JP6034288B2 - ルテニウム錯体を用いる併用療法 - Google Patents
ルテニウム錯体を用いる併用療法 Download PDFInfo
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- JP6034288B2 JP6034288B2 JP2013520771A JP2013520771A JP6034288B2 JP 6034288 B2 JP6034288 B2 JP 6034288B2 JP 2013520771 A JP2013520771 A JP 2013520771A JP 2013520771 A JP2013520771 A JP 2013520771A JP 6034288 B2 JP6034288 B2 JP 6034288B2
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- cancer
- treated
- anticancer agents
- anticancer
- indazole
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Description
本願は、2010年7月18日出願の米国仮出願第61/365,329号の優先権を主張し、その内容全体を参照により本明細書に組み入れる。
本発明は、概ね、癌を処置する方法に関し、特に、トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]またはその薬学的に許容できる塩を用いて癌を処置する方法に関する。
多くのルテニウム錯体化合物が抗腫瘍化合物として有用であることが、当技術分野で公知である。例えば、米国特許第4,843,069号(特許文献1)、PCT公開第WO9736595号(特許文献2)および米国出願公開第2005032801号(特許文献3)を参照されたい。特にルテニウム錯体塩であるトランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]インダゾリウム(KP1099)およびトランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]ナトリウム(KP1339)は、前臨床研究において、結腸癌細胞でアポトーシスを誘導するのに有効であることが示されている。例えば、Kapitza et al., J. Cancer Res. Clin. Oncol., 131(2):101-10 (2005)(非特許文献1)を参照されたい。さらに、ルテニウム錯体塩化合物であるトランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]インダゾリウム(KP1019)は、第I相臨床試験において一定の抗癌活性を示した。
トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]またはその薬学的に許容できる塩と多くの他の抗癌化合物の併用が、癌の処置において有意な相乗効果を生じることが見出された。
白金薬剤(例えば、シスプラチン、カルボプラチン、オキサリプラチン、およびピコプラチン)、タキサン(例えば、ドセタキセル、パクリタキセル)、アントラサイクリン(例えば、ドキソルビシン、ダウノルビシン、エピルビシン、イダルビシン)、5-FUおよびそのプロドラッグ(例えば、カペシタビン、テガフールおよびS1)、ニトロソ尿素化合物(例えば、カルムスチン(BCNU)、ロムスチン(CCNU)、セムスチン、エチルニトロソ尿素(ENU)およびストレプトゾトシン)、ゲムシタビン、テモゾロミド、EGFR阻害剤(例えば、エルロチニブ、ゲフィチニブ、セツキシマブ、パヌムチマブ)、mTOR阻害剤(例えば、エベロリムス、テムシロリムス、リダフォロリムス、およびシロリムス)、ソラフェニブ、レゴラフェニブ、ならびにスニチニブからなる群より選択される1つまたは複数の抗癌剤と組み合わせて癌を処置するのに有用な医薬の製造のための、トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]の薬学的に許容できる塩の使用。
[本発明1002]
トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]の薬学的に許容できる塩が、トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]ナトリウムである、本発明1001の使用。
[本発明1003]
1つまたは複数の抗癌剤が白金薬剤を含む、本発明1001または1002の使用。
[本発明1004]
白金薬剤が、シスプラチン、カルボプラチン、またはオキサリプラチンである、本発明1001の使用。
[本発明1005]
1つまたは複数の抗癌剤がアントラサイクリンを含む、本発明1001または1002の使用。
[本発明1006]
アントラサイクリンがドキソルビシンである、本発明1005の使用。
[本発明1007]
1つまたは複数の抗癌剤が5-FUまたはそのプロドラッグを含む、本発明1001または1002の使用。
[本発明1008]
1つまたは複数の抗癌剤がニトロソ尿素化合物を含む、本発明1001または1002の使用。
[本発明1009]
ニトロソ尿素化合物がBCNUである、本発明1008の使用。
[本発明1010]
1つまたは複数の抗癌剤がゲムシタビンを含む、本発明1001または1002の使用。
[本発明1011]
1つまたは複数の抗癌剤がテモゾロミドを含む、本発明1001または1002の使用。
[本発明1012]
1つまたは複数の抗癌剤がEGFR阻害剤を含む、本発明1001または1002の使用。
[本発明1013]
EGFR阻害剤がエルロチニブである、本発明1012の使用。
[本発明1014]
1つまたは複数の抗癌剤がmTOR阻害剤を含む、本発明1001または1002の使用。
[本発明1015]
mTOR阻害剤がエベロリムスである、本発明1013の使用。
[本発明1016]
1つまたは複数の抗癌剤がソラフェニブまたはレゴラフェニブを含む、本発明1001または1002の使用。
[本発明1017]
1つまたは複数の抗癌剤がスニチニブを含む、本発明1001または1002の使用。
[本発明1018]
1つまたは複数の抗癌剤がタキサンを含む、本発明1001または1002の使用。
[本発明1019]
タキサンがドセタキセルまたはパクリタキセルである、本発明1017の使用。
[本発明1020]
仕切りされた容器に以下のものを含むキット:
トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]の薬学的に許容できる塩の第1の単位剤形;ならびに
白金薬剤(例えば、シスプラチン、カルボプラチン、オキサリプラチン、およびピコプラチン)、タキサン(例えば、ドセタキセルおよびパクリタキセル)、アントラサイクリン(例えば、ドキソルビシン、ダウノルビシン、エピルビシン、イダルビシン)、5-FUおよびそのプロドラッグ(例えば、カペシタビン、テガフールおよびS1)、ニトロソ尿素化合物(例えば、カルムスチン(BCNU)、ロムスチン(CCNU)、セムスチン、エチルニトロソ尿素(ENU)およびストレプトゾトシン)、ゲムシタビン、テモゾロミド、EGFR阻害剤(例えば、エルロチニブ、ゲフィチニブ、セツキシマブ、パヌムチマブ)、mTOR阻害剤(例えば、エベロリムス、テムシロリムス、リダフォロリムス、およびシロリムス)、ソラフェニブ、レゴラフェニブ、ならびにスニチニブからなる群より選択される1つの抗癌剤の第2の単位剤形。
本発明の上記およびその他の利点および特徴、ならびにそれらを達成する方法は、以下の本発明の詳細な説明を、好ましくかつ例示的な態様を表す付属の実施例と共に検討することで、より容易に明らかにできるであろう。
本発明は、併用療法により癌を処置する方法を提供する。この方法は、治療有効量のトランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]またはその薬学的に許容できる塩と、白金薬剤(例えば、シスプラチン、カルボプラチン、オキサリプラチンおよびピコプラチン)、タキサン(例えば、ドセタキセルおよびパクリタキセル)、アントラサイクリン(例えば、ドキソルビシン、ダウノルビシン、エピルビシン、イダルビシン)、5-FUおよびそのプロドラッグ(例えば、カペシタビン、テガフールおよびS1)、ニトロソ尿素化合物(例えば、カルムスチン(BCNU)、ロムスチン(CCNU)、セムスチン、エチルニトロソ尿素(ENU)およびストレプトゾトシン)、ゲムシタビン、テモゾロミド、EGFR阻害剤(例えば、エルロチニブ、ゲフィチニブ、セツキシマブ、パヌムチマブ)、mTOR阻害剤(例えば、エベロリムス、テムシロリムス、リダフォロリムス、シロリムス等)、ソラフェニブ、レゴラフェニブならびにスニチニブからなる群より選択される1つまたは複数の薬物で、処置が必要な癌患者を処置する工程を包含する。本明細書で使用される場合、「薬学的に許容できる塩」という用語は、活性化合物の比較的非毒性の、有機または無機塩を表し、その化合物の無機または有機塩が含まれる。トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]の例示的な塩には、インダゾリウム塩(例えば、トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]インダゾリウム)およびアルカリ金属塩(例えば、トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]ナトリウム)等が含まれる。本明細書で使用される場合、「・・・を・・・で処置する」というフレーズは、患者への化合物の投与または患者体内での化合物の形成のいずれかを意味する。
細胞培養:A549、HCT-116、Hep 3B2.1-7、LNCapクローンFGC、LoVo、N87、PANC-1およびZR-75-1を含むヒト腫瘍細胞株を、American Type Culture Collection(ATCC)またはUNC Lineberger Comprehensive Cancer Centerから入手した。MKL-1ヒト神経内分泌皮膚癌腫細胞株は、ECACC(European Collection of Cell Cultures)から入手した。細胞培養物は、標準的なインビトロ培養法ならびに供給元推奨の培地および添加物を用いて、175 cm2 Greiner(登録商標)またはCorning(登録商標)組織培養用処理フラスコ中で調製した。すべての細胞培養物を、加湿された37℃、5% CO2、95%大気の環境でインキュベートした。細胞は、対数期成長を維持するために定期的に継代培養した。
細胞培養:肝細胞癌腫細胞株Hep3B(ATCC製)は、10%ウシ胎仔血清を補充したRMPI 1640中で成長させた。表皮癌腫由来細胞株KB-3-1は、RPMI 1640 + 10% FCS中で成長させた。Shen et al., J. Biol. Chem., 261:7762-7770 (1986)を参照されたい。
ソラフェニブは、LC Laboratories(Woburn, USA)から購入した。その他の物質はすべて、Sigma-Aldrich(St. Louis, USA)から購入した。
この実験の目的は、雌性ヌードマウス内の初期段階のN87ヒト胃癌腫異種移植片に対する、単独薬剤としてのおよびシスプラチンと組み合わせての、静脈内(IV)投与されたトランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]ナトリウムの効能を評価することであった。
この実験の目的は、雌性ヌードマウス内の初期段階のA549ヒト肺癌腫異種移植片に対する、単独薬剤としてのおよびパクリタキセルとの組み合わせとしての、トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]ナトリウムの効能を評価することであった。トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)]ナトリウムは3回の処置において2日ごとに静脈内投与し、パクリタキセルは5日間連続で静脈内投与し、これらは両方とも移植後第3日に開始した。以下、そうでないことが明記されていない限り、上記の実施例5と同様に動物を成長させ、腫瘍を移植し、実験した。
Claims (13)
- シスプラチン、オキサリプラチン、ドセタキセル、パクリタキセル、ドキソルビシン、5-FU、カルムスチン(BCNU)、ゲムシタビン、テモゾロミド、エルロチニブ、エベロリムス、ソラフェニブ、ならびにスニチニブからなる群より選択される1つまたは複数の抗癌剤と組み合わせて癌を処置するための医薬の製造のための、トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)] ナトリウムの使用であって、かつ
(1) 1つまたは複数の抗癌剤がシスプラチンを含む場合、処置される癌が胃癌、肺癌または結腸直腸癌であり;
(2) 1つまたは複数の抗癌剤がオキサリプラチンを含む場合、処置される癌が結腸直腸癌であり;
(3) 1つまたは複数の抗癌剤がドセタキセルを含む場合、処置される癌が前立腺癌または胃癌であり;
(4) 1つまたは複数の抗癌剤がパクリタキセルを含む場合、処置される癌が肺癌であり;
(5) 1つまたは複数の抗癌剤がドキソルビシンを含む場合、処置される癌が肝細胞癌種であり;
(6) 1つまたは複数の抗癌剤が5-FUを含む場合、処置される癌が結腸直腸癌または乳癌であり;
(7) 1つまたは複数の抗癌剤がカルムスチン(BCNU)を含む場合、処置される癌が肝細胞癌種または頸癌であり;
(8) 1つまたは複数の抗癌剤がゲムシタビンを含む場合、処置される癌が肺癌または膵臓癌であり;
(9) 1つまたは複数の抗癌剤がテモゾロミドを含む場合、処置される癌が肝細胞癌種または頸癌であり;
(10) 1つまたは複数の抗癌剤がエルロチニブを含む場合、処置される癌が肺癌、頸癌または肝細胞癌種であり;
(11) 1つまたは複数の抗癌剤がエベロリムスを含む場合、処置される癌が神経内分泌腫瘍であり;
(12) 1つまたは複数の抗癌剤がソラフェニブを含む場合、処置される癌が肝細胞癌種、肺癌、中皮腫、黒色腫または結腸癌であり;
(13) 1つまたは複数の抗癌剤がスニチニブを含む場合、処置される癌が肝細胞癌種である、
使用。 - 1つまたは複数の抗癌剤がシスプラチン、またはオキサリプラチンを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がドキソルビシンを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤が5-FUを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がBCNUを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がゲムシタビンを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がテモゾロミドを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がエルロチニブを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がエベロリムスを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がソラフェニブを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がスニチニブを含む、請求項1記載の使用。
- 1つまたは複数の抗癌剤がドセタキセルまたはパクリタキセルを含む、請求項1記載の使用。
- 仕切りされた容器に以下のものを含む、癌の処置用のキット:
トランス-[テトラクロロビス(1H-インダゾール)ルテニウム酸(III)] ナトリウムの第1の単位剤形;ならびに
シスプラチン、オキサリプラチン、ドセタキセル、パクリタキセル、ドキソルビシン、5-FU、カルムスチン(BCNU)、ゲムシタビン、テモゾロミド、エルロチニブ、エベロリムス、ソラフェニブ、ならびにスニチニブからなる群より選択される1つの抗癌剤の第2の単位剤形、
であって、かつ
(1) 抗癌剤がシスプラチンである場合、処置される癌が胃癌、肺癌または結腸直腸癌であり;
(2) 抗癌剤がオキサリプラチンである場合、処置される癌が結腸直腸癌であり;
(3) 抗癌剤がドセタキセルである場合、処置される癌が前立腺癌または胃癌であり;
(4) 抗癌剤がパクリタキセルである場合、処置される癌が肺癌であり;
(5) 抗癌剤がドキソルビシンである場合、処置される癌が肝細胞癌種であり;
(6) 抗癌剤が5-FUである場合、処置される癌が結腸直腸癌または乳癌であり;
(7) 抗癌剤がカルムスチン(BCNU)である場合、処置される癌が肝細胞癌種または頸癌であり;
(8) 抗癌剤がゲムシタビンである場合、処置される癌が肺癌または膵臓癌であり;
(9) 抗癌剤がテモゾロミドである場合、処置される癌が肝細胞癌種または頸癌であり;
(10) 抗癌剤がエルロチニブである場合、処置される癌が肺癌、頸癌または肝細胞癌種であり;
(11) 抗癌剤がエベロリムスである場合、処置される癌が神経内分泌腫瘍であり;
(12) 抗癌剤がソラフェニブである場合、処置される癌が肝細胞癌種、肺癌、中皮腫、黒色腫または結腸癌であり;
(13) 抗癌剤がスニチニブである場合、処置される癌が肝細胞癌種である、
キット。
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WO2014001956A2 (en) * | 2012-06-25 | 2014-01-03 | Ning Man Cheng | Combinational use of pegylated recombinant human arginase with chemotherapeutic/target therapeutic drug in cancer treatment |
US9585841B2 (en) * | 2013-10-22 | 2017-03-07 | Tyme, Inc. | Tyrosine derivatives and compositions comprising them |
WO2017151762A1 (en) * | 2016-03-01 | 2017-09-08 | Intezyne Technologies | Use of trans-[tetrachlorobis(1h-indazole)ruthenate (iii)] for the treatment of cancer |
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US20230024119A1 (en) * | 2019-12-05 | 2023-01-26 | Bold Therapeutics, Inc. | Combined use of sodium trans-[tetrachloridobis(1h-indazole)ruthenate(iii)] and etomoxir for treating cancers |
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