CN1794986A - Novel methods for the treatment of cancer - Google Patents

Novel methods for the treatment of cancer Download PDF

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CN1794986A
CN1794986A CN200480014321.1A CN200480014321A CN1794986A CN 1794986 A CN1794986 A CN 1794986A CN 200480014321 A CN200480014321 A CN 200480014321A CN 1794986 A CN1794986 A CN 1794986A
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carboline
tryptophan
inhibitor
ido
methyl
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CN1794986B (en
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G·C·普瑞德尔盖斯特
A·J·马勒
J·B·杜哈戴卫
W·迈拉仇斯基
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Lankenau Institute for Medical Research
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Lankenau Institute for Medical Research
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Abstract

Compositions and methods for the treatment of malignancy and chronic viral infection are disclosed.

Description

The new method of treatment cancer
According to United States code the 35th chapter § 119 (e), U.S. Provisional Application number 60/527,449 is enjoyed in the application's request, (December was submitted on the 5th in 2003) and U.S. Provisional Application No.60/458, and 162 (submissions on March 27th, 2003) are priority.This paper is incorporated herein by reference the content of two parts of applications.
Technical field
The application relates to oncology and chemotherapy field, especially provides new method for treatment of cancer.
Background technology
Tumor can specificly make atypia, have potential immunoreactive antigen expresses, and this class antigen is generically and collectively referred to as tumor antigen.A large amount of evidences show, the reason that immune system fails effectively to suppress the growth of carrying out property of tumor is not for discerning the shortage of tumor antigen.People understand as yet fully to tumour immunity inhibitory reaction and tumour immunity escape mechanism.Recently studies show that,, make cytotoxic T cell produce toleration by reducing the local concentration of tryptophan; This cell can be by indoleamine 2, and 3-dioxygenase (IDO) activates.
IDO belongs to oxidoreductase, but the rate-limiting step in the catalysis tryptophan catabolism.Its structure is different with tryptophan dioxygenase (TDO), and the latter is worked in the catabolism in the liver of food tryptophan.IDO is the target gene of interferon-(IFN-γ), may play a role in immunomodulating.(Mellor and Munn (1999) Immunol.Today.20:469-473).The active increase of IDO makes that the level of tryptophan reduces in the local cells environment.Activation antigen is IDO on the delivery cell (be subjected to IFN-gamma regulated) T cytoactive capable of blocking; This cell is responsive especially to the minimizing of tryptophan.The T cell must be through 1～2 division cycle before activation; After tryptophan was consumed, the T cell was in the G1 phase all the time.Said circumstances shows that IDO has the helper T cell of inhibition 1 (T H1) Fan Ying effect; This reaction can promote the T cell development.
The main effect of IDO in the immunosuppressant reaction can be confirmed by the function of 1-methyl-tryptophan (1MT); 1MT is the bioactive IDO inhibitor of a species specificity, tool (Cady and Sono (1991) Arch.Biochem.Biophys.291:326-333), can bring out the gene expression of the restricted and allos mice that regulate through the T cell of MHC (main tissue compatible complex).(Mellor etc. (2001) Nat.Immunol.2:64-68; Munn etc. (1998) Science.281:1191-1193).The above-mentioned effect of IDO is consistent with its high level expression in placental trophoblasts.(Sedlmayr etc. (2002) Mol.Hum.Reprod.8:385-391).
Particularly, the verified active normal increase of IDO in human tumor and/or cancer patient.(Yasui etc. (1986) Proc.Natl.Acad.Sci. U.S. .83:6622-6626; Taylor and Feng (1991) FASEB J.5:2516-22).IDO has the immunoreactive effect of adjusting; Thereby infer that the IDO level rises in cancer patient's body, but induced tumor immunosuppressant reaction.(Mellro and Munn (1999) Immunol.Today.20:469-473; Munn etc. (1999) J.Exp.Med.189:1363-1372; Munn etc. (1998) Science.281:1191-1193).The above-mentioned deduction of following discovery susceptible of proof: in multiple cancer (comprising breast carcinoma), useful immunologic function forfeiture; This function helps to limit the development of malignant tumor.For example, in the cancer progression process, T H1 reaction (being generated as sign with IFN-γ) is suppressed; This reaction can be brought out the generation of cytotoxic T cell.Thereby can suppose that if IDO can then suppress the interior IDO level of animal body and can hinder tumor growth by the active cancer development that promotes of suppressor T cell, its mechanism is: reverse the IDO modulability and exempt to establish inhibitory reaction.But in mouse model, after giving IDO and suppressing 1-methyl-tryptophan (1MT), can only delay but not stop tumor growth (Friberg etc. (2002) Int.J.Cancer 101:151-155; United States Patent (USP) 6,482,416).
Under normal and morbid state, cell signalling (be a series of from the extracellular extremely intracellular incident) is an aspect of cell function.People have identified multiple protein molecule with signal transduction functionality, comprise that receptor and nonreceptor tyrosine kinase, phosphatase and other have the molecule of enzymatic activity or regulatory function.Usually, these molecular energies combine with other protein generation specificitys, form the signal complex, thereby regulate cell proliferation.
Formation, growth and the progress that can cause malignant tumor unusually of signal transduction.Thereby the signal transduction pathway inhibitor can be used for treating cancer.In the past few years, developed multiple signal transduction inhibitor (STI), the effect that a few days ago still needs it to be suppressed tumor growth is observed.
Summary of the invention
An aspect according to the application provides a kind of method for cancer for the treatment of among the patient who needs it, and this method suppresses active chemical compound by at least a chemical compound of using the patent effective dose IDO that has of the present invention.This chemical compound can be through the administration of pharmaceutical acceptable carrier medium.
In another embodiment of the present invention, a kind of method for cancer for the treatment of among the patient who needs it is provided, this method is passed through at least a indoleamine 2 of administering therapeutic effective dose, 3-dioxygenase (IDO) inhibitor and at least a signal transduction inhibitor (STI) simultaneously or sequentially.In specific implementations of the present invention, at least a STI is selected from: bcr/abl inhibitors of kinases, epidermal growth factor (EGF) acceptor inhibitor, her-2/neu acceptor inhibitor and farnesyl transferase inhibitor (FTI).These chemical compounds can be through the administration of pharmaceutical acceptable carrier medium.
According to another embodiment of the present invention, a kind of method for cancer that needs among its patient for the treatment of is provided, this method is passed through at least a indoleamine 2 of administering therapeutic effective dose simultaneously or sequentially, 3-dioxygenase (IDO) inhibitor and at least a chemotherapeutics.In specific implementations of the present invention, at least a chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many paclitaxels, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.These chemical compounds can be through the administration of pharmaceutical acceptable carrier medium.
According to the application on the other hand, a kind of method for cancer that needs among its patient for the treatment of is provided, this method is passed through at least a immunomodulator of administering therapeutic effective dose (except that the IDO inhibitor) simultaneously or sequentially, with at least a cytotoxicity chemotherapeutics, at least a STI, or the associating of at least a cytotoxicity chemotherapeutics and at least a STI.In a specific implementations, at least a immunomodulator is selected from: CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, the 4-IBB part, the dendritic cell Theratope, (interleukin II) IL2, IL 12, ELC/CCL19, SLC/CCL21, monocyte chemotactic factor-1 (MCP-1), IL-4, IL-18, tumor necrosis factor, IL-15, macrophage derivation chemotactic factor (MDC), interferon a/b (IFN a/b), macrophage-colony stimulating factor (M-CSF), IL-3, granulocyte-colony stimulating factor (GM-CSF), IL-13, and anti-IL-10.In another specific implementations, at least a cytotoxicity chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, formylmerphalan pterin, cycli phosphate amine, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.The STI of this aspect of enforcement the present invention as previously mentioned.
In another embodiment of the present invention, provide a kind of in its patient of needs the method for treatment slow virus sexually transmitted disease, this method provides at least a indoleamine 2 of administering therapeutic effective dose simultaneously or sequentially, 3-dioxygenase (IDO) inhibitor and at least a chemotherapeutics.At least a chemotherapeutics can be selected from: paclitaxel (taxol ), cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cycli phosphate amine, CPT-11, the 5-fluorine derivant of urinating close pyridine (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.Taxol Provide by Hanna pharmaceutical Co. Ltd (German Wilmington city) with cisplatin.
In a specific implementations of the present invention, the chronic viral of being treated infects and is selected from: hepatitis B virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), epstein-barr virus (EB) (EBV), varicella zoster virus, Coxsackie virus and HIV (human immunodeficiency virus) (HIV).In a specific implementations, described chemical compound can be through the administration of pharmaceutical acceptable carrier medium.
The accompanying drawing summary
Figure 1A and 1B have shown the result who the IDO inhibitor is carried out the enzyme analysis.In human IDO research, as A) 1MT and B) when the MTH-tryptophan levels raises, the enzyme kinetics data are carried out overall nonlinear regression analysis.Adopt Prism4 software kit (GraphPad) to carry out the drawing and the analysis of data.The suitableeest Ki value of 1MT is 34.6 μ M, and the suitableeest Ki value of MTH-tryptophan is 11.4 μ M.
The analysis result of the horizontal IDO inhibitor of Fig. 2 showed cell.Suppress IDO, 1MT at 1MT and suppress in TDO and the MTH-Trp inhibition IDO test, the amplification of utilization 2log amount is studied.Adopt Prism4 software kit (GraphPad) to carry out the drawing and the analysis of data.Obtain the numerical value of Hillslope and EC50 by nonlinear regression analysis.
Fig. 3 is the sketch map of kynurenin metabolic pathway.IDO is a kind of liver oxidoreductase outer, that can induce IFN-γ that is present in.N-formoxyl kynurenin is the IDO product, can be hydrolyzed into kynurenin rapidly.Because the further azymia or the non-activity of metabolism kynurenin in the tissue, thus kynurenin be distributed in tissue and blood between.Though it is the intermediate product of nicotinamide adenine dinucleotide (NAD) biosynthesis pathway, the main reset mode of kynurenin is: change into xanthurenic acid (4,8-after urine is discharged at liver and/or kidney.(Takikawa etc. (1986) J.Biol.Chem..261:3648-3653; Thomas and Stocker (1999) Redox.Report4:199-220).
Fig. 4 A-D shows, mice serum is carried out the chromatogram of efficient liquid phase chromatographic analysis gained.Under 4 ℃, the blood sample of collecting is carried out cultivation overnight and removes blood clot preparing serum.Adopt the settlement separate protein of TCA.Test sample placed in the 250mm * 4.5mm Luna 5 μ C18 posts that are immersed in level pad dissolve, this level pad contains 20%MeOH, 5% acetonitrile, 10mM KPO 4(pH5.3) and 0.15mM EDTA.From handling following male FVB is that mice prepares serum sample: A) untreated (serum being mixed with following each control compound of 30 μ M: tryptophan, kynurenin and 1MT); B) untreated (can record the serum tryptophan of 55 μ M); C) LPS stimulates 24 hours (can record the kynurenin of 5.6 μ M); D) subcutaneous implantation 1MT ball 3 days (can record the 1MT of 104 μ M).In the time of 6.66 and 14.5 minutes, the output sensitivity is adjusted, to obtain optimization expection peak height value.The Ky=kynurenin, W=tryptophan, 1MT=1-methyl-tryptophan.
Fig. 5 is that (untreated) intend handled in expression or with 1MT, L-744,832 (FTI), 1MT add L-744,832 or 1MT add or do not add the diagrammatic sketch that gross tumor volume changes in the MMTVneu mice of some chemotherapeutics processing.The corresponding test mice of each data point, the average of strip chart registration strong point (listing in the figure below).
Fig. 6 shows, multiple IDO inhibitor material standed for is carried out The selection result behind the external biochemical analysis.Gained data and the kynurenin content under the condition when no IDO inhibitor is relevant.
Fig. 7 A and 7B show, multiple IDO inhibitor material standed for is carried out The selection result after cellular level is analyzed.Data among Fig. 7 A and the kynurenin content under the condition when no IDO inhibitor is relevant.Fig. 7 B shows the data relevant with fluorescence, and this fluorescence indicates the generation (being the IDO activity) of kynurenin.The expression vector that utilizes empty expression vector (carrier) or contain IDO cDNA carries out cell transfecting.
Fig. 8 represents multiple IDO inhibitor material standed for is carried out the data of the thio-hydantoin derivant of the relevant indole amine that obtains after the cellular level Analysis and Screening.Utilize empty expression vector (carrier) or contain IDO or the expression vector of TDO carries out cell transfecting.As a comparison, under adding 1MT, utilize the IDO expression vector to carry out analyzing behind the cell transfecting.
Fig. 9 represents some IDO inhibitor under the concentration of 250 μ M, its structure and inhibition IDO thereof and the active ability of TDO are carried out the chart that cellular level is analyzed.
Figure 10 shows provides diagrammatic sketch, confirms the toxicity of some IDO inhibitor to cancerometastasis mammary gland (being shown in top) cancer or prostate (being shown in the bottom) cancerous cell.Cell unprocessed (Untx) or adopt the inhibitor of 100 μ M to handle.
Figure 11 shows (being untreated) of intend handling or adds the gross tumor volume that paclitaxel (taxol ), cisplatin or 1MT add the MMTVneu mice of cisplatin treated with 1MT, paclitaxel (taxol ), 1MT and always changes.The corresponding test mice of each data point, the average of strip chart registration strong point (listing in the figure below).
Detailed Description Of The Invention
In an embodiment of the invention, provide one group of new IDO inhibitor. The present invention relates in addition to contain the pharmaceutical composition of described IDO inhibitor and it suppresses the method for tumor growth.
In another embodiment of the present invention, a kind of combined treatment is provided, comprising using IDO inhibitor and chemotherapeutics, thereby reach the purpose of establishment tumor growth.
In another embodiment of the present invention, a kind of combined treatment is provided, comprising using IDO inhibitor and signal transduction inhibitor (STI), thus but establishment tumor growth.
In another embodiment of the present invention, provide a kind of combined treatment, comprising using immunomodulator and chemotherapeutics, the method for establishment tumor growth thus.
According to another embodiment of the present invention, provide a kind of combined treatment that is used for the treatment of chronic viral infection, comprising using IDO inhibitor and chemotherapeutics.
I. definition
Term " IDO inhibitor " is meant that a class can suppress indoleamine 2,3-dioxygenase (IDO) thus activity reverse the medicine of the immunosuppressive action of IDO mediation.The IDO inhibitor can show as competitiveness, noncompetitive or irreversibility." competitive IDO inhibitor " is for suppress the chemical compound (for example, indefiniteness, 1-methyl-tryptophan) of IDO enzymatic activity in the catalytic site reversibility; " noncompetitive IDO inhibitor " can on-catalytic site reversibility suppress the IDO enzymatic activity (for example, indefiniteness, norharman); " irreversibility IDO inhibitor " thus be the chemical compound that can form the irreversible destruction IDO of covalent bond enzymatic activity, (for example, indefiniteness, cyclopropyl/acridinyl tryptophan derivative) with enzyme.
IDO inhibitor of the present invention comprises, but be not limited to: i) be accredited as in the past and have IDO and suppress active chemical compound, for example: 1MT (Sigma-Aldrich, St. Louis, the Missouri State), β-(3-benzofuranyl)-DL-alanine (Sigma-Aldrich), β-(3-benzo (b) thienyl)-DL-alanine (Sigma-Aldrich), 6-nitro-L-tryptophan (Sigma-Aldrich), indole 3-methanol (LKT laboratory; Sao Paulo, Minnesota State city), 3,3 '-two Yin stamp methane (DIM; The LKT laboratory), gallic acid epi-nutgall catechu phenolic ester (LKT laboratory), 5-bromo-4-chloro-indoxyl 1,3-diacetate (Sigma-Aldrich), 9-VCz (Sigma-Aldrich), acemetacin (Sigma-Aldrich), 5-bromo-DL-tryptophan (Sigma-Aldrich), 5-bromo indole diacetate (Sigma-Aldrich), brassilexin (Sigma-Aldrich), 3-amino-2-naphthoic acid (Sigma-Aldrich), B-carboline (Sigma-Aldrich), 3-butyl-B-carboline (Peterson, A.C. etc. (1993) Med.Chem.3:473-482), 6-fluoro-3-formyl-B-carboline (Sigma-Aldrich), 6-isothiocyanic acid-3-carbomethoxy (carbomethyoxy)-B-carboline (Sigma-Aldrich), 3-propoxyl group-B-carboline (Sigma-Aldrich), 3-carboxyl-B-carboline (Sigma-Aldrich), the 3-third oxygen formoxyl (carbopropoxy)-B-carboline (Sigma-Aldrich) and 3-carbon-uncle-butoxy-B-carboline (Sigma-Aldrich); Ii) find to have IDO and suppressed the active chemical compound of the present invention that is suitable for, but its antitumor action is not determined as yet, include, but are not limited to: phenyl-TH-DL-trp (3-(N-phenyl-thio-hydantoin)-indole) (Sigma-Aldrich), acrylic-TH-DL-trp (3-(N-pi-allyl-thio-hydantoin)-indole) (Asinex; Moscow, Russia) and methyl-TH-DL-trp (3-(N-methyl-thio-hydantoin)-indole) (Sigma-Aldrich); Iii) having found to have IDO suppresses active and is applicable to chemical compound of the present invention, and be used as antitumor agent, comprise singly and being not limited to: brassinin (LKT laboratory), 5-methyl-brassinin (Mehta etc. (1994) Anticancer.14:1209-1213), 3,3 '-di-indole methyl hydride (DIM; The LKT laboratory) and Indole-3-carbinol (13C; The LKT laboratory).
" signal transduction inhibitor " is the committed step of selective exclusion signal path in the normal function of cancerous cell, thereby brings out apoptotic medicine.
Signal transduction inhibitor of the present invention (STI) includes but not limited to: (i) bcr/abl inhibitors of kinases, as STI 571 (imatinib mesylate, Gleevec) and derivant; (ii) epidermal growth factor (EGF) acceptor inhibitor, as inhibitors of kinases (lressa, SSI-774) and antibody (Imclone:C225[Goldstein etc. (1995), Clin Cancer Res.1:1311-1318], and Abgenix:ABX-EGF); (iii) her-2/neu acceptor inhibitor such as Trastuzumab TM(Herceptin) and farnesyl transferase inhibitor (FTI) be as L-744,832 (Kohl etc. (1995), Nat Med.1 (8): 792-797); The (iv) inhibitor of Akt family kinases or Akt path, thunderous fearness mycin (referring to Sekulic etc. (2000) Cancer Res.60:3504-3513); (v) cell cycle kinase inhibitors is as by flavopiridol and UCN-01 (referring to Sausville (2003) Curr.Med.Chem. cancer therapy drug 3:47-56); (vi) phosphatidylinositols creatase inhibitor, as LY294002 (referring to Vlahos etc. (1994) J.Biol.Chem.269:5241-5248).
" the effectively therapeutic dose " of chemical compound or pharmaceutical composition is meant animal, especially be enough to regulate the amount of growth of tumor or transfer among the mankind, include but not limited to reduce tumor growth rate or volume or prevent from not have animal tumor formation, the i.e. preventive administration before administration that tumor forms.
" pharmacy can be accepted " is meant through the approval of the relevant administrative organization of federal government or state government or through American Pharmacopeia or other and is applicable to animal, the especially approval of listed relevant administrative organization in the Ren Lei general pharmacopeia.
" carrier " is meant diluent, adjuvant, excipient, adjuvant or helps the media of active agent delivery of the present invention.This class pharmaceutical carrier can be a sterilized liquid, and for example water and oils comprise oil, and animal, plant class or artificial oil are as Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Semen Sesami wet goods.The aqueous solution of water or saline solution and dextrose and glycerol is preferably used as carrier, particularly as injection solution.The description of relevant pharmaceutical carrier, can show referring to E.W.Martin " Remington ' s Pharmaceutical Sciences ".
" simultaneously " synchronous on expression (1) time, or the different periods during (2) same treatment.
" in proper order " administration of a kind of activating agent that uses in the described method of expression is to carry out after the administration of another activating agent.After giving certain activating agent, following a kind of activating agent can administration at once after first kind of active agent delivery basically; Or next activating agent can administration in the effectual time after first activating agent; Effectual time is meant from giving first kind of medicament and produces the time of maximum utility to it.
II. the therapy of treatment of cancer
The present invention also provides the pharmaceutical composition that contains at least a IDO inhibitor, wherein at least a IDO inhibitor contains at least a IDO that has that finds according to the present invention and suppresses active, but the not confirmed before this chemical compound of its antitumor action, this IDO inhibitor is selected from but is not limited to: phenyl-TH-DL-tryptophan (3-(N-phenyl-thio-hydantoin)-indole), acrylic-TH-DL-tryptophan (3-(N-alkene-propyl group-thio-hydantoin)-indole) and methyl-TH-DL-tryptophan (3-(N-methyl-thio-hydantoin)-indole), these inhibitor can be through the administration of pharmaceutical acceptable carrier medium.Described pharmaceutical composition can be with the treatment effective dose to its patient's administration of needs.
In addition, the invention provides a kind of method of treatment of cancer, at least a above-mentioned IDO inhibitor of the patient treatment effective dose of this method by needing it.
The treatable cancer of the present invention includes, but are not limited to: prostate, knot rectum, pancreas, cervix uteri, stomach, endometrium, brain, liver, wing take off, ovary, testis, head, cervical region, skin (comprising melanoma and basal cell carcinoma), a cortex, leukocyte (comprising lymphoma and leukemia), esophagus, mammary gland, muscle, connective tissue, lung (comprising small cell lung cancer and non-small cell carcinoma), adrenal gland, thyroid, kidney or bone; Also comprise following tumor: Glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, subcutaneous basal cell carcinoma and seminoma of testis.
III. the conjoint therapy of treatment of cancer
The invention provides the additive method that treatment suppresses.The combination that has been found that IDO inhibitor and STI according to the present invention has synergism for suppressing tumor growth.Thereby, the invention provides a kind of pharmaceutical composition of in the patient, treating cancer, said composition contains at least a IDO inhibitor and at least a STI in pharmaceutical acceptable carrier.A kind of method for cancer for the treatment of in the patient also is provided, and this method is by using at least a IDO inhibitor and at least a STI of effective dose.The IDO inhibitor that is fit to comprises that any IDO of having suppresses active chemical compound.As mentioned above, the STIs that is fit to includes, but are not limited to: (i) bcr/abl inhibitors of kinases, as STI 571 (imatinib mesylate, Gleevec) and derivant; (ii) epidermal growth factor (EGF) receptor suppresses, as inhibitors of kinases (lressa, SSI-774) and antibody (Imclone:C225[Goldstein etc. (1995), Clin Cancer Res..1:1311-1318], and Abgenix:ABX-EGF); (iii) her-2/neu acceptor inhibitor such as Trastuzumab TM(Herceptin) and farnesyl transferase inhibitor (FTI) be as L-744,832 (Kohl etc. (1995), Nat Med.1 (8): 792-797); (iv) Akt inhibitors of kinases or Akt path blocker, thunderous fearness mycin (referring to (2000) CancerRes.60:3504-3513 such as Sekulic); (v) cell cycle kinase inhibitors is as flavpiridol and UCN-01 (referring to Sausville (2003) Curr.Med.Chem. cancer therapy drug 3:47-56); (vi) phosphatidylinositols creatase inhibitor, as LY294002 (referring to Vlahos etc. (1994) J.Biol.Chem.269:5241-5248).
At least a IDO inhibitor can be selected from following chemical compound: confirmed in the past i) that having IDO suppressed active chemical compound, comprise, but be not limited to: 1-methyl-tryptophan (1MT), β-(3-benzofuranyl)-DL-alanine, β-(3-benzo (b) thienyl)-DL-alanine, 6-nitro-L-tryptophan, indole 3-methanol, 3,3 '-di-indole methyl hydride (DIM), epi-nutgall catechu phenol gallic acid (LKT laboratory), 5-bromo-4-chloro-indoxyl 1, the 3-diacetate, the 9-VCz, acemetacin, 5-bromo-DL-tryptophan, 5-bromo indole diacetate, brassilexin, 3-amino-2-naphthoic acid, B-carboline, 3-butyl-B-carboline, 6-fluoro-3-carbomethoxy-B-carboline, 6-isothiocyanic acid-3-carbomethoxy-B-carboline, 3-propoxyl group-B-carboline, 3-carboxyl-B-carboline, 3-third oxygen formyl-B-carboline, and 3-carbon-uncle-butoxy-B-carboline; Ii) found to have the chemical compound that IDO suppresses active and is applicable to the application, but its antitumor action is definite as yet, as: phenyl-TH-DL-trp (3-(N-phenyl-thio-hydantoin)-indole), acrylic-TH-DL-trp (3-(N-pi-allyl-thio-hydantoin)-indole) and methyl-TH-DL-trp (3-(N-methyl-thio-hydantoin)-indole).In some embodiments, one group of IDO inhibitor can comprise in addition that those have found to have IDO and suppressed chemical compound active, that be applicable to the application and be used as antitumor agent, it comprises, but be not limited to: brassinin, 5-methyl-brassinin, 3,3 '-di-indole methyl hydride (DIM) and Indole-3-carbinol (I3C).
According to a specific embodiment of the present invention, can give patient IDO inhibitor and at least a STI simultaneously or sequentially.In other words, at first use at least a IDO inhibitor, perhaps at least a IDO inhibitor and at least a STI administration simultaneously.In addition, when using more than a kind of IDO inhibitor and/or STI, then chemical compound can be with any order administration.
The cancer that is fit to scheme for combining treatment of the present invention includes, but are not limited to tumor type mentioned above.
Except that IDO, known other molecular substances also participate in immune regulation mechanism.These other molecules also may become the target molecule that suppresses tumor growth among the cancer patient.In view of the above, the invention provides the integrated processes of treatment of cancer, this method is by using at least a immunomodulator except that the IDO inhibitor, and at least a chemotherapeutics of coupling.The immunomodulator that can adopt among the present invention includes, but are not limited to: costimulatory molecules, as CD40L, B7 and B7RP1; The bonded active monoclonal antibody of costimulatory receptor (mAbs) together is as anti-CD 40, anti-cd 38, anti--ICOS and 4-IBB part; Dendritic cell antigen load (external or body in): dendritic cell Theratope; Cytokine/chemokines is as IL1, IL2, IL12, IL18, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa/b, M-CSF, IL-3, GM-CSF, IL-13 and anti-IL-10; Bacteria lipopolysaccharide (LPS); Immunostimulatory oligonucleotide is as poly CpG DNA (referring to Verthelyi and Zeuner (2003) Tr.Immunol.24:519-522).Suitable chemotherapeutics includes but not limited to following chemotherapeutics, and signal transduction inhibitor (STI) then as mentioned above.
In the present invention, the associating of also having found IDO inhibitor and chemotherapeutics can be worked in coordination with the inhibition tumor growth.Thereby, the invention provides a kind of in its patient of needs the pharmaceutical composition of treatment cancer, wherein in pharmaceutical acceptable carrier, comprise at least a IDO inhibitor and at least a chemotherapeutics.The present invention also provides a kind of method for cancer for the treatment of in the patient, this method is by using at least a IDO inhibitor and at least a chemotherapeutics of effective dose.The IDO inhibitor that is fit to comprises that any tool IDO suppresses active any chemical compound.Suitable chemotherapeutics includes, but are not limited to: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cycli phosphate amine, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.
At least a IDO inhibitor can be selected from: i) aforesaid known IDO inhibitor; The ii) aforesaid chemical compound of having found tool IDO inhibition activity and being applicable to the application.In some embodiments, one group of IDO inhibitor can comprise in addition finds that tool IDO suppresses active, is applicable to that the application and its have been used as the chemical compound of antitumor agent, comprise, but be not limited to: brassinin, 5-methyl-brassinin, 3,3 '-di-indole methyl hydride (DIM) and Indole-3-carbinol (I3C).
In a specific embodiment of the present invention, can simultaneously or sequentially at least a IDO inhibitor and at least a STI be administered to the patient.In other words, at first use at least a IDO inhibitor, perhaps at least a IDO inhibitor and at least a STI administration simultaneously.In addition, when more than a kind of IDO inhibitor and/or STI administration, then chemical compound can be with any order administration.
The cancer that is fit to scheme for combining treatment of the present invention includes, but are not limited to tumor type mentioned above.
IV. the conjoint therapy of chronic viral treatment of infection
The present invention also provides a kind of method that chronic viral infects for the treatment of, and this method is by using IDO inhibitor and chemotherapeutics.In addition, this method also comprises co-administered antiviral agent (medicine that promptly is used for the treatment of viral infectious) and IDO inhibitor and chemotherapeutics.
Thereby, the invention provides the pharmaceutical composition for the treatment of the chronic viral infection among the patient, wherein in pharmaceutical acceptable carrier, comprise at least a IDO inhibitor, at least a cancer treatment drugs, and optionally contain at least a antiviral agent.A kind of method that chronic viral infects for the treatment of also is provided, and this method is by using at least a IDO inhibitor of effective dose, and at least a chemotherapeutics of coupling, optionally uses at least a antiviral agent simultaneously.
At least a IDO inhibitor can be selected from: i) aforesaid known I DO inhibitor; The ii) aforesaid chemical compound of having found tool IDO inhibition activity and being applicable to the application.In some embodiments, one group of IDO inhibitor can comprise in addition finds that tool IDO suppresses active, is applicable to that the application and its have been used as the chemical compound of antitumor agent, comprise, but be not limited to: brassinin, 5-methyl-brassinin, 3,3 '-di-indole methyl hydride (DIM) and Indole-3-carbinol (I3C).
Suitable chemotherapeutics is all chemical compounds with active anticancer, and include but not limited to: (nitrogen mustards is as chlorambucil, cyclophosphamide, isofamide, dichloromethyldiethylamine, alkeran and uracil mustard for alkylating agent; Aziridines is as tespamin; The methanesulfonic acid esters is as busulfan; Nitroso-group carbamide class is as carmustine, lomustine and streptozotocin; The platinum complexing agent is as cisplatin and carboplatin; The biological reducing alkylating agent is as mitomycin, methylbenzyl hydrazine, dacarbazine and Altretamine); The DNA agent (as bleomycin) of unwinding; II type topoisomerase enzyme inhibitor (as amsacrine, more contain mycin, daunorubicin, idarubicin, dithranol, amycin, etoposide and teniposide); DNA minor groove binding (as plicamycin); (antifol is as methotrexate and trimetrexate for antimetabolite; The pyrimidine antagonist is as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytosine arabinoside and floxuridine; Purine antagonist is as purinethol, 6-thioguanine, fludarabine, pentostatin; Asparaginase; Ribonucleotide reductase inhibitor is as hydroxyurea); The tubulin reactant is (as vincristine, vinblastine and paclitaxel (taxol )); Hormones is (as estrogen; Conjugated estrogens; Estrin; Diethylstilbestrol; Chlortrianisen; Idenestrol; Progestational hormone is as delalutin, medroxyprogestetone acetate and megestrol; The androgen class is as guilt ball element, propanoic acid guilt ball element, fluorine first guilt ketone and methyl guilt ball element); Adrenocortical hormone (as prednisone, dexamethasone, methyl meticortelone and andrographolide); Lutropin releasing agent or GnRF antagonist (as leuprolide acetate and goserelin acetate); Hormone antagonist antigen (tamoxifen, antiandrogen such as flutamide; Antiadrenergic drug is as mitotane and aminoglutethimide).Preferably, this chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.
Suitable antiviral agent includes, but are not limited to: acyclovir; Gangcyclovir; Phosphine formic acid; Virazole; Antiretroviral agent is as nucleoside analog reverse transcriptase inhibitors (as Azidothymidine (AZT), didanosine, zalcitabine, lamivudine, take charge of his furan pyridine), non-nucleoside reverse transcriptase inhibitor (as uncommon peaceful, nevirapine), nucleoside analog reverse transcriptase inhibitors and protease inhibitor.
In a specific embodiment of the present invention, can use at least a IDO inhibitor and at least a chemotherapeutics to the patient simultaneously or sequentially.In other words, can at first use at least a IDO inhibitor, or at first use at least a chemotherapeutics, perhaps use at least a IDO inhibitor and at least a STI simultaneously.In addition, during as if the IDO inhibitor of using more than one and/or chemotherapeutics, chemical compound can be with any female administration.Similarly, can add at any time and use antiviral agent.
Chemical compound in this therapeutic alliance can also be used for local infection.Particularly, at least a IDO inhibitor, at least a chemotherapeutics, and can select at least a antiviral agent for use, can use and treat skin infection, as herpes zoster and wart.This compounds can pass through the acceptable topical carrier administration of pharmacy, includes but not limited to: the regular dosage form of gel, Emulsion, lotion, ointment, powder, gaseous solvents and other aid in skin administrations.
The treatable chronic viral of conjoint therapy of the present invention infects and includes, but are not limited to the disease that causes because of following factors: hepatitis B virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), epstein-barr virus (EB) (EBV), varicella zoster virus, Coxsackie virus and HIV (human immunodeficiency virus) (HIV).
It should be noted that said method also is applicable to treatment parasitic infection (as malaria), wherein become known for treating the chemical compound of parasitic disease randomly to substitute antiviral agent.
V. the administration of pharmaceutical composition and chemical compound
Pharmaceutical composition of the present invention can pass through any suitable administration, for example by the injection, oral, through lung, nasal administration or other administering modes.Usually, pharmaceutical composition of the present invention contains pharmacy acceptable diluent, antiseptic, solubilizing agent, emulsifying agent, adjuvant and/or mounting medium.Described compositions comprises: the diluent of different cushions (as Tris-hydrochloric acid (Tris-HCL), acetate, phosphate), Ph and ion concentration; Additive is as detergent and solubilizing agent (as Tween 80, polysorbate80), antioxidant (as ascorbic acid, sodium metabisulfite), antiseptic (as hydrargyrum, benzyl alcohol) and extender (as lactose, mannitol).This pharmaceutical composition can be doped in the microparticle formulation or liposome of poly-compounds such as polylactic acid, polyglycolic acid etc.This type of composition medicine compositions can influence the interior release rate of physical state, stability, body and the interior clearance rate of body of the composition of pharmaceutical composition of the present invention.Can be referring to the 1435th～1712 page of part of, Remington ' s Pharmaceutical Sciences the 18th edition (1990, Mack publishing company, Easton, PA 18042).Pharmaceutical composition of the present invention can be prepared into liquid or therapy in dry powder form (as lyophilized powder).The concrete approach of pharmaceutical composition administration as mentioned above.
In another embodiment, pharmaceutical composition of the present invention can pass through the controlled release system administration, for example adopts that intravenous is inculcated, implantable osmotic pump, transdermal patch, liposome, or other administering modes.In a specific embodiment, can adopt pump formula administering mode (referring to Langer, as above; Sefton, CRC Crit.Ref.Biomed.Eng. (1987) 14:201; Buchwald etc., Surgery (1980) 88:507; Saudek etc., N.Engl.J.Med. (1989) 321:574).In another embodiment, can use the administration of poly material (referring to Medical Applications of Controlled Releas, Langer and Wise (eds.), CRC publishing house: Boca Raton, Florida (1974); The bioavailability of controlled release drug, the invention of medicine and effectiveness, Smolen and Ball (eds.), Wiley: New York (1984); Ranger and Peppas, J.Macromol.Sci.Rev.Macromol.Chem., (1983) 23:61; Also can be referring to Levy etc., Sciencs (1985) 228:190; During etc., Ann.Neurol. (1989) 25:351; Howard etc., J.Neurosurg. (1989) 71:105).In another specific embodiment, controlled drug delivery system can be placed the target tissue near-end of animal; Make like this dosage only be the part that is administered systemically (referring to Goodson, the medical application of controlled release technology, as above, (1984) vol.2, pp.115-138).Particularly, controlled-release device can be incorporated into the proximal end of intravital suitable activation of animal or tumor.The argumentation of relevant other controlled release systems is referring to the summary (Scienc (1990) 249:1527-1533) of Langer.
Provide the following example that numerous embodiments of the present invention is described.These embodiment limit the present invention never in any form.
Embodiment 1:
The evaluation of Novel IDO inhibitor
1. the evaluation of Novel IDO inhibitor biochemical characteristic:
General introduction: the biochemistry of IDO is clear at present, and this enzyme was separated first in 1963.(Higuchi, K. etc. (1963) Federation proc.22:243 (summary); Shimizu, T. etc. (1978) J.Biol.Chem.253:4700-6).IDO is a kind of haplotype, contains the oxidoreductase of haemachrome that its molecular weight is about 41kDa.For keeping the active ferrous iron form in the external catalytic process, need to use methylene blue and peroxide or Reducing agent (as ascorbic acid).In vivo, suggestion flavin or the alternative methylene blue of tetrahydrobiopterin dye, and may have the specificity site of noncompetitive IDO inhibitor.Mammalian genes can be expressed in antibacterial through cloning and histidine mark, can produce active enzyme (Littlejohn, T.K. etc. (2000) Prot.Exp.Purif.19:22-29).This biochemical analysis for enzyme provides source easily.Measure transforming the kynurenin (hydrolyzate of N-formyl-kynurenin) that generates by tryptophan in the conventional IDO active biochemical that adopts photometry is analyzed, this biochemical analysis can carry out at enzyme level and cellular level.This enzyme level analysis suppresses active chemical compound flexible, high-throughout method is provided for evaluation has IDO.This analytical method also can be used for measuring the Ki value of special compound, and its exploitation for the SAR of different series of compounds is significant.The IDO that the cellular level analysis can be used for measuring known compound suppresses active, and reaches initially selecting the inhibition ability of bioavailability-be IDO in the chemical compound pair cell.In cellular level is analyzed, can pass through the contrast of tryptophan dioxygenase (TDO also has document to claim TDO2) and other known tryptophan alienation enzymes, carry out the inhibiting mensuration of IDO.
Method: isolated cDNA clone's thing of the mankind and mice IDO at present and passed through the order-checking check.For the enzyme in the preparative biochemistry research, use IPTG induces the IDO protein of pET5a carrier system synthetic C-terminal His-labelling in escherichia coli, and separates by the nickel post.Adopt gel electrophoresis that the proteic product of partial purification is measured, and can calculate its concentration by the protein standard substance contrast.For detecting the enzymatic activity of IDO, according to disclosed detection method (Littlejohn, T.K. etc. (2000) Prot.Exp.Purif.19:22-29; Takikawa, O. etc. (1988) J.Biol.Chem.263:2041-8), the kynurenin that adopts 96 orifice plate spectrphotometric method for measuring to generate, thus the IDO enzymatic activity can be detected.IDO suppresses active evidence for screening, single concentration can be mixed with the IDO enzyme of 50ng as the chemical compound of 200 μ M to reach 100 μ l reaction volumes, and adding concentration increases progressively the tryptophan of (0,2,20 and 200Mm).Can the kynurenin that generate be detected after 1 hour.Can collect more multienzyme dynamics data, so that choose compound of interest.The mensuration of the suitableeest Ki value (11.4 μ M) of the suitableeest Ki value of relevant 1MT (34.6 μ M) and MTH-tryptophan is shown in Figure 1A and 1B.These data show that thio-hydantoin can directly suppress the DOI enzymatic activity, compare with 1MT, and this inhibitory action is strong about 3 times.
Following method is the example that cellular level is analyzed.The Lipofectamine 2000 (lnvitrogen) that adopts manufacturer to recommend induces plasmid to make the COS-1 cell that temporary transfection take place with the CMV promoter of expressing IDO cDNA.Follow the cell of (campanion) series with the temporary transfection of TDO expression plasmid.Transfection was dispensed to 96 orifice plate lattice with this cell after 48 hours, and every hole contains 6 * 10 4Individual cell.Next day, the flushing orifice plate also adds new culture medium (no phenol red) and the inhibitor that contains 20 μ g/ml tryptophans.End this reaction after 5 hours, abandoning supernatant adopts with enzyme and detects identical photometry detection kynurenin water.(Littejohn, T.K. etc. (2000) Prot.Exp.Purif.19:22-29; Takikawa, O. etc. (1988) journal of biological chemistry .263:2041-8).For obtaining to the active initial confirmation of IDO, can to single concentration for example the chemical compound of 100Mm assess.The performance that the more multiple dose of collection selected compounds increases.The mensuration of the EC50 value (EC50=12.9 μ M) of the EC50 value of relevant 1MT (EC50=267 μ M) and MTH-tryptophan as shown in Figure 2.These data show, compare with 1MT, and the inhibitory action of IDO is stronger in the MTH-tryptophan pair cell, is about the former 20 times.
2. find to have the evaluation that IDO suppresses the pharmacodynamics/pharmacokinetics of active chemical compound among the application:
Overview: the IDO activation in the multiple tissue is brought out in the intraperitoneal administration of bacteria lipopolysaccharide (LPS), thereby generates kynurenin and be released into (Fig. 3) in the blood.But give kynurenin level peaking after LPS1 days (Takikawa, O. etc. (1986) H.Biol.Chemm.261:3648-53; Yoshida, H etc. (1998) Cell 94:739-750).Serum levels based on detecting kynurenin and tryptophan carries out pharmacodynamic analysis.The ratio that calculates kynurenin/tryptophan to be estimating the IDO activity, this activity and baseline tryptophan levels (Fuchs.D. etc. (1991) Immunol.Lett.28:207-11 that has nothing to do; Gasse, T etc. (1994) Eur.J.Clin.Chem.Clin Biochem.32:685-9), and the active detection method of this IDO is usually used in human body.Compare with the direct detection of IDO enzymatic activity in the tissue, the major advantage of this method is that it is non-invasion procedure, can gather a plurality of samples from same animal.Can guarantee by this method single mice to be carried out the active detection of IDO at many time points.Adopt the HPLC analytic process can detect the serum levels of tryptophan and kynurenin.The serum-concentration of chemical compound also can adopt identical HPLC method to measure, thus synchronous acquisition pharmacokinetic data available in single test.
Method: because its genetic background is with to be used for the MMTV-neu female mice that assessing compound tires in mammary tumor model identical, FVB MMTV-neu male mice (8～10 all ages) can be utilized and carry out pharmacodynamic analysis.When being compared analysis, the LPS preparation from different strains finds, the LPS that bring out Salmonella Minnesota mutant R-595 (S.mimesotaR) can cause highly continuing level the kynurenin inducing action (Yoshida, R. etc. (1981) Arch.Biochem.Biophys.212:629-37).Because it provides the wideest form for the effect of assessment IDO inhibitor, so this LPS preparation can be used for pharmacodynamic analysis.Report is arranged, the interior injected dose of vena minima of bringing out the active S.minnesota R of maximum IDO LPS is～1mg/kg, and adopting the LPS treatment after～24 hours, that the IDO activity can reach is maximum (Yoshida, R. etc. (1981) Arch.Biochem.Biophys..212:629-37).
Can carry out detection by quantitative (Hwu.P. etc. (2000) J Immunol 164:3596-9 to the serum levels of kynurenin and tryptophan by the HPLC analytic process; Widner, B etc. (1997) Clin.Chem.43:2424-6; Fig. 4 A-4D).By this method, the serum-concentration that records kynurenin is at least 1.25 μ M, and tryptophan is at least 3 μ M.For unprovoked FVB male mice, the interior kynurenin serum levels of its body is in or is lower than detectability, and the level of tryptophan is easy to measure, and is 50 μ M (Fig. 4 B).LPS stimulated back 24 hours, lured that serum kynurenin level reaches～6 μ M (Fig. 4 C) into.When being at least 5 μ M, the concentration of 1MT in serum also can effectively detect.Its serum levels is well below～100 μ M (Fig. 4 D) when the biological effective dose of use 1MT reaches 2 * 140mg 1MT pill.
Chemical compound assessed at first need apply LPS and stimulate, when the kynurenin serum levels is in plateau, give the chemical compound of bolus injection dosage subsequently.Because the half-life of kynurenin in serum is less than 10 minutes, (Bender and McCreanor (1982) Biochim.Biophys.Acta.717:56-60 so its level can descend rapidly; Takikawa, O. etc. (1986) J.Biol.Chem.261:3648-53), therefore the kynurenin that is pre-stored in is not considered to excessively to cover the impact effect that inhibition IDO generates kynurenin.The selection of drug administration carrier is depended primarily on the physical characteristic of chemical compound.Preferred carrier is an isotonic saline solution, but requires chemical compound water soluble solution.If some chemical compound of precognition can't fully dissolve, can use Methocel in this case Or Tween Suspension (0.5% methylcellulose or 1%Tween 80).
The mice that can select for use non-LPS to expose in each test is tested (with the baseline values of mensuration kynurenin, thereby comparing with other mices) and only gives the mice (for the IDO activity provides positive control) of the LPS exposure of carrier.Give behind the mice LPS it to be monitored, should implement euthanasia to it immediately if the sign (as fur gauffer, dull) of tangible endotoxemia occurs.Each chemical compound can be at first assessed with the high dosage of single i.p. of 100mg/kg at least in mice.At the appointed time at interval (for example, behind the administered compound 5,15,30 minutes, 1,2,4,6,8,24 hour) interior blood sample collection (every part 50 μ l), detect kynurenin and tryptophan levels (pharmacodynamic analysis) by HPLC, and the level of detection compound (pharmacokinetic analysis).According to the pharmacokinetics data, can measure the peak serum-concentration of chemical compound, and can calculate clearance rate.By the chemical compound serum levels of comparison different time points and the ratio of kynurenin/tryptophan, but rough calculation goes out the effective IC50 value when suppressing in the IDO body.
Based on the result of single dose research, can carry out secondary dosage to each active compound and increase research.For example, the target of this research can be that administration concentration peaking in one group of mouse test (if possibility) also produces the 100%IDO inhibition, thereby reach maximum dosage, in another group test, administration concentration reduces with 3 times of amounts, thereby has covered the 2log between maximal dose and the minimum dose 10Scope.Can accurately measure IC by above-mentioned data 50This method can be used for the oral administration biaavailability of test organisms reactive compound equally, at first tests the single Cmax of each chemical compound p.o. dosage, and further assessing chemical compound then increases the remarkable oral effect of performance in the research at dosage.Irrelevant for guaranteeing medicine body internal reaction and both sexes sex, can carry out single dose i.p. medicine-feeding test to female mice, the dosage of each reactive compound is IC 50
Embodiment 2:
The use in conjunction treatment tumor of IDO inhibitor and signal transduction inhibitor
Use MMTVneu transgenic " breast carcinoma mice (the oncomouse) " model of breast carcinoma to detect IDO inhibitor and STI to the physiopathologic influence of tumor.Make the MMTVneu transgenic mice develop into the aggressive breast tumor, it and PD people's duct carcinoma are similar.In this MMTVneu mouse model, the tissue specific expression by the HER-2/Neu gene mutation body brings out breast carcinoma, and this gene often is in state of activation when suffering from aggressive people mammary gland duct carcinoma.HER-2 belongs to a member of cell surface growth factor receptors EGF-R family.Myc is the downstream effect thing of HER-2Neu, can bring out cancer.Make female MMTVneu " breast carcinoma mice " copulation twice, to bring out the expression of mouse mammary tumor virus (MMTV) promoter; This promoter can be brought out transcribing of Neu/HER2 oncogene in the mammary gland tissue.The occurrence rate of the mouse mammary tumor at 5 monthly ages surpasses 90% in this model system.To have～150mm 3The MMTVneu of tumor size " breast carcinoma mice " random packet is matched group and test processed group.For control group mice implant the comfort dosage form regularly discharge pill (Innovative Research, Inc., Sarasota, FL).The mice of test group is that (1) is implanted the timing contain 1MT and discharged pill, and (2) use L-744, and 832 handle, or (3) implant and contain the pill that 1MT regularly discharges, and uses L-744,832 processing.L-744,832 is a kind of potent, selectivity farnesyl tranfering enzyme (FTI) inhibitor, its simulation has increased CaaX motif (Kohl etc., (1995) Nat Med.1 (8): 747-748) of farnesyl-.
This regularly discharges pill and contains a kind of inertia copolymer that can dissolve, resolve into innocuous substance gradually, and this innocuous substance mainly is local distribution in process of the test.It is 10mg/ days (claiming according to the medicine seller) that this slow release pill that contains 1MT discharges dosage, and sustainable release 14 days (Innovative Research, Inc., Sarasota, FL).Implant 2 pills for every mice, thereby discharge 20mg/ days accumulated dose.Thereby accumulated dose is that 800mg/kg/ days or 280mg continue 14 days for a 25g mice.According to the description of manufacturer, in 12～24 hours, reach steady-state level, and be maintained at during the whole test.This dosage effectively induces the allogeneic conceptus to repel (result of the test is not delivered for A.Muller, J.B.DuHadaway.G.C.Prendergast), also as (Science281:1199-1193,1998) as described in the Munn etc.
Mouse muscle is injected ketamine/xylazine anesthesia back, and this regularly discharges pill in the subcutaneous implantation in its back.Use mosquito forceps to carry out passivity and dissect, skin is separated with lower floor muscle, form subcutaneous pocket shape gap.1 or 2 biodegradable timing is discharged pill implant in this gap, but not directly place the otch below, to prevent to produce mechanical pressure and wound dehiscence.With suture clip otch is sealed.Still have conceived ability based on being loaded with the female mice that the comfort dosage form regularly discharges tablet, thereby the adverse effect that the test intervention is produced can be ignored.
Relevant signal transduction inhibitor, as FTI L-744,832 preparation and administering mode are as (Nature Med. (1995) 1:792-797) as described in Kohl etc.
Fig. 5 represents to test 1MT and FTI L-744, the discovery in 832 the synergistic test, and this causes establishing the degeneration of tumor in MMTVneu " breast carcinoma mice " model.Duration of test in 2 weeks finds that the gross tumor volume of the control group mice of simulation process increases 200%.Discharge the 20mg/ days 1MT that pill discharges by subcutaneous timing and handle mices, can slow down but can't stop tumor growth.Similarly, use FTI L-744,832 processing tumor-bearing mices also slow down but can't stop tumor growth.On the contrary, 1MT and L-744,832 associating can make the tumour regression in the model.
Embodiment 3:
Novel IDO inhibitor
According to screening multiple chemical compound as the effect of IDO inhibitor.Biochemical analysis below adopting screens some chemical compound.IDO cDNAs can express in antibacterial, synthetic histidine tagged protein and purified processing, method the same (Littlejohn etc. (2000) Prot.Exp.Purif.19:22-29).In brief, purified IDO cultivates with substrate and not commensurability IDO inhibitor material standed for.Because the product kynurenin has fluorescence, so can determine the effect of follow-up inhibitor by the fluorescence of assaying reaction mixture.The external biochemical process of relevant employing carries out results of screening, as shown in Figure 6.
Also can by the cellular level analysis to candidate compound screen (related genera can be referring to Munn like analytic process etc. (1999) J.Exp.Med..189:1363-1372).In brief, personnel selection IDO or the temporary transient transfection people of TDO Cdna expression vector 293/Phoenix cell.The candidate compound of variable concentrations is joined this cells transfected.Use fluorescence method that the kynurenin in the tissue culture medium (TCM) is carried out quantitative assay.The result of these tests is referring to Fig. 7～9.
As shown in the figure, the most effective inhibitor through confirming is the thio-hydantoin derivant of indole amine.Fig. 8 shows the result of the test that adopts this class special inhibitor.Wherein rendeing a service the strongest in these inhibitor is methyl-TH-DL-tryptophan, and the active inhibitory action of its IDO is 2.7 times (Fig. 9) of 1MT (concentration is 250Mm).
Except that the thio-hydantoin derivant of indole amine, also can screen natural materials.What is interesting is that the effective inhibitor that wherein filters out makes from the chemical compound with anticancer property food (as brassicaceous vegetable).Brassinin is a kind of chemical compound that is found in Chinese cabbage, in the natural product of measuring the IDO inhibitor, and its effectiveness the strongest (Fig. 7 A).
Tackle some chemical compound in addition and carry out the toxicity detection through screening.As shown in figure 10, most of IDO inhibition chemical compounds itself there is no growth inhibited or toxic action (Figure 10) for breast carcinoma or prostate gland cancer cell through oncogenic transformation.
Embodiment 4:
IDO inhibitor and cellulotoxic chemotherapeutics use in conjunction treatment tumor
Adopt MMTVneu transgenic " breast carcinoma mice " model to detect IDO inhibitor and cellulotoxic chemotherapeutics in the physiopathologic influence of tumor.
To have 150mm 3The MMTVnet of size tumor " breast carcinoma mice " random packet is matched group and test of cure group.Control mice implant the comfort dosage form regularly discharge pill (InnovativeResearch, Inc., Sarasota, FL).The mice of test group discharges pill for (1) implants the timing that contains 1MT, and as described in embodiment 2, (2) use paclitaxel (taxol ) or other cell toxicity medicaments handle, or (3) implant the timing that contains 1MT and discharge pill, and give paclitaxel or other cell toxicity medicaments.
Discharge pill for subcutaneous the implantations timing of mouse back, method is as described in the embodiment 2.
The preparation of cellulotoxic chemotherapeutics and administration process, as described below.Paclitaxel is dissolved in the dehydrated alcohol of volume and clinical Cremophor as solubilizing agent EL.This solution is placed this 20mg/ml stock solution 1 weeks down at 4 ℃ then through supersound process 30 minutes.Before the use, solution dilution is become 1: 5 with physiological saline solution.Give the paclitaxel that the injection of (through the tail vein) single dose is prepared as upper type in the mouse vein.Can be in advance mouse tail being carried out warm processing helps the identification vein to go forward side by side to inject in the row vein.In the test of 2 weeks, paclitaxel maximum tolerated dose (MTD) is 13.3mg/kg, can divide 5 administrations, and administration (is to implant pill Friday 3 times weekly; Monday/Wednesday/Friday, inject paclitaxel Monday/Wednesday; Put to death animal Friday, carry out tumor analysis).The MTD of cisplatin (1mg/kg) obtains through prepared in saline in clinical, and its intravenous injection administering mode is identical.The mice of control treatment only accepts not contain the Cremophor of paclitaxel The EL carrier formulation.
Discovery to 1MT test in Figure 11 and table 1 is summarized, and this test causes having the degeneration (relevant other chemotherapeutics can referring to Fig. 5) of tumor to 1MT and two kinds of cell toxicity medicaments synergism in MMTVneu " breast carcinoma mice " model.Find that in the test in 2 weeks the gross tumor volume of the control mice of simulation process increases by 200%.Discharge the 20mg/ days 1MT that pill gives by subcutaneous timing and handle mices, can slow down but can't stop tumor growth.Similarly, reaching maximum tolerated dose in the mouse vein have tumor injection paclitaxel or cisplatin treated also can slow down but can't stop tumor growth.On the contrary, the combination of 1MT and paclitaxel or cisplatin makes the tumour regression in the model.When paclitaxel be reduced to MTD～also can obtain similar results (not showing related data) 25% the time.Cell toxicity medicament used in the research has toxic action to the T cell, and the IDO inhibitor can make T cellular-restoring and activation, and these results are unforeseen in the prior art
Be untreated 1MT only Taxol The 1MT+ taxol Cisplatin The 1MT+ cisplatin
Mice quantity 5 5 195.1 97.54 43.62 122.2 134.4 336.5 73.95 316.2 5 7 80.27 73.12 27.64 0 25 72.87 130.4 215 12.65 147.9 5 6 139.4 118.1 48.2 20 40.25 130.4 247.6 360.8 15.52 263.3 6 9 -30.2 30.7 10.23 -78.4 -56.5 -23.44 -6.445 12.5 -53.8 -6.605 3 5 91.35 118.5 53 -26.53 40 255.6 -55.79 238.5 3 5 -27.94 35.1 15.7 -67.86 -30.56 14.29 -71.52 15.64
The tumor number
Meansigma methods
Standard deviation
Standard error
Minima
25% percentage place value
Intermediate value
75% percentage place value
Maximum
95% credibility interval, left side
95% credibility interval, right side
Table 1
Mice is handled the back tumor of MMTVneu mice is carried out statistical analysis.Relatively the gross tumor volume before treatment back and the treatment draws percent value.Be lower than 95%CL and be higher than 95%CL representative less than with greater than 95% credibility interval.
The tumor biopsy of taking from matched group and test group mice is carried out histology and immunohistochemical analysis, and the result shows: only significant change occurs at the mouse test group tumor tissues that gives therapeutic alliance.Introducing most what attract attention is that the evidence of the infiltration of obviously hemorrhage, natural death of cerebral cells and CD3 positive T cell can be found (data does not show) in accepting the mice of scheme for combining.In a word, the use in conjunction of 1MT and cell toxicity medicament can effectively be induced the degeneration that has breast tumor in MMTVneu " breast carcinoma mice " model system.
Though above stated the application's some preferred implementation and instantiation, its application is not confined to these embodiments.Also allow in the application's scope related content to be improved, details are referring to following claims.
Quote some publications and patent documentation in the application's book, be intended to the situation of the affiliated prior art of full-time instruction the application.These citing documents content separately is hereby incorporated by.

Claims (52)

1. treat method for cancer for one kind in its patient of needs, this method comprises at least a indoleamine 2 of administering therapeutic effective dose, 3-dioxygenase (IDO) inhibitor and at least a signal transduction inhibitor (STI) simultaneously or sequentially to this patient.
2. the process of claim 1 wherein that at least a STI is selected from bcr/abl inhibitors of kinases, epidermal growth factor (EGF) acceptor inhibitor, her-2/neu acceptor inhibitor, farnesyl transferase inhibitor (FTI), AKt family kinase inhibitors or Akt path blocker and cell cycle kinase inhibitors.
3. the method for claim 2, wherein at least a STI also can be selected from: STI 571, SSI-774, C225, ABX-EGF, Herceptin, L-744,832, rapamycin, LY294002, flavopiridal and UNC-01.
4. the method for claim 3, wherein at least a STI is L-744,832.
5. the method for claim 1, wherein at least a IDO inhibitor is selected from: 1-methyl DL-tryptophan (1MT), β-(3-benzofuranyl)-DL-alanine, β-(3-benzo (b) thienyl)-DL-alanine, 6-nitro-L-tryptophan, indole 3-methanol, 3,3 '-di-indole methyl hydride, brassinin, 5-methyl-brassinin, gallic acid epi-nutgall catechu phenolic ester, 5-bromo-4-chloro-indoxyl 1, the 3-diacetate, the 9-VCz, acemetacin, 5-bromo-DL-tryptophan, 5-bromo indole diacetate, phenyl-TH-DL-trp, acrylic-TH-DL-trp, methyl-TH-DL-trp, brassilexin, 3-amino-2-naphthoic acid, B-carboline, 3-butyl-B-carboline, 6-fluoro-3-carbomethoxy-B-carboline, 6-isothiocyanic acid-3-carbomethoxy-B-carboline, 3-propoxyl group-B-carboline, 3-carboxyl-B-carboline, 3-propyl ester base-B-carboline, and 3-carbon-uncle-butoxy-B-carboline.
6. the method for claim 5, wherein at least a I DO inhibitor is 1-methyl-tryptophan (1MT).
7. the process of claim 1 wherein and use at least a IDO inhibitor and at least a STI simultaneously.
8. the process of claim 1 wherein and use at least a IDO inhibitor and at least a STI in proper order.
9. the method for claim 8, wherein at least a IDO inhibitor is to use before at least a STI.
10. the method for claim 8, wherein at least a STI used before at least a IDO inhibitor.
11. the process of claim 1 wherein that described cancer is selected from following cancer: prostate, knot rectum, pancreas, cervix uteri, stomach, endometrium, brain, liver, wing take off, ovary, testis, head, cervical region, skin (comprising melanoma and basal cell carcinoma), a cortex, leukocyte (comprising lymphoma and leukemia), esophagus, mammary gland, muscle, connective tissue, lung (comprising small cell lung cancer and non-small cell carcinoma), adrenal gland, thyroid, kidney or bone; Also comprise: Glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, subcutaneous basal cell carcinoma and seminoma of testis.
12. a pharmaceutical composition for the treatment of cancer wherein contains at least a indoleamine 2 for the treatment of effective dose in the pharmaceutical acceptable carrier medium, 3-dioxygenase (IDO) inhibitor and at least a signal transduction inhibitor (STI).
13. the pharmaceutical composition of claim 12, wherein at least a STI is selected from: bcr/abl inhibitors of kinases, epidermal growth factor (EGF) acceptor inhibitor, hef-2/neu acceptor inhibitor, farnesyl transferase inhibitor (FTI), Akt family kinase inhibitors or Akt path blocker and cell cycle kinase inhibitors.
14. the pharmaceutical composition of claim 13, wherein at least a STI is selected from: STI 571, SSI-774, C225, ABX-EGF, Herceptin, L-744,832, rapamycin, LY294002, flavopiridal and UNC-01.
15. the pharmaceutical composition of claim 13, wherein at least a STI is L-744,832.
16. the pharmaceutical composition of claim 12; wherein at least a IDO inhibitor is selected from: 1-methyl DL-tryptophan (1MT); β-(3-benzofuranyl)-DL-alanine; β-(3-benzo (b) thienyl)-DL-alanine; 6-nitro-L-tryptophan; indole 3-methanol; 3; 3 '-di-indole methyl hydride; brassinin; 5-methyl-brassinin; gallic acid epi-nutgall catechu phenolic ester; 5-bromo-4-chloro-indoxyl 1,3-diacetic acid enzyme; the 9-VCz; acemetacin; 5-bromo-DL-tryptophan; 5-bromo indole diacetate; phenyl-TH-DL-tryptophan; acrylic-TH-DL-tryptophan; methyl-TH-DL-tryptophan; brassilexin; 3-amino-2-naphthoic acid; B-carboline; 3-butyl-B-carboline; 6-fluoro-3-carbomethoxy-β carboline; the different methyllanthionine of 6--3-carbomethoxy-β-click beautiful jade; 3-propoxyl group-B-carboline; 3-carboxyl-B-carboline; 3-third oxygen formoxyl-B-carboline; and 3-carbon-uncle-butoxy-B-carboline.
17. the pharmaceutical composition of claim 12, wherein at least a I DO inhibitor is 1-methyl DL-tryptophan (1MT).
18. treat method for cancer for one kind in its patient of needs, this method comprises the immunomodulator except that the IDO inhibitor of administering therapeutic effective dose and at least a cell toxicity medicament or at least a STI of treatment effective dose simultaneously or sequentially to this patient.
19. the method for claim 18, wherein at least a immunomodulator is selected from: CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB part, dendritic cell Theratope, IL2, IL12, ELC/CCL19, SLC/CCL21, MCP-1), IL-4, IL-18, TNF, IL-15, MDC, IFN a/b, M-CSF, IL-3, GM-CSF, IL-13, anti-IL-10, LPS and poly CpG DNA.
20. the method for claim 18, wherein at least a cellulotoxic chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.
21. the method for claim 18, wherein at least a STI is selected from: STI 571, SSI-774, C225, ABX-EGF, Herceptin, L-744,832, rapamycin, LY294002, flavpiridal and UNC-01.
22. the method for a tumor chronic viral infection in its patient of needs, this method comprise at least a indoleamine 2 of administering therapeutic effective dose simultaneously or sequentially to this patient, 3-dioxygenase (IDO) inhibitor and at least a chemotherapeutics.
23. the method for claim 22; wherein this at least a IDO inhibitor is selected from: 1-methyl DL-tryptophan (1MT); β-(3-benzofuranyl)-DL-alanine; β-(3-benzo (b) thienyl)-DL-alanine; 6-nitro-L-tryptophan; indole 3-methanol; 3; 3 '-di-indole methyl hydride (DIM); brassinin; 5-methyl-brassinin; gallic acid epi-nutgall catechu phenolic ester; 5-bromo-4-chloro-indole phenol 1, the 3-diacetate; the 9-VCz; acemetacin; 5-bromo-DL-tryptophan; 5-bromo indole diacetate; phenyl-TH-DL-color-propylhomoserin; acrylic-TH-DL-tryptophan; methyl-TH-DL-tryptophan; brassilexin; 3-amino-2-naphthoic acid; B-carboline; 3-butyl-B-carboline; 6-fluoro-3-carbomethoxy-B-carboline; 6-isothiocyanic acid-3-carbomethoxy-B-carboline; 3-propoxyl group-B-carboline; 3-carboxyl-B-carboline; 3-third oxygen formoxyl-B-carboline; and 3-carbon-uncle-butoxy-B-carboline.
24. the method for claim 22, wherein at least a IDO inhibitor are 1-methyl DL-tryptophan (1MT).
25. the method for claim 22, wherein at least a chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.
26. the method for claim 22 is wherein used at least a IDO inhibitor and at least a chemotherapeutics simultaneously.
27. the method for claim 22, wherein order is used at least a IDO inhibitor and at least a chemotherapeutics.
28. the method for claim 27, wherein at least a IDO inhibitor is to use before at least a chemotherapeutics.
29. the method for claim 27, wherein at least a chemotherapeutics are to use before at least a IDO inhibitor.
30. the method for claim 22, wherein said chronic viral infect and are selected from: hepatitis B virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), epstein-barr virus (EB) (EBV), varicella zoster virus, Coxsackie virus and HIV (human immunodeficiency virus) (HIV).
31. treat the pharmaceutical composition that chronic viral infects for one kind, said composition contains at least a indoleamine 2 for the treatment of effective dose in the pharmaceutical acceptable carrier medium, 3-dioxygenase (IDO) inhibitor and at least a chemotherapeutics.
32. the pharmaceutical composition of claim 31; wherein the inhibitor of at least a IDO is selected from: 1-methyl DL-tryptophan (1MT); β-(3-benzofuranyl)-DL-alanine; β-(3-benzo (b) thienyl)-DL-alanine; 6-nitro-L-tryptophan; indole 3-methanol; 3; 3 '-di-indole methyl hydride (DIM); brassinin; 5-methyl-brassinin; gallic acid epi-nutgall catechu phenolic ester; 5-bromo-4-chloro-indoxyl 1, the 3-diacetate; the 9-VCz; acemetacin; 5-bromo-DL-tryptophan; 5-bromo indole diacetate; phenyl-TH-DL-tryptophan; acrylic-TH-DL-tryptophan; methyl-TH-DL-tryptophan; brassilexin; 3-amino-2-naphthoic acid; B-carboline; 3-butyl-B-carboline; 6-fluoro-3-carbomethoxy-B-carboline; 6-isothiocyanic acid-3-carbomethoxy-B-carboline; 3-propoxyl group-B-carboline; 3-carboxyl-B-carboline; 3-third oxygen formoxyl-B-carboline; and 3-carbon-uncle-butoxy-B-carboline.
33. the pharmaceutical composition of claim 32, wherein at least a IDO inhibitor are 1-methyl DL-tryptophan (1MT).
34. the pharmaceutical composition of claim 31, wherein at least a chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.
35. in its patient of needs, treat method for cancer for one kind, this method comprises at least a indoleamine 2 to this patient's administering therapeutic effective dose, 3-dioxygenase (IDO) inhibitor inhibitor, wherein this IDO inhibitor is selected from: phenyl-TH-DL-Trp (3-(N-phenyl-thio-hydantoin)-indole), acrylic-TH-DL-trp (3-(N-pi-allyl-thio-hydantoin)-indole) and methyl-TH-DL-trp (3-(N-methyl-thio-hydantoin)-indole).
36. the method for claim 35, wherein said cancer is selected from following cancer: prostate, knot rectum, pancreas, cervix uteri, stomach, endometrium, brain, liver, wing take off, ovary, testis, head, cervical region, skin (comprising melanoma and basal cell carcinoma), a cortex, leukocyte (comprising lymphoma and leukemia), esophagus, mammary gland, muscle, connective tissue, lung (comprising small cell lung cancer and non-small cell carcinoma), adrenal gland, thyroid, kidney or bone; Also comprise: Glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, subcutaneous basal cell carcinoma and seminoma of testis.
37. pharmaceutical composition for the treatment of cancer, said composition contains the indoleamine 2 of at least a treatment effective dose in the pharmaceutical acceptable carrier medium, 3-dioxygenase (IDO) inhibitor, wherein this IDO inhibitor is selected from: phenyl-TH-DL-Trp (3-(N-phenyl-thio-hydantoin)-indole), acrylic-TH-DL-trp (3-(N-pi-allyl-thio-hydantoin)-indole) and methyl-TH-DL-trp (3-(N-methyl-thio-hydantoin)-indole).
38. treat method for cancer for one kind in its patient of needs, this method comprises at least a indoleamine 2 of administering therapeutic effective dose simultaneously or sequentially, 3-dioxygenase (IDO) inhibitor and at least a chemotherapeutics.
39. the method for claim 38, wherein at least a chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.
40. the method for claim 39, wherein at least a chemotherapeutics is a paclitaxel.
41. the method for claim 38, wherein at least a IDO inhibitor is selected from: 1-methyl DL-tryptophan (1MT), β-(3-benzofuranyl)-DL-alanine, β-(3-benzo (b) thienyl)-DL-alanine, 6-nitro-L-tryptophan, indole 3-methanol, 3,3 '-di-indole methyl hydride (DIM), brassinin, 5-methyl-brassinin, epi-nutgall catechu phenol gallic acid, 5-bromo-4-chloro-indoxyl 1, the 3-diacetate, the 9-VCz, acemetacin, 5-bromo-DL-tryptophan, 5-bromo indole diacetate, phenyl-TH-DL-tryptophan, acrylic-TH-DL-tryptophan, methyl-TH-DL-tryptophan, brassilexin, 3-amino-2-naphthoic acid, B-carboline, 3-butyl-B-carboline, 6-fluoro-3-carbomethoxy-B-carboline, 6-isothiocyanic acid-3-carbomethoxy-B-carboline, 3-propoxyl group-B-carboline, 3 carboxyls-B-carboline, 3-third oxygen formyl-B-carboline, and 3-carbon-uncle-butoxy-B-carboline.
42. the method for claim 41, wherein at least a IDO inhibitor are 1-methyl DL-tryptophan (1MT).
43. the method for claim 38 is wherein used at least a IDO inhibitor and at least a chemotherapeutics simultaneously.
44. the method for claim 38, wherein order is used at least a IDO inhibitor and at least a chemotherapeutics.
45. the method for claim 44, wherein at least a IDO inhibitor is to use before at least a chemotherapeutics.
46. the method for claim 44, wherein at least a chemotherapeutics are to use before at least a IDO inhibitor.
47. the method for claim 38, wherein said cancer is selected from following cancer: prostate, knot rectum, pancreas, cervix uteri, stomach, endometrium, brain, liver, wing take off, ovary, testis, head, cervical region, skin (comprising melanoma and basal cell carcinoma), a cortex, leukocyte (comprising lymphoma and leukemia), esophagus, mammary gland, muscle, connective tissue, lung (comprising small cell lung cancer and non-small cell carcinoma), adrenal gland, thyroid, kidney or bone; Also comprise: Glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, subcutaneous basal cell carcinoma and seminoma of testis.
48. a pharmaceutical composition for the treatment of cancer, said composition contain at least a indoleamine 2 in the pharmaceutical acceptable carrier medium, 3-dioxygenase (IDO) inhibitor and at least a chemotherapeutics.
49. the pharmaceutical composition of claim 48, wherein at least a chemotherapeutics is selected from: paclitaxel (taxol ), the derivant of cisplatin, western many taxols, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11,5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, amycin, etoposide, arsenic trioxide, irinotecan and Epothilones.
50. the pharmaceutical composition of claim 49, wherein at least a STI is a paclitaxel.
51. the pharmaceutical composition of claim 48, wherein the inhibitor of at least a IDO is selected from: 1-methyl DL-tryptophan (1MT), β-(3-benzofuranyl)-DL-alanine, β-(3-benzo (b) thienyl)-DL-alanine, 6-nitro-L-tryptophan, indole 3-methanol, 3,2 '-di-indole methyl hydride (DIM), brassinin, 5-methyl-brassinin, epi-nutgall catechu phenol gallic acid, 5-bromo-4-chloro-indoxyl 1, the 3-diacetate, the 9-VCz, acemetacin, 5-bromo-DL-tryptophan, 5-bromo indole diacetate, phenyl-TH-DL-tryptophan, acrylic-TH-DL-tryptophan, methyl-TH-DL-tryptophan, brassilexin, 3-amino-2-naphthoic acid, B-carboline, 3-butyl-B-carboline, 6-fluoro-3-carbomethoxy-B-carboline, 6-isothiocyanic acid-3-carbomethoxy-B-carboline, 3-propoxyl group-B-carboline, 3-carboxyl-B-carboline, 3-third oxygen formyl-B-carboline, and 3-carbon-uncle-butoxy-B-carboline.
52. the pharmaceutical composition of claim 48, wherein at least a IDO inhibitor are 1-methyl DL-tryptophan (1MT).
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