발생일자 2015.03.27 

사건번호 1:15-cv-00276 

법원국가 UNITED STATES OF AMERICA 

관할법원명 D.C.Delaware(지방법원) 

침해권리 특허 

원고명 IPXpharma, LLC ( 미국 / 외국기업 )  

피고명 Millennium Pharmaceuticals, Inc. ( 미국 / 외국기업 )  

소송유형 침해금지 

[IPXpharma, LLC v. Millennium Pharmaceuticals, Inc.] 사건번호 1:15-cv-00276에 따르면 원고 IPXpharma, LLC는 피고 Millennium Pharmaceuticals, Inc.을 상대로 특허 US6171786을 침해하였다는 이유로 미국 델라웨어 지방법원에 소를 제기하였다. 

분쟁결과 분쟁중 

산업분류 화학∙바이오 > 생명공학기술 

계쟁제품 Velcade 

지재권번호/명칭

US6171786   Methods for preventing multidrug resistance in cancer cells 

This invention is directed to methods for preventing the emergence of multidrug resistance in tumor cells during cancer chemotherapy. In particular, it relates to the use of cytoplasmic calcium antagonists and calmodulin inhibitors, phosphoinositol-dependent phospholipase C inhibitors, and substances that inhibit activation of the transcription factor NF-.kappa.B to prevent the induction of expression of the multidrug resistance gene (MDR1) encoding P-glycoprotein by chemotherapeutic drugs. MDR1 expression, which results in tumor cell resistance to subsequent treatment with certain chemotherapeutic drugs, is shown herein to be induced in response to treatment with various cytotoxic agents, including such agents that are or are not substrates for P-glycoprotein-mediated efflux from cancer cells. Cytoplasmic calcium antagonists and calmodulin inhibitors, phosphoinositol-dependent phospholipase C inhibitors, and substances that inhibit activation of the transcription factor NF-.kappa.B are shown herein to suppress this cellular response. The invention also provides methods for identifying cytoplasmic calcium antagonists and calmodulin inhibitors, phosphoinositol-dependent phospholipase C inhibitors, and substances that inhibit activation of the transcription factor NF-.kappa.B that suppress induction of MDR1 gene expression by cytotoxic drugs. Thus, the invention provides useful methods and reagents for preventing the emergence of multidrug resistance in tumor cells treated with cytotoxic and chemotherapeutic drugs in cancer patients undergoing chemotherapy, when cytoplasmic calcium antagonists and calmodulin inhibitors, phosphoinositol-dependent phospholipase C inhibitors, and substances that inhibit activation of the transcription factor NF-.kappa.B are administered prior to or simultaneously with cytotoxic drug treatment in such individuals. 

1. A method of inhibiting MDR1 induction in a cancer cell by treatment with a cytotoxic drug, comprising contacting the cell with a phosphoinositol-dependent phospholipase C inhibitor coincident with treatment with the cytotoxic drug. 

2. The method according to claim 1, wherein the phosphoinositol-dependent phospholipase C inhibitor is neomycin sulfate, 1-(6-((17.beta.-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1-H-pyrr ole-2,5-dione, or phospholipase C-inhibiting analogues thereof. 

3. The method according to claim 1, wherein the cytotoxic drug is a chemotherapeutic drug. 

4. The method of claim 1 wherein the cancer cells contain little or no detectable MDR1-encoded P-glycoprotein, as determined by immunoreactivity with anti-P-glycoprotein antibodies, accumulation or efflux of P-glycoprotein transported dyes, or MDR1 mRNA expression assay. 

5. The method of claim 1 in which the cancer cells are derived from hematopoietic tumors. 

6. The method of claim 1 in which the cancer cells are derived from solid tumors. 

7. A method of inhibiting MDR1 induction in a cancer cell by treatment with a cytotoxic drug, comprising contacting the cell with an cytoplasmic calcium antagonist or calmodulin inhibitor, coincident with treatment with the cytotoxic drug. 

8. The method according to claim 7, wherein the cytoplasmic calcium antagonist is 1,2-bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester, 8-(dimethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride, or analogues thereof that are cytoplasmic calcium ion antagonists. 

9. The method according to claim 7, wherein the calmodulin inhibitor is 1-{6-{{17.beta.-3-methoxyestra-1,3,5(10)-trien-17-yl}amino}hexyl}-1-H-pyrr ole-2,3-dione, or calmodulin-inhibiting analogues thereof. 

10. The method according to claim 7, wherein the cytotoxic drug is a chemotherapeutic drug. 

11. The method of claim 7 wherein the cancer cells contain little or no detectable MDR1-encoded P-glycoprotein, as determined by immunoreactivity with anti-P-glycoprotein antibodies, accumulation or efflux of P-glycoprotein transported dyes, or MDR1 mRNA expression assay. 

12. The method of claim 7 in which the cancer cells are derived from hematopoietic tumors. 

13. The method of claim 7 in which the cancer cells are derived from solid tumors. 

14. A method of inhibiting MDR1 induction in a cancer cell by treatment with a cytotoxic drug, comprising contacting the cell with an inhibitor of activation of eukaryotic transcription factor NF-.kappa.B, coincident with treatment with the cytotoxic drug. 

15. The method according to claim 14, wherein the inhibitor of activation of eukaryotic transcription factor NF-.kappa.B is pyrrolidone dithiocarbamate, N-tosyl-L-phenylalanine chloromethyl ketone, sodium salicylate or acetysalicylic acid, or analogues thereof that inhibit activation of eukaryotic transcription factor NF-.kappa.B. 

16. The method according to claim 14, wherein the cytotoxic drug is a chemotherapeutic drug. 

17. The method of claim 14 wherein the cancer cells contain little or no detectable MDR1-encoded P-glycoprotein, as determined by immunoreactivity with anti-P-glycoprotein antibodies, accumulation or efflux of P-glycoprotein transported dyes, or MDR1 mRNA expression assay. 

18. The method of claim 14 in which the cancer cells are derived from hematopoietic tumors. 

19. The method of claim 14 in which the cancer cells are derived from solid tumors. 

20. A pharmaceutical composition comprising therapeutically-effective amount of a phosphoinositol-dependent phospholipase C inhibitor and a pharmaceutically-acceptable carrier. 

21. A pharmaceutical composition comprising therapeutically-effective amount of an cytoplasmic calcium antagonist or calmodulin inhibitor, and a pharmaceutically-acceptable carrier. 

22. A pharmaceutical composition comprising therapeutically-effective amount of an inhibitor of activation of eukaryotic transcription factor NF-.kappa.B, and a pharmaceutically-acceptable carrier. 

23. The pharmaceutical composition of claim 20 also comprising a chemotherapeutic drug. 

24. The pharmaceutical composition of claim 21 also comprising a chemotherapeutic drug. 

25. The pharmaceutical composition of claim 22 also comprising a chemotherapeutic drug.