content of serum albumin may be appropriately adjusted, but for example, the ratio of serum albumin to paclitaxel can be 5% by mass or more and 10% by mass or less, preferably 8 ± 0.1% by mass. The average particle size of nabu paclitaxel can be 130 ± 10 nm.
本発明に係る膵癌治療剤は、１製剤中に全ての有効成分が含まれるものであってもよいが、投与態様を有効成分ごとに調整できるようにするために、２以上の製剤からなり、各製剤に１以上の有効成分が含まれることが好ましい。各製剤には、その剤形に応じた添加成分を配合してもよい。添加成分としては、例えば、基材、賦形剤、着色剤、滑沢剤、矯味剤、乳化剤、増粘剤、湿潤剤、安定剤、保存剤、溶剤、溶解補助剤、懸濁化剤、抗酸化剤、佐薬、緩衝剤、ｐＨ調整剤、甘味料、香料などが挙げられる。 The therapeutic agent for pancreatic cancer according to the present invention may contain all the active ingredients in one preparation, but is composed of two or more preparations so that the administration mode can be adjusted for each active ingredient. It is preferable that each preparation contains one or more active ingredients. An additive component according to the dosage form may be added to each pharmaceutical product. Examples of additive components include base materials, excipients, colorants, lubricants, flavoring agents, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizing agents, suspending agents, etc. Examples include antioxidants, solvents, buffers, pH regulators, sweeteners, flavors and the like.
例えばシロリムスは、錠剤、カプセル剤、顆粒剤、散剤などの有効成分とすることが好ましく、錠剤の有効成分にすることが好ましい。シロリムス以外の錠剤の添加物としては、例えば、カルナウバロウ、結晶セルロース、酸化チタン、ステアリン酸マグネシウム、白糖、セラック、タルク、トコフェロール、乳糖水和物、ポビドン、ポリエチレングリコール、ポリオキシエチレンポリオキシプロピレングリコール、物オレイン酸グリセリン、硫酸カルシウム等が挙げられる。また、錠剤は糖でコーティングしてもよい。 For example, sirolimus is preferably an active ingredient such as tablets, capsules, granules, and powders, and is preferably an active ingredient of tablets. Additives for tablets other than sirolimus include, for example, carnauba wax, crystalline cellulose, titanium oxide, magnesium stearate, sucrose, serrac, talc, tocopherol, lactose hydrate, povidone, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, and the like. Examples thereof include glycerin oleate and calcium sulfate. The tablets may also be coated with sugar.
ゲムシタビンは、注射用製剤、特に静脈注射用製剤の有効成分とすることが好ましい。注射用製剤として、例えば、有効成分であるゲムシタビンに加えて、Ｄ−マンニトール、酢酸ナトリウム水和物、ｐＨ調整剤などの添加物を含む凍結乾燥製剤であって、使用時に生理食塩水に溶解するものとすることができる。 Gemcitabine is preferably used as an active ingredient of an injectable preparation, particularly an intravenous injection preparation. As an injectable preparation, for example, a lyophilized preparation containing additives such as D-mannitol, sodium acetate hydrate, and a pH adjuster in addition to the active ingredient gemcitabine, which is dissolved in physiological saline at the time of use. Can be.
ＴＳ−１は、有効成分としてテガフール、ギメラシルおよびオテラシルカリウムを含有する、カプセル剤、散剤、顆粒剤、錠剤などの経口製剤とすることが好ましい。例えば、有効成分であるテガフール、ギメラシルおよびオテラシルカリウムに加えて、乳糖水和物、ステアリン酸マグネシウム、ゼラチン、ラウリル硫酸ナトリウム、酸化チタン、Ｄ−マンニトール、ヒドロキシプロピルセルロース等の添加剤を含む経口製剤とすることができる。 TS-1 is preferably an oral preparation such as a capsule, a powder, a granule, or a tablet, which contains tegafur, gimeracil, and oteracil potassium as active ingredients. For example, an oral preparation containing additives such as lactose hydrate, magnesium stearate, gelatin, sodium lauryl sulfate, titanium oxide, D-mannitol, hydroxypropyl cellulose, etc., in addition to the active ingredients tegafur, gimeracil and oteracil potassium. Can be.
パクリタキセルは、注射用製剤、特に静脈注射用製剤の有効成分とすることが好ましい。注射用製剤として、例えば、有効成分であるパクリタキセルに加えて、血清アルブミンなどの添加物を含む凍結乾燥製剤であって、使用時に生理食塩水に溶解または懸濁するものとすることができる。 Paclitaxel is preferably used as an active ingredient of an injectable preparation, particularly an intravenous injection preparation. As an injectable preparation, for example, a lyophilized preparation containing an additive such as serum albumin in addition to the active ingredient paclitaxel, which may be dissolved or suspended in physiological saline at the time of use.
本発明に係る膵癌治療剤が２以上の製剤からなるものである場合、各製剤を同時に投与してもよいが、各製剤における有効成分の投与量や投与頻度に応じて、時間をおいて別々に投与することが好ましい。 When the therapeutic agent for pancreatic cancer according to the present invention consists of two or more pharmaceutical products, each pharmaceutical product may be administered at the same time, but they are separated at different times depending on the dose and frequency of administration of the active ingredient in each pharmaceutical product. It is preferable to administer to.
本発明に係る膵癌治療剤の投与対象は膵癌患者であるが、膵癌の更なる浸潤転移を抑制するために、膵癌細胞がリンパ節や他の臓器に転移した患者に投与してもよい。 The target of administration of the pancreatic cancer therapeutic agent according to the present invention is a pancreatic cancer patient, but in order to suppress further infiltration metastasis of pancreatic cancer, it may be administered to a patient in which pancreatic cancer cells have metastasized to lymph nodes or other organs.
以下、実施例を挙げて本発明をより具体的に説明するが、本発明はもとより下記実施例によって制限を受けるものではなく、前・後記の趣旨に適合し得る範囲で適当に変更を加えて実施することも勿論可能であり、それらはいずれも本発明の技術的範囲に包含される。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited by the following examples as well as the present invention, and appropriate modifications are made to the extent that it can meet the purposes of the preceding and the following. Of course, it is possible to carry out, and all of them are included in the technical scope of the present invention.
実施例１： 膵癌細胞に対するシロリムスの効果
（１）ｍＴＯＲに対する阻害作用
６ウェルプレートの各ウェルにダルベッコ改変イーグル培地（ＤＭＥＭ，Ｇｉｂｃｏ−ＢＲＬ社製）を２ｍＬずつ加え、ヒト膵癌細胞株Ｓ２−０１３を３．０×１０5ｃｅｌｌｓ／ｗｅｌｌの割合で播種し、３７℃で４８時間前培養した。次いで、シロリムスを２０ｎＭまたは２００ｎＭの濃度で添加するか、或いは添加せずに、３７℃で１８時間培養した。
培養後、細胞ペレットを、２０ｍＭ Ｈｅｐｅｓ（ｐＨ７．４）、１００ｍＭ塩化カリウム、２ｍＭ塩化マグネシウム、０．５％Ｔｒｉｔｏｎ(R) Ｘ−１００、「Ｐｒｏｔｅａｓｅ Ｉｎｈｉｂｉｔｏｒ Ｃｏｃｋｔａｉｌ」（Ｒｏｃｈｅ社製）、および「ホスファターゼ阻害剤カクテル」（ナカライテスク社製）を含むライシスバッファーに再懸濁し、細胞溶解物を得た。次いで、ビシンコニン酸（ＢＣＡ）アッセイ法を用い、各細胞溶解物に含まれるタンパク質濃度を求めた。具体的には、各細胞溶解物を、総タンパク質量の最終濃度が１〜２μｇ／μＬとなるようにサンプルバッファー（５０ｍＭ Ｔｒｉｓ，２％ドデシル硫酸ナトリウム（ＳＤＳ），０．１％ブロモフェノールブルー、および１０％グリセロールを含有）に懸濁し、抗リン酸化ｐ７０Ｓ６Ｋ抗体（Ｃｅｌｌ Ｓｉｎｎａｌｉｎｇ社製）、抗ｐ７０Ｓ６Ｋ抗体（Ｃｅｌｌ Ｓｉｎｎａｌｉｎｇ社製）、および４−２０％グラジエントゲル（Ｂｉｏ−Ｒａｄ社製）を用い、ＳＤＳ−ＰＡＧＥとウェスタンブロッティングにより分析した。結果を図１に示す。
図１に示される結果の通り、培地への２０ｎＭおよび２００ｎＭの濃度のシロリムス添加により、膵癌細胞のｐ７０Ｓ６Ｋの活性は濃度依存性に低下したことから、膵癌細胞のｍＴＯＲ活性に対するシロリムスの阻害効果が認められた。
Example 1: Effect of sirolimus on pancreatic cancer cells (1) Inhibition effect on
After culturing, the cell pellet was subjected to 20 mM Hepes (pH 7.4), 100 mM potassium chloride, 2 mM magnesium chloride, 0.5% Triton (R) X-100, "Protease Inhibitor Cocktail" (Roche), and "phosphatase inhibition". The cell lysate was obtained by resuspending in a Lysis buffer containing "agent cocktail" (manufactured by Nakaraitesk). Bicinchoninic acid (BCA) assay was then used to determine the protein concentration in each cytolyte. Specifically, each cell lysate was prepared with a sample buffer (50 mM Tris, 2% sodium dodecyl sulfate (SDS), 0.1% bromophenol blue, etc.) so that the final concentration of the total protein amount was 1 to 2 μg / μL. And 10% glycerol (containing 10% glycerol), using anti-phosphorylated p70S6K antibody (manufactured by Cell Sinaling), anti-p70S6K antibody (manufactured by Cell Sinaling), and 4-20% gradient gel (manufactured by Bio-Rad). Analyzed by SDS-PAGE and Western blotting. The results are shown in FIG.
As shown in the results shown in FIG. 1, the addition of 20 nM and 200 nM concentrations of sirolimus to the medium reduced the activity of p70S6K in pancreatic cancer cells in a concentration-dependent manner, indicating that the inhibitory effect of sirolimus on the mTOR activity of pancreatic cancer cells was observed. Was done.
（２）生膵癌細胞数の測定
６ウェルプレートの各ウェルにダルベッコ改変イーグル培地（ＤＭＥＭ，Ｇｉｂｃｏ−ＢＲＬ社製）を２ｍＬずつ加え、ヒト膵癌細胞株Ｓ２−０１３を３．０×１０5ｃｅｌｌｓ／ｗｅｌｌの割合で播種し、３７℃で４８時間前培養した。次いで、シロリムスを２０ｎＭまたは２００ｎＭの濃度で添加するか、或いは添加せずに、３７℃で１８時間培養した。
次いで、ＭＴＴ［３−（４，５−ジメチルチアゾール−２−イル）−２，５−ジフェニルテトラゾリウムブロミド］アッセイによって、生細胞数を測定した。ＭＴＴは、生細胞内に取り込まれ、ミトコンドリアにある脱水素酵素により還元され、ホルマザン色素が生じる。色素量は代謝活性のある生細胞数と相関するため、吸光度測定により、生細胞数や生細胞率を評価することができる。具体的には、ＭＴＴアッセイキット（「Ｃｅｌｌ Ｃｏｕｎｔｉｎｇ Ｋｉｔ−８」同仁化学研究所社製）に附属のＣｅｌｌ Ｃｏｕｎｔｉｎｇ Ｋｉｔ−８溶液（２００μＬ）を各ウェルに加え、３７℃で３時間インキュベートした。次に、Ｍｉｃｒｏｐｌａｔｅ Ｒｅａｄｅｒ ５５０（Ｂｉｏ−Ｒａｄ社製）を用いて、４５０ｎｍでの吸光度を測定した。結果を図２に示す。
図２に示される結果の通り、シロリムスはヒト膵癌細胞の増殖を抑制しなかった。
本発明者はｍＴＯＲ阻害剤であるエベロリムスがヒト膵癌細胞の増殖を有意に抑制することを実験的に明らかにしているが（特開２０１９−２０６５１６号公報）、本実験により、同じくｍＴＯＲ阻害剤であるシロリムスはヒト膵癌細胞の増殖を阻害しないことが示された。
(2) Measurement of the number of live pancreatic cancer cells Add 2 mL each of Dulbecco's modified Eagle's medium (DMEM, manufactured by Gibco-BRL) to each well of the 6-well plate, and add human pancreatic cancer cell line S2-013 to 3.0 × 10 5 cells /. It was sown at the proportion of well and cultured at 37 ° C. for 48 hours before. Sirolimus was then cultured at 37 ° C. for 18 hours with or without addition at a concentration of 20 nM or 200 nM.
The viable cell count was then measured by MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] assay. MTT is taken up into living cells and reduced by dehydrogenase in mitochondria to produce formazan pigment. Since the amount of pigment correlates with the number of living cells having metabolic activity, the number of living cells and the percentage of living cells can be evaluated by measuring the absorbance. Specifically, the Cell Counting Kit-8 solution (200 μL) attached to the MTT assay kit (“Cell Counting Kit-8” manufactured by Dojin Chemical Research Institute) was added to each well and incubated at 37 ° C. for 3 hours. Next, the absorbance at 450 nm was measured using a Microplate Reader 550 (manufactured by Bio-Rad). The results are shown in FIG.
As shown in FIG. 2, sirolimus did not suppress the growth of human pancreatic cancer cells.
The present inventor has experimentally revealed that everolimus, which is an mTOR inhibitor, significantly suppresses the growth of human pancreatic cancer cells (Japanese Patent Laid-Open No. 2019-206516). One sirolimus has been shown not to inhibit the growth of human pancreatic cancer cells.
（３）マトリゲル浸潤アッセイ
６ウェルプレートの各ウェルにダルベッコ改変イーグル培地（ＤＭＥＭ，Ｇｉｂｃｏ−ＢＲＬ社製）を２ｍＬずつ加え、ヒト膵癌細胞株Ｓ２−０１３を３．０×１０5ｃｅｌｌｓ／ｗｅｌｌの割合で播種し、３７℃で４８時間前培養した。次いで、シロリムスを２０ｎＭまたは２００ｎＭの濃度で添加するか、或いは添加せずに、３７℃で１８時間培養した。無血清培地に懸濁した４．０×１０4個の細胞を、「Ｍａｔｒｉｇｅｌ Ｉｎｖａｓｉｏｎ Ｃｈａｍｂｅｒ」Ｂｅｃｔｏｎ Ｄｉｃｋｉｎｓｏｎ製（孔径：８μｍ）の上部チャンバーのウェルに播種し、下部チャンバーには、化学誘引物質が含まれている５％ＦＣＳを添加した。２０時間のインキュベーション後、顕微鏡観察を用い、独立した４視野を調べ、下部チャンバーに移動した細胞を計数した。結果を図３に示す。なお、図３中の「＊」は、ｔ−テストにおいてコントロールに対してｐ＜０．０５で有意差があることを示す。
図３に示される結果の通り、ヒト膵癌細胞の浸潤は、シロリムスの添加により濃度依存的に有意に抑制された。
本発明者はｍＴＯＲ阻害剤であるエベロリムスがヒト膵癌細胞の浸潤を抑制することを実験的に明らかにしているが（特開２０１９−２０６５１６号公報）、同じくｍＴＯＲ阻害剤であるシロリムスによるヒト膵癌細胞の浸潤抑制効果は、エベロリムスに比べて明らかに強かった。
(3) Matrigel
As shown in the results shown in FIG. 3, the infiltration of human pancreatic cancer cells was significantly suppressed in a concentration-dependent manner by the addition of sirolimus.
The present inventor has experimentally shown that everolimus, an mTOR inhibitor, suppresses the infiltration of human pancreatic cancer cells (Japanese Patent Laid-Open No. 2019-206516), but human pancreatic cancer cells caused by sirolimus, which is also an mTOR inhibitor. The infiltration inhibitory effect of was clearly stronger than that of everolimus.
実施例２： 動物実験
ヒト膵癌細胞株Ｓ２−０１３、ヒト臍帯静脈内皮細胞、およびヒト間葉系幹細胞を共培養して、大きさが約５００μｍのヒト膵癌オルガノイドを形成させた。ヒト膵癌オルガノイドをヌードマウスの背部皮下に移植すると、１週後には数ミリの腫瘍を確認できた。ヒト膵癌オルガノイド移植マウスから摘出した腫瘍組織では癌間質が豊富に存在し、腺腔構造・微小乳頭状構造を呈する部分が混在している。これらの所見は膵癌症例から手術摘出した臨床的膵癌の組織構造に類似しており、大きい腫瘍では浸潤性腺癌像を示すことから、ヒト膵癌オルガノイドは薬効評価に適したモデルであるといえる。
ヒト膵癌オルガノイド移植モデルマウスに、ゲムシタビン＋パクリタキセル、またはゲムシタビン＋パクリタキセル＋シロリムスを投与してそれぞれの薬効を評価した。具体的には、ヌードマウス２４匹を、８匹ずつ任意に、投薬を行わないコントロール群、ゲムシタビン＋パクリタキセル投与群と、ゲムシタビン＋パクリタキセル＋シロリムス投与群とに分け、第１日目にヒト膵癌オルガノイドの移植手術を行った。
ゲムシタビン＋パクリタキセル投与群には、移植後３週目から９週目まで、５０ｍｇ／ｋｇのゲムシタビンと０．５ｍｇ／ｋｇのナブパクリタキセルを、１日／週の頻度で３週連続腹腔内注射投与して１週休薬し更に３週連続投与した。ゲムシタビン＋パクリタキセル＋シロリムス投与群には、移植後３週目から９週目まで、前記のゲムシタビンとナブパクリタキセルの腹腔内注射投与に加えて、８ｍｇ／ｋｇのシロリムスを５日／週の頻度で腹腔内注射投与した。
ヒト膵癌オルガノイドの移植から、ノギスを使って、腫瘍の長径と短径を毎週定期的に計測し、計測値に基づいて、式：長径×長径×短径／２により腫瘍体積を求めた。結果を図４に示す。図４中、「Ｃｏｎｔｒｏｌ」は投薬を行わないコントロール群の結果を示し、「ＧｎＰ」はゲムシタビン＋パクリタキセル群の結果を示し、「ＧｎＰ+Ｌａｐａ」はゲムシタビン＋パクリタキセル＋シロリムス投与群の結果を示し、「＊」はゲムシタビン＋パクリタキセル投与群に対してｐ＜０．０５で有意差があることを示す。
また、ヒト膵癌オルガノイドの移植から９週間後、腫瘍を摘出し、ホルマリンを使って固定した後、ヘマトキシリン−エオシンで染色した観察した。結果を図５に示す。
図４に示される結果の通り、ゲムシタビン＋パクリタキセル群でもコントロール群に比較して腫瘍体積が低減されたが、ゲムシタビン＋パクリタキセル＋シロリムス投与群では、ゲムシタビン＋パクリタキセル投与群に対しても腫瘍体積が有意に低減され、強い腫瘍増大抑制効果が認められた。
また、図５に示される結果の通り、ゲムシタビン＋パクリタキセル＋シロリムス投与群では腫瘍内は壊死しており、腫瘍細胞の集簇が分断し、腫瘍量が明らかに減少していた。ゲムシタビン＋パクリタキセル投与群では、シロリムスを併用した群に比べて、壊死傾向が顕著ではなく腫瘍組織の分断は見られなかった。
以上の結果の通り、ゲムシタビンとパクリタキセルに加えてシロリムスを併用することにより、膵癌細胞の増殖を抑制できるのみならず、膵癌を治療できることが実証された。
Example 2: Animal Experiment Human pancreatic cancer cell line S2-013, human umbilical vein endothelial cells, and human mesenchymal stem cells were co-cultured to form human pancreatic cancer organoids having a size of about 500 μm. When a human pancreatic cancer organoid was transplanted subcutaneously into the back of a nude mouse, a tumor of several millimeters could be confirmed one week later. Tumor tissue excised from human pancreatic cancer organoid transplanted mice is rich in cancer stroma, and has a mixture of glandular cavity structures and micropapillary structures. Since these findings are similar to the histological structure of clinical pancreatic cancer surgically removed from pancreatic cancer cases and show invasive adenocarcinoma in large tumors, it can be said that human pancreatic cancer organoids are a suitable model for drug efficacy evaluation.
Gemcitabine + paclitaxel or gemcitabine + paclitaxel + sirolimus was administered to human pancreatic cancer organoid transplantation model mice, and their efficacy was evaluated. Specifically, 24 nude mice were divided into a control group, gemcitabine + paclitaxel-administered group, and gemcitabine + paclitaxel + sirolimus-administered group, in which 8 animals were arbitrarily administered, and human pancreatic cancer organoids were administered on the first day. Was transplanted.
In the gemcitabine + paclitaxel administration group, 50 mg / kg gemcitabine and 0.5 mg / kg nab-paclitaxel were administered intraperitoneally for 3 consecutive weeks at a frequency of 1 day / week from 3 to 9 weeks after transplantation. The drug was withdrawn for 1 week and administered for another 3 consecutive weeks. In the gemcitabine + paclitaxel + sirolimus-administered group, 8 mg / kg sirolimus was intraperitoneally administered at a frequency of 5 days / week in addition to the above-mentioned intraperitoneal injection of gemcitabine and nab-paclitaxel from 3 to 9 weeks after transplantation. Intraperitoneal injection was administered.
From transplantation of human pancreatic cancer organoids, the major axis and minor axis of the tumor were measured weekly using calipers, and the tumor volume was calculated by the formula: major axis x major axis x minor axis / 2 based on the measured values. The results are shown in FIG. In FIG. 4, "Control" shows the results of the non-medicated control group, "GnP" shows the results of the gemcitabine + paclitaxel group, and "GnP + Lapa" shows the results of the gemcitabine + paclitaxel + sirolimus-administered group. “*” Indicates that there is a significant difference in p <0.05 with respect to the gemcitabine + paclitaxel administration group.
In addition, 9 weeks after the transplantation of the human pancreatic cancer organoid, the tumor was excised, fixed with formalin, and then stained with hematoxylin-eosin for observation. The results are shown in FIG.
As shown in the results shown in FIG. 4, the tumor volume was reduced in the gemcitabine + paclitaxel group as compared with the control group, but in the gemcitabine + paclitaxel + sirolimus administration group, the tumor volume was also significant in the gemcitabine + paclitaxel administration group. It was reduced to a strong tumor growth inhibitory effect.
In addition, as shown in the results shown in FIG. 5, in the gemcitabine + paclitaxel + sirolimus-administered group, the tumor was necrotic, the tumor cell collection was divided, and the tumor volume was clearly reduced. In the gemcitabine + paclitaxel-administered group, the necrotic tendency was not remarkable and the tumor tissue was not divided as compared with the group in which sirolimus was used in combination.
From the above results, it was demonstrated that the combined use of sirolimus in addition to gemcitabine and paclitaxel can not only suppress the growth of pancreatic cancer cells but also treat pancreatic cancer.
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