JP2012197294A - 癌治療感作物質 - Google Patents
癌治療感作物質 Download PDFInfo
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- JP2012197294A JP2012197294A JP2012128544A JP2012128544A JP2012197294A JP 2012197294 A JP2012197294 A JP 2012197294A JP 2012128544 A JP2012128544 A JP 2012128544A JP 2012128544 A JP2012128544 A JP 2012128544A JP 2012197294 A JP2012197294 A JP 2012197294A
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Abstract
【解決手段】SPARCファミリーポリペプチドまたはポリヌクレオチドを包む組成物および、SPARCファミリーポリペプチドまたはポリヌクレオチドを含む組換え細胞を提供する。該組成物及び方法は、癌治療抵抗性のインビトロ試験においてのみならず、癌のエキソビボ及びインビボ治療において有用である。
【選択図】図1
Description
ここで使用する、「SPARCファミリーポリペプチド」は、細胞外タンパク質のファミリーのポリペプチド(そのフラグメントまたは変異体を含む)を指す。この細胞外タンパク質のファミリーは、SPARC、及びSMOC−1、hevin、SC1、QR−1、フォリスタチン様タンパク質(TSC−36)及びtesticanなどのファミリーの他の成員を含む(例えば、参照してここに組み込まれる、Vannahmeら,(2002),J.Biol.Chem.277(41):37977−37986;Johnston,I.G.,Paladino,T.,Gurd,J.W.,及びBrown,1.R.(1990)Neuron 2,165−176;Guermah,M.,Crisanti,P.,Laugier,D.,Dezelee,P.,Bidou,L.,Pessac,B.,及びCalothy,G.(1991)Proc.Natl.Acad.Sci.U.S.A.88,4503−4507;Shibanuma,M.,Mashimo,J.,Mita,A.,Kuroki,T.,及びNose,K.(1993)Eur.J.Biochem.217,13−19;Alliel,P.M.,Perin,J.P.,Jolles,P.,及びBonnet,F.J.(1993)Eur.J.Biochem.214,347−350参照)。SPARCファミリーポリペプチドは、典型的には3つの独立した折りたたみドメインから成る(参照してここに組み込まれる、YanとSage,1999,J.Histochem.&Cytochem.,47(12):1495−1505)。N−末端ドメイン(例えばSPARC内の2個の隣接するN末端Glu3及びGlu4)は負に荷電しており、2番目のドメイン(例えばSPARC内の残基53−137)は、典型的パターンでは10個のシステインを有するフォリスタチン(FS)1に相同であり、C末端細胞外カルシウム結合(EC)ドメイン(例えばSPARC内の残基138−286)は、各々がX線構造で結合カルシウムイオンを備える、2つのEFハンドカルシウム結合モチーフを有する(Maurer,P.,Hohenadl,C.,Hohenester,E.,Goring,W.,Timpl,R.,及びEngel,J.(1995)J.Mol.Biol.253,347−357;Hohenester,E.,Maurer,P.,Hohenadl,C.,Timpl,R.,Jansonius,J.N.,及びEngel,J.(1996)Nat.Struct.Biol.3,67−73)。
1つの実施形態では、本発明は、(a)配列番号1−17から成る群より選択されるSPARCファミリーポリペプチド;(b)(a)の前記SPARCファミリーポリペプチドに少なくとも60%の相同性を有するアミノ酸配列を有するポリペプチド;(c)少なくとも50アミノ酸の長さである、(a)−(b)のポリペプチドフラグメント;及び(d)(a)−(c)のポリペプチドを含む融合ポリペプチドを提供する。
本発明によって提供されるSPARCファミリーポリペプチドは、何らかの公知の方法、例えば組換えDNA手法を用いて原核または真核細胞において生産しうる。組換え宿主細胞法は、ここで以下に述べるように、または例えば、その開示が参照してここに組み込まれる、T.Maniatisら,「分子クローニング(Molecular Cloning)」第二版,Cold Spring Harbor Laboratory,Cold Spring Harbor,N.T.(1989);日本生化学界(Biochemical Society of Japan)編,「続生化学実験講座 1,遺伝子研究法II(Lectures on Biochemical Experiments(Second Series;1),Methods for Gene Study II)」,東京科学同人,日本(1986);日本生化学界(Biochemical Society of Japan)編,「新生化学実験講座2、核酸III(組換えDNA技術)(New Lectures on Biochemical Experiments 2,Nucleic Acids III(Recombinant DNA Technique))」,東京科学同人,日本(1992);R.Wu(編),「酵素学における手法(Methods in Enzymology)」Vol.68,Academic Press,ニューヨーク(1980);R.Wuら(編),「酵素学における手法」,Vols.100および101,Academic Press,ニューヨーク(1983);R.Wuら(編),,「酵素学における手法」,Vols.153,154および155,Academic Press,ニューヨーク(1987)等に開示されている方法によって、並びにここで引用する参考文献の中で開示されている手法によって、実施しうる。そのような手法及び手段はまた、本発明の目的に応じて従来の手法から個別に修正/改善されたものでありうる。
SPARCファミリーポリペプチド配列をコードするポリヌクレオチドは、治療を感作するための本発明のSPARCファミリーポリペプチドを生産するために、原核または真核細胞に導入されて、複製することができるベクターに組み込みうるか、もしくは細胞または組織を形質移入または感染して、SPARCファミリーポリペプチドを発現することによって直接感作機能を達成するために使用できる。ベクターは、形質移入細胞または感染細胞のゲノム内に組み込まれてもよくまたは組み込まれなくてもよい。
前述したように、精製のためにSPARCファミリーポリペプチドを発現するためもしくは発現して本発明の感作作用を達成するために、当技術分野で周知の方法、例えば分子生物学の最新プロトコル(Current Protocols in Molecular Biology),Ausubel,F.M.ら(編),1989,Greene Publishing Associates,Section 9.1、及び分子クローニング:実験マニュアル(Molecular Cloning:A Laboratory Manual),第2版,Sambrookら,1989,Cold Spring Harbor Laboratory Pressにおける方法に従って本発明のSPARCファミリーポリヌクレオチドを細胞に導入しうる。
SPARCファミリーポリペプチドをコードするポリヌクレオチドは、ポリヌクレオチドとリン酸カルシウムを含む沈殿物を形成することによって細胞に導入することができる。例えばHEPES緩衝食塩水を、塩化カルシウム及びポリヌクレオチドを含む溶液と混合して沈殿物を形成することができ、その後前記沈殿物を細胞と共にインキュベートする。一定の細胞によって取り込まれるポリヌクレオチドの量を高めるためにグリセロールまたはジメチルスルホキシドショック工程を付加することができる。CaPO4媒介形質移入は、細胞を安定に(または一過性に)形質移入するために使用でき、細胞にインビトロ修飾にのみ適用できる。CaPO4媒介形質移入についてのプロトコルは、分子生物学の最新プロトコル(Current Protocols in Molecular Biology),Ausubel,F.M.ら(編),1989,Greene Publishing Associates,Section 9.1及び分子クローニング:実験マニュアル(Molecular Cloning:A Laboratory Manual),第2版,Sambrookら,1989,Cold Spring Harbor Laboratory Press,Sections 16.32−16.40または他の標準実験室マニュアルに認められる。
SPARCファミリーポリペプチドをコードするポリヌクレオチドは、ポリヌクレオチドとDEAE−デキストランの混合物を形成し、その混合物を細胞と共にインキュベートすることによって細胞に導入することができる。ポリヌクレオチド取込みの量を高めるためにジメチルスルホキシドまたはクロロキンショック工程を付加することができる。DEAE−デキストラン媒介形質移入についてのプロトコルは、分子生物学の最新プロトコル(Current Protocols in Molecular Biology),Ausubel,F.M.ら(編),1989,Greene Publishing Associates,Section 9.1、及び分子クローニング:実験マニュアル(Molecular Cloning:A Laboratory Manual),第2版,Sambrookら,1989,Cold Spring Harbor Laboratory Press,Sections 16.41−16.46または他の標準実験室マニュアルに見出される。
SPARCファミリーポリペプチドをコードするポリヌクレオチドはまた、適切な緩衝液中で細胞とポリヌクレオチドを一緒にインキュベートし、細胞を高圧電気パルスに供することによって細胞に導入することができる。電気穿孔によってポリヌクレオチドが細胞に導入される効率は、適用される電界の強さ、電気パルスの長さ、温度、ポリヌクレオチドの立体配座と濃度及び媒質のイオン組成によって影響される。電気穿孔は幅広い細胞型を安定に(または一過性に)形質移入するために使用できる。細胞を電気穿孔するためのプロトコルは、Ausubel,F.M.ら(編)、前出、Section 9.3及びSambrookら,前出、Sections 16.54−16.55または他の標準実験室マニュアルに認められる。
SPARCファミリーポリペプチドをコードするポリヌクレオチドはまた、カチオン脂質を含むリポソーム懸濁液とポリヌクレオチドを混合することによって細胞に導入することができる。次にポリヌクレオチド/リポソーム複合体を細胞と共にインキュベートする。リポソームを介した形質移入は、インビトロで培養中の細胞を安定に(または一過性に)形質移入するために使用できる。プロトコルは、Ausubel,F.M.ら(編)、前出、Section 9.4及び他の標準実験室マニュアルに認められる。加えて、リポソームを使用してインビボでの遺伝子送達が達成された。例えばNicolauら,1987,Mets.Enz.,149:157−176;Wang,ら,1987,Proc.Natl.Acad.Sci.USA,84:7851−7855;Brighamら,1989,Am.J:Med.Sci.,298:278;及びGould−Fogeriteら,1989,Gene,84:429−438参照。
SPARCファミリーポリペプチドをコードするポリヌクレオチドは、ポリヌクレオチドを細胞に直接注入することによって細胞に導入することができる。細胞のインビトロ培養のために、微量注入によってポリヌクレオチドを導入することができる。各々の細胞を個別に微量注入するので、多数の細胞を修飾するときにはこのアプローチは非常に労力を要する。しかし、微量注入が選択方法である状況は、トランスジェニック動物の作製においてである(以下でより詳細に論じる)。この状況では、ポリヌクレオチドを受精卵母細胞に安定に導入し、次にそれを動物へと成長させる。生じた動物は、卵母細胞に導入されたポリヌクレオチドを担持する細胞を含む。直接注入は、SPARCファミリーポリペプチドをコードするポリヌクレオチドをインビボで細胞に導入するために使用しうる(例えばAcsadiら,1991,Nature,332:815−818;Wolffら,l990,Science,247:1465−1468参照)。インビボでDNAを細胞に注入するための送達装置(例えば「遺伝子ガン」)が使用できる。そのような装置は市販されている(例えばBioRadから)。
SPARCファミリーポリペプチドをコードするポリヌクレオチドはまた、ポリヌクレオチドをポリリシンなどのカチオンと複合体形成し、それを細胞表面受容体についてのリガンドに結合することによって細胞に導入することができる(Wu,ら,1988,J.Biol.Chem.,263:14621;Wilsonら,1992,J.Biol.Chem.,267:963−967;及び米国特許第5,166,320号参照)。ポリヌクレオチド−リガンド複合体の受容体への結合は、受容体を介したエンドサイトーシスによるポリヌクレオチドの取込みを促進する。ポリヌクレオチド−リガンド複合体が標的する受容体は、トランスフェリン受容体及びアシアロ糖タンパク質受容体を含む。天然でエンドソームを破壊し、それによって細胞質内に物質を放出するアデノウイルスカプシドに結合したポリヌクレオチド−リガンド複合体は、細胞内リソソームによる複合体の分解を回避するために使用できる(例えばCurielら,1991,Proc.Natl.Acad.Sci.USA,88:8850;Cristianoら,1993,Proc.Natl.Acad.Sci.USA,90:2122−2126参照)。受容体を介したポリヌクレオチド取込みは、インビトロまたはインビボでSPARCファミリーポリペプチドをコードするポリヌクレオチドを細胞に導入するために使用でき、加えて、対象とする標的細胞上で選択的に発現される受容体に結合するリガンドの使用により、ポリヌクレオチドが特定細胞型を選択的に標的することができるという付加的な特徴を有する。
SPARCファミリーポリペプチドをコードするポリヌクレオチドを細胞に導入するためのもう1つのアプローチは、SPARCファミリーポリペプチドをコードするポリヌクレオチドを含むウイルスベクターの使用によるものである。ウイルスベクターによる細胞の感染は、大きな割合の細胞がポリヌクレオチドを受け取るという利点を有しており、これは、ポリヌクレオチドを受け入れた細胞を選択する必要性を回避することができる。加えて、例えばウイルスベクター内に含まれるcDNAによって、ウイルスベクター内にコードされる分子は、ウイルスベクターポリヌクレオチドを取り込んだ細胞において効率よく発現され、またウイルスベクター系はインビトロまたはインビボで使用することができる。
レトロウイルスは、逆転写の工程により、感染細胞においてそれらのRNAを二本鎖DNAに変換する能力によって特徴付けられる一本鎖RNAウイルスの群である(Coffin,1990,in Fieldsら,Ceds,Virology,Raven Press,ニューヨーク,pp.1437−1500)。生じたDNAは、その後、プロウイルスとして細胞染色体に安定に組み込まれ、ウイルスタンパク質の合成を指令する。組込みは、レシピエント細胞及びその子孫におけるウイルス遺伝子配列の維持をもたらす。レトロウイルスゲノムは、それぞれカプシドタンパク質、ポリメラーゼ酵素及びエンベロープ成分をコードする3つの遺伝子、gag、pol及びenvを含む。gag遺伝子から上流に認められる配列は、ビリオンへのゲノムのパッケージングのためのシグナルとして機能する。2つのロングターミナルリピート(LTR)配列がウイルスゲノムの5’及び3’末端に存在する。これらは強力なプロモーター及びエンハンサー配列を含み、対象細胞ゲノムへの組込みのためにも必要である(Coffin、前出)。
36kBの線状二本鎖DNAウイルスであるアデノウイルスの遺伝子機構についての知識は、アデノウイルスDNAの大きな断片を7kBまでの外来配列で置換することを可能にする(Grunhaus,ら,1992,Seminar in Virology,3:237−252)。レトロウイルスと異なり、アデノウイルスDNAは潜在的な遺伝毒性を伴わずにエピソーム様式で複製することができるので、対象細胞へのアデノウイルスDNAの感染は染色体組込みを生じさせない。また、アデノウイルスは構造的に安定であり、広汎な増幅後もゲノム再編成は検出されていない。アデノウイルスは、細胞周期段階に関わりなく実質的にすべての上皮細胞に感染しうる。
本発明における発現構築物として他のウイルスベクターも使用しうる。ワクシニアウイルス(Ridgeway,1988,in:Rodriguez R L,Denhardt D T,編,ベクター:分子クローニングベクターおよびその使用の調査(Vectors:A Survey of Molecular Cloning Vectors and Their Uses).Stoneham:Butterworth,pp.467−492;Baichwalら,1986。Kucherlapati R.編,遺伝子導入(Gene Transfer)、ニューヨーク:Plenum Press,pp.117−148;Coupar,ら,1988,Gene,68:1−10,中)、アデノ関連ウイルス(AAV)(Baichwal,ら,1986,前出;Hermonat,ら,1984,Proc.Natl.Acad.Sci.USA,81:6466−6470)及びヘルペスウイルスなどのウイルスから誘導されるベクターが使用しうる。それらは、様々な哺乳動物の細胞のためにいくつかの魅力的な特徴を提供する(Friedmann,1989,Science,244:1275−1281;Baichwal,ら,1986,前出;Coupar,ら,1988,前出;Horwich,ら,1990,J.Virol.,64:642−650)。
癌は、典型的には手術、化学療法または放射線療法によって治療される。免疫療法及び遺伝子療法などの生物学的療法も開発されつつある。他の療法は、温熱療法、光線力学的療法等を含む(国立癌研究所のホームページ、world wide web nci.nih.gov参照)。
化学療法は、癌細胞を破壊するための抗癌(細胞傷害性)薬剤の使用である。50以上の異なる化学療法剤が存在し、一部はそれらだけで投与されるが、しばしばいくつかの薬剤が併用される(これは併用化学療法として知られる)。World wide web cancerbacup.org.uk/info/actinomycin.htmに記述されている、化学療法剤の例示リストは、アクチノマイシンD、アドリアマイシン、アルトレタミン、アスパラギナーゼ、ブレオマイシン、ブスルファン、カペシタビン、カルボプラチン、カルムスチン、クロラムブシル、シスプラチン、CPT−11、シクロホスファミド、シタラビン、ダカルバジン、ダウノルビシン、ドキソルビシン、エピルビシン、エトポシド、フルダラビン、フルオロウラシル、ゲムシタビン、ヒドロキシウレア、イダルビシン、fosfamide、イリノテカン、リポソームドキソルビシン、ロムスチン、メルファラン、メルカプトプリン、メトトレキサート、マイトマイシン、ミトザントロン、オキサリプラチン、プロカルバジン、ステロイド類、ストレプトゾシン、タキソール、タキソテール、タキソテール−TACTトライアル、Tamozolomide、チオグアニン、チオテパ、トムデックス、トポテカン、トレオサルファン、UFT(ウラシル−テガフール)、ビンブラスチン、ビンクリスチン、ビンデシン、ビノレルビンを含む。
一般的に使用される放射線療法の1つのタイプは、エネルギーの「パケット」である光子を含む。X線は癌を治療するために使用される光子放射線の最初の形態であった。放射線は、それらが有するエネルギーの量に依存して、身体の表面上またはより深部の癌細胞を破壊するために使用できる。X線束のエネルギーが高いほど、X線は標的組織のより深部に進むことができる。線形加速器及びベータトロンは、漸次より大きなエネルギーのX線を発生する機器である。癌部位に放射線(X線など)を集中するための機器の使用は外部照射治療と呼ばれる。
身体組織を高温(106°Fまで)に曝露する手法である温熱療法は、癌の治療におけるその有効性を評価するための試験が進行中である。熱は、細胞を損傷するまたは生存に必要な物質を欠乏させることによって腫瘍を縮小するのを助けうる。温熱療法は、外部及び内部加熱装置を使用する、局所(local)、領域(regional)及び全身温熱療法でありうる。温熱療法は、それらの有効性を高める試みとしてほとんど常に他の形態の治療(放射線療法、化学療法及び生物学的療法)と共に使用される。
光線力学的療法(PDT、光放射線療法、光線療法または光線化学療法とも呼ばれる)は一部の種類の癌のための治療である。これは、光感作物質として知られるある種の化学物質は、単細胞生物を特定の種類の光線に曝露したとき、その生物を死滅させることができるという発見に基づく。PDTは、光感作物質と組み合わせた固定周波数レーザー光の使用を通して癌細胞を破壊する。
レーザー療法は、癌細胞を破壊するための高輝度光線の使用を含む。この手法はしばしば出血または閉塞などの癌の症状を緩和するため、特に癌が他の処置では治療できないときに使用される。また、腫瘍を縮小または破壊することによって癌を治療するためにも使用しうる。
遺伝子治療は、疾患と闘うために生体細胞の遺伝物質を修飾することを含む実験的医療介入である。遺伝子治療は多くの異なる種類の癌及び他の疾患のために臨床試験(ヒトに関する研究試験)において検討されている。
免疫系が壊れるかまたは適切に機能していないとき、癌が発現しうる。免疫療法は、癌と戦うためまたは一部の癌治療によって引き起こされることがある副作用を軽減するために、直接または間接的に身体の免疫系を利用する。免疫療法は免疫系の応答を修復、刺激または増強するように設計される。
本発明は、SPARCファミリーポリペプチドまたはそのようなポリペプチドをコードするポリヌクレオチド及び治療薬を含む組成物を提供する。SPARCポリペプチドまたはポリヌクレオチドは、前記治療薬による治療に対して癌細胞または患者を感作するための治療上有効な量として提供される。
本発明によって提供される組成物は、当技術分野で公知の方法を用いて、及びここで前述したように、インビトロで癌細胞を感作するために使用しうる。従って、本発明は、癌試料を、SPARCファミリーポリペプチドまたはSPARCファミリーポリペプチドをコードするポリヌクレオチドを含む組成物の有効量に接触させることを含む、癌細胞を治療処置に対して感作するための方法を提供する。本発明はまた、(1)哺乳動物から癌試料を得ること;(2)前記癌試料を、SPARCファミリーポリペプチドまたはSPARCファミリーポリペプチドをコードするポリヌクレオチドを含む組成物の有効量に接触させること;及び(3)(2)の接触後に癌試料を哺乳動物に戻すこと、を含む、癌と診断された哺乳動物を治療処置に対してエキソビボで感作するための方法を提供する。
本発明によって提供される組成物は、例えば治療処置を感作する方法において、哺乳動物に投与することができる。そこで本発明は、癌と診断された哺乳動物に、SPARCファミリーポリペプチドまたはSPARCファミリーポリペプチドをコードするポリヌクレオチドを含む組成物の有効量を投与することを含む、前記哺乳動物を治療処置に対してインビボで感作するための方法を提供する。
治療処置に応答する癌試料(例えば細胞または組織)の判定は、当技術分野で公知のいずれかの方法によって、例えば細胞培養薬剤耐性試験(CCDRT)によって実施できる。CCDRTは、実験室において、患者の癌を治療するために使用する薬剤に対して癌試料(例えば哺乳動物患者から採取した)を試験することを指す。この試験は、癌試料がどの薬剤に対して感受性であり、どの薬剤に対して耐性であるかを特定することができ、それは、患者においてどの薬剤がより作用する可能性が高いか及びどの薬剤が効きそうにないかを示す。癌試料(従って、患者)の感受性は、本発明によって提供される組成物での治療によって感作されうる。感作治療に関して再びCCDRTを実施し、本発明によって提供される感作組成物が特定治療に対する癌試料の応答を感作することができるか否かを判定することができる。CCDRTによって測定される応答が、感作組成物の不在下での応答に比べて少なくとも20%、例えば30%、40%、50%、80%、100%(2倍)または3倍、4倍または5倍またはそれ以上まで増大した場合は、組成物は治療処置を感作すると言える。
本発明によって提供される組成物の治療効果は、様々な動物モデルにおいて試験しうる。これは、ここで前述したようにインビトロ、エキソビボまたはインビボで実施しうる。
本発明は、SPARCが化学療法抵抗性細胞において有意に過少発現されることが認められたこと、SPARCをコードするDNAは細胞を癌治療に対して感作すること、及びSPARC形質転換体細胞を移植した動物は、対照を移植した動物に比べて腫瘍増殖の劇的な低下を示すことの所見に基づく。
細胞培養―結腸直腸細胞系統MIP−101を、37℃及び5%CO2で、10%ウシ胎仔血清(FBS)(Invitrogen)、1%ペニシリン/ストレプトマイシン(Invitrogen)を添加したダルベッコ改変イーグル培地(DMEM)(Invitrogen)中に維持した。漸増濃度の5−フルオロウラシル(5−FU)、イリノテカン(CPT−11)、シスプラチン(CIS)及びエトポシド(ETO)と共に長期間培養した後、抵抗性MIP101細胞が発現した。SPARCで形質導入した安定なMIP101細胞(MIP/SP)を、37℃及び5%CO2で、10%FBS、1%ペニシリン/ストレプトマイシンを添加したDMEM中に維持した。
コロニー形成アッセイ(図3)及びTUNELアッセイ(図4)によって裏付けられた、2つの化学療法抵抗性クローン(MIP−5FUR及びMIP−ETOR)を、化学療法抵抗性細胞におけるSPARCの検出のために使用した。マイクロアレイ分析は、SPARCを含む、抵抗性細胞において過少発現される多くの遺伝子を特定した。
この潜在的な役割をさらに正確にするために、我々は、抵抗性表現型を逆転させる上での外来性SPARCに対する抵抗性MIP101細胞の応答(図6)を評価した。初期実験で示されたように、5−FUに抵抗性のMIP101細胞(MIP−5FUR)は、500μMの濃度の5−FUによってアポトーシスの引き金を引かれなかったが、親感受性細胞系統からの有意の数の細胞が、同様の濃度の5−FUへの曝露後にアポトーシスを受けた。抵抗性細胞のSPARCとの外因性曝露に関して重要な所見が認められた:SPARCと抵抗性クローンの24時間のインキュベーション及びそれに続く化学療法剤への12時間曝露は、それまでは細胞死を刺激しなかった化学療法剤の濃度に曝露した細胞においてTUNELアッセイによって再びアポトーシスが検出されたので、抵抗性表現型を逆転させるのに十分であった。その後の化学療法への曝露を伴わない、外来性SPARCとのインキュベーション単独では、親MIP101または抵抗性細胞のいずれにおいてもアポトーシスを誘導しなかった。
この仮説を調べるため、さらなるインビトロ試験用の過剰発現系を生成するためにMIP101細胞をSPARCで形質移入した。SPARCを過剰発現する2つのクローン(クローン4、5;図7)をその後の試験のために使用した。
インビトロでの化学療法に対する感受性上昇はインビボモデル系に翻訳され、SPARC形質移入体を移植した動物では、6サイクルの化学療法後に4匹の動物のうち2匹が完全な腫瘍後退を示した(図11)。SPARC形質移入体を移植した残りの動物は、親MIP101を移植した動物と比較して腫瘍増殖速度に劇的な低下があった。すべての対照動物(化学療法で処置したMIP101の異種移植)は、化学療法処置の開始後50日目までに>400mm2の腫瘍を有していたが、完全な腫瘍後退を受けなかったSPARC形質移入体移植動物では、腫瘍は化学療法の開始後140日目まで<300mm2のままであった(結果は示さず)。
SPARCポリペプチド発現の調節因子のスクリーニングは、簡単な哺乳動物細胞に基づくスクリーニングとして実施できる。哺乳動物組織培養細胞系統、例えばHela細胞を、最初にランダムな候補低分子と共にプレインキュベートする。次に抗SPARCウエスタンブロット法またはELISAを用いて細胞クローンをスクリーニングする。あるいは、SPARC mRNA発現への調節を調べるためのRT−PCR反応を実施する。
様々な動物モデル治療を実施し、その結果を図14に示している。
Claims (23)
- SPARCファミリーポリペプチド及び化学療法剤を包む組成物。
- SPARCファミリーポリペプチド及び化学療法抵抗性細胞を包む組成物。
- SPARCファミリーポリヌクレオチドに作動可能に連結された異種転写制御領域を含む組換え細胞。
- 前記細胞が化学療法抵抗性細胞である、請求項3の細胞。
- 組換えSPARCファミリーポリヌクレオチドを包む、単離された化学療法抵抗性細胞。
- 前記細胞が腫瘍細胞である、請求項3または5の細胞。
- 前記SPARCファミリーポリペプチドまたは遺伝子が、SMOC−1、SPARC、hevin、SC1、QR−1、フォリスタチン様タンパク質(TSC−36)、testicanから選択される、請求項1及び2の組成物、もしくは請求項3または5の細胞。
- 癌と診断された哺乳動物に、SPARCファミリーポリペプチドまたはSPARCファミリーポリペプチドをコードするポリヌクレオチドの有効量を投与することを包む、前記哺乳動物を治療処置に対してインビボで感作するための方法。
- 哺乳動物にSPARCファミリーポリペプチドまたはSPARCファミリーポリペプチドをコードするポリヌクレオチドを包む細胞であって、前記SPARCポリペプチドの増加量を生産する細胞の、有効量を投与することを包む、癌と診断された哺乳動物を治療処置に対しエキソビボで感作するための方法。
- 前記哺乳動物が前記治療処置に対して抵抗性を示す、請求項8または9の方法。
- 前記治療処置が化学療法である、請求項8または9の方法。
- 癌細胞を、SPARCファミリーポリペプチドまたはSPARCファミリーポリペプチドをコードするポリヌクレオチドを包む組成物の有効量に接触させることを包む、前記癌細胞を治療処置に対して感作するための方法。
- 前記癌細胞が前記治療処置に対して抵抗性を示す、請求項12の方法。
- 前記癌細胞に、(e)−(f)の前記ポリヌクレオチドを形質移入するかまたは感染させることをさらに包含する、請求項12の方法。
- (a)第一癌細胞におけるSPARCファミリーmRNAまたはポリペプチドの発現レベル、もしくはSPARCファミリーポリペプチドの細胞外レベルを測定すること;及び
(b)(a)で得た発現レベルまたは細胞外レベルを、治療処置に対して抵抗性を示さない第二癌細胞における前記SPARCファミリーmRNAまたはポリペプチドの発現レベル、もしくは前記SPARCファミリーポリペプチドの細胞外レベルと比較して、(a)におけるより低いレベルの発現または細胞レベルが、前記第一癌細胞が前記治療処置に対して抵抗性であることを示すこと
を含む、第一癌細胞を治療処置に対するその抵抗性について、評価するための方法。 - 前記第一試料が第一哺乳動物に由来し、(a)におけるより低いレベルの発現または細胞外レベルが、第一哺乳動物が前記治療処置に対して抵抗性であることをさらに示す、請求項15の方法。
- 前記第二癌細胞が、前記第一癌細胞を提供する第一哺乳動物に由来する、請求項15の方法。
- 前記第二癌細胞が、前記第一癌細胞を提供する第一哺乳動物とは異なる第二哺乳動物に由来する、請求項15の方法。
- 前記第一哺乳動物及び前記第二哺乳動物が同じ癌を有すると診断される、請求項18の方法。
- (a)試料中のSPARCファミリーmRNAまたはポリペプチドの発現レベル、もしくはSPARCファミリーポリペプチドの細胞外レベルを測定すること;
(b)候補物質を前記試料と接触させること;
(c)(b)の前記接触後、(b)の前記試料中の前記SPARCファミリーmRNAまたはポリペプチドの発現または細胞外レベル、もしくは前記SPARCファミリーポリペプチドの細胞外レベルを測定すること;
(d)(a)と(c)における発現レベルまたは細胞外レベルを比較して、(a)と(c)における異なるレベルの発現または細胞外レベルが、前記候補物質がSPARCファミリーmRNAまたはポリペプチドの発現もしくはSPARCファミリーポリペプチドの分泌を調節する物質であることを示すこと
を包む、SPARCファミリーmRNAまたはポリペプチドの発現、もしくはSPARCファミリーポリペプチドの分泌を、調節する物質を特定するための方法。 - (a)癌細胞におけるSPARCファミリーmRNAまたはポリペプチドの発現レベル、もしくはSPARCファミリーポリペプチドの細胞外レベルを測定すること;
(b)候補物質を前記癌細胞と接触させること;
(c)(b)の前記接触後、(b)の前記癌細胞における前記SPARCファミリーmRNAまたはポリペプチドの発現レベル、もしくは前記SPARCファミリーポリペプチドの細胞外レベルを測定すること;
(d)(a)と(c)で得た発現レベルまたは細胞外レベルを比較して、(c)における発現または細胞外レベルのレベル上昇が、前記候補物質が癌細胞を治療処置に対して感作する物質であることを示すこと
を包む、癌細胞を治療処置に対し感作する物質を特定するための方法。 - 前記癌細胞が癌と診断された哺乳動物に由来し、前記発現または細胞外レベルのレベル上昇が、前記候補物質が前記哺乳動物を治療処置に対して感作する物質であることをさらに示す、請求項21の方法。
- (a)第一哺乳動物からの第一試料において、SPARCファミリーmRNAまたはポリペプチドの発現もしくはSPARCファミリーポリペプチドの細胞外レベルが、治療処置に対して抵抗性を示さない第二試料よりも低いかどうかを判定すること;及び
(b)(a)が明確である場合、前記治療処置に対する応答を高めるために前記第一哺乳動物への前記治療処置の強度を高めること
を包む、癌と診断された第一哺乳動物のための治療処置プロトコルを決定するための方法。
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