CN109833324A - The anticancer medical usage of glufosfamide - Google Patents

Abstract

Glufosfamide or its analog have the cell that specific gene makes a variation the inhibiting effect of specificity, it is specifically exactly that DNA repairs impaired cell, the cell or tissue at least BRCA1, BRCA2, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, FAM175, NBN, Rad50, MER11, p53, NBS1, XRS2, XRCC2, XRCC3, ERCC1, ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT , gene mutation or more gene mutation in PARP or ERCC5.Analog refers to: the ester that hydroxyl in glufosfamide molecule or more hydroxyl and organic acid, inorganic oxacid are obtained by esterification；The ester that a hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification；Glufosfamide molecule reacts resulting salt with acid.It provides glufosfamide thus or its analog states the tumour of cancer patient of specific gene variation, the medical usage in Cancerous disease in the treatment.

Description

The anticancer medical usage of glufosfamide

Technical field

Cancer that the present invention relates to glufosfamide, especially glufosfamides to mutate to specific gene or tumor patient The treatment of cancer, tumour.

Background technique

Glufosfamide (glufosfamide), entitled β-D- glucopyranosyl-N, N '-two (2- chloroethyl) phosphinylidyne of chemistry Amine, entitled β-D-Glucopyranosyl- [N, N '-bis [(2-chloroethyl)] the phosphoric acid of English Diamide is the ifosfamide nitrogen for having direct alkanisation by a molecule for a kind of novel alkylating agent antitumor drug Mustard and a molecule glucose, which are connected by glycosidic bond, to be formed.Glucose transmembrane transporter of the glufosfamide in sodium dependence It is transported into tumour cell under the action of SAAT1, isophosphoramide mustard is then discharged by glucoside enzyme hydrolysis and plays work Property.

The compound is at first by the Asta Medica (Degussa) and Cancer Research Center positioned at Heidelberg, Germany (DKFZ) develop cooperatively.In October, 2001, Baxter International Baxter have purchased the tumor section of ASTAMedica, and are renamed as Baxter Oncology GmbH (IonNiculescu-Duvaz, Current opinion in investigational Drug, 2002,3 (10): 1527-1532), the glufosfamide project of rear Baxter Oncology is by Threshold company, the U.S. Catcher, and location technology is metabolized using it to carry out the quotient of glufosfamide selectively by glufosfamide targeted to tumor locus Industryization research.

Threshold company, the U.S. obtained the quick examination & approval qualification of U.S. FDA in 2004, for receiving before treating Gemcitabine (gemcitabine) treatment the Locally Advanced that can not be cut off again or transfer cancer of pancreas (W.Steve Ammons, Jin-Wei Wang y, Zhijian Yang y, George F.Tidmarshz and Robert M.Hoffmany, Neoplasia, 2007.8,9 (8): 625-633), but the said firm in 2007 announces to be used for metastatic cancer of pancreas as second line treatment III clinical trial phase of patient do not dramatically increase total survival rate (Tudor E.Ciuleanua, AlexanderV.Pavlovskyb, Gyorgy Bodokyc, Avgust M.Garind, Virginia K.Langmuire, Stewart Krolle, George T.Tidmarshe, Arandomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic Adenocarcinomapreviously treated with gemcitabine, European Journal Of Cancer, 45 (2009): 1589-1596), i.e., the subsequent development of the drug due to III last clinical trial phase could not pass through to fail and Come to an end.

Existing Qilu Pharmaceutical Co., Ltd., the country, Jiangsu Haosen Pharmaceutical Co., Ltd also carried out new drug Shen in 2005 Please, and the certification of Chinese food pharmaceuticals administration general bureau is obtained, but subsequent also without exploitation listing.

Summary of the invention

Inventor pass through experimental studies have found that, glufosfamide has high sensitive for the cancer cell for having specific gene to make a variation Growth inhibition effect, is specifically exactly the impaired cell of DNA repair enzyme, which is at least BRCA1, BRCA2, FANCA, FANCD1、FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、 RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/ One or more genes are prominent in XPFERCC1, ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP or ERCC5 The cell of change.

For this purpose, finding based on above experiment, technical solution below is provided:

Technical solution 1:

Glufosfamide or its analog are used to treat the impaired tumour of DNA repair enzyme or cancer patient.Tumour (tumour) Referring to body under the effect of the various tumorigenesis factors, local organization hyperplasia is formed by neoformation (neogrowth), because this Kind neoformation is in occupancy block-like protrusions more, also referred to as neoplasm (neoplasm).Medically, cancer refers to originating from epithelium group The malignant tumour knitted is most common one kind in malignant tumour.Corresponding, the malignant tumour originating from mesenchymal tissue is referred to as Sarcoma.There are a small number of malignant tumours not name by mentioned above principle, such as the nephroblastoma, malignant teratoma.Described in general people " cancer " traditionally refers to all malignant tumours.Tumour or cancerous tissue at least BRCA1, BRCA2, FANCA of the patient, FANCD1、FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、 RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/ A gene mutation, excellent in XPFERCC1, ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP and ERCC5 It is selected as BRCA1, BRCA2, BARD1, FANCA, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, XRCC3, One or more gene mutations in XRCC4/XPF.

Technical solution 2:

Application according to technical solution 1, wherein DNA reparation, which is damaged, is

Homologous recombination DNA repair enzyme (homologous recombination repair) is impaired,

Nucleotide Sequence Analysis enzyme (nucleotide excision repair) is impaired,

Non-homologous end joining enzyme be damaged (nonhomologous endjoining),

Base-excision repair enzymes (base excision repair) are impaired,

Mismatch repair enzyme (mismatch repair) is impaired,

Fanconi anaemia approach repair enzyme is one of impaired or more, and preferably homologous recombination DNA is repaired Homologous recombination repair is impaired, Nucleotide Sequence Analysis nucleotide excision repair It is impaired.

Technical solution 3:

The application according to any one of technical solution 1-2, wherein the drug also contains other anticarcinogens, resists Tumour medicine and cellular immunotherapy, radiotherapy and operative treatment, other anticarcinogens, antineoplastic include hdac inhibitor, female Hormone receptor modulator, retinoid receptor modulators, cytotoxicity/cytostatic agent, resists androgen receptor modifier Multiplication agent, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcription Enzyme inhibitor and other angiogenesis inhibitors, the inhibitor of cell Proliferation and survival-signal conduction, cell death inducer and The drug of cell cycle checkpoint is interfered, PD-1 (immunosupress receptor), PD-L1 (immunosupress receptors ligand) and CTL4 are (molten Solution property T lymphocyte 4) etc. inhibitor.

Technical solution 4:

The application according to any one of technical solution 1-3, wherein the tumour, cancer include:

Lung cancer, non-small cell lung cancer, liver cancer, cancer of pancreas, gastric cancer, osteocarcinoma, cancer of the esophagus, mastocarcinoma, prostate cancer, testis Cancer, colon cancer, oophoroma, wing moon bright cancer, cervix cancer, melanoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, Carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinoma, adenocarcinoma cystic, cystocarcinoma, soft cancer, bronchiolar carcinoma, bone cell cancer, epithelioma, Cholangiocarcinoma, choriocarcinoma, embryo cancer, spermatogonium cancer, Willms cancer, spongiocyte cancer, astrocytoma, medulloblast Tumor, craniopharyngioma, ependymoma, pinealoma, hemocytoblastoma, acoustic neuromas, meningioma, neuroblastoma, at view Nerve-cell tumor, retinoblastoma, neurofibroma, fibrosarcoma, desmocytoma, fibroma, adenofibroma, fibre Tie up chondroma, inocystoma, fibromyxoma, fibro-osteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, mucus Cystoma, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, sarcolipoma, rouge Fat tumor, lipoadenoma, lipoblastoma, lipochondroma, adipofibroma, lipoangioma, myxolioma, chondrosarcoma, Chondroma, chondromyoma, chordoma, chorioadenoma, chorioepithelium tumor, chorioblastoma, osteosarcoma, osteoblast Tumor, osteochondrofibroma, osteochondrosarcoma, osteochondroma, osteocystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, blood vessel Sarcoma, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angioceratoma, angioglioma, blood vessel Endothelioma, angiofibroma, angiomyoma, angiolipoma, hematolymphangioma, angiolipoleiomyoma, blood vessel flesh rouge Tumor, angiomyoneuroma aglomus tumor, angiomyxoma, angioreticuloendothelioma, lymphangioendothelial sarcoma, lymph granulation tumor, lymphangioma, lymph Tumor, lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, endothelium Tumor, endothelioblastoma, synovialoma, synovial sarcoma, celiothelioma, mesocytoma, ewing's tumor, liomyoma, leiomyosarcoma, It is leiomyoblastoma, leiomyofibroma, rhabdomyoma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphatic leukaemia, acute Myelomatosis, chronic disease cell, polycythemia, lymthoma, carcinoma of endometrium, glioma, colorectal cancer, thyroid gland Cancer, bladder transitional cell carcinoma and Huppert's disease, preferably oophoroma, cervical carcinoma, prostate cancer, cancer of pancreas, breast cancer.

Technical solution 5:

The application according to any one of technical solution 1-4, wherein the analog refers to: glufosfamide can medicine Salt, solvate, hydrate, stereoisomer, inclusion compound or prodrug (such as ester), are particularly preferred as

A, hydroxyl in glufosfamide molecule or more hydroxyl and organic acid, inorganic oxacid pass through esterification Obtained ester；

B, the ester that hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification；

C, glufosfamide molecule reacts resulting salt with acid.

Technical solution 6:

The application according to any one of technical solution 1-5, wherein patient refer to mankind humanbeings patient and Mammal mammals patient in addition to the mankind.

Technical solution 7:

Tumour, the pharmaceutical composition of cancer of the impaired patient for the treatment of DNA repair enzyme containing glufosfamide or its analog, Tumour or cancerous tissue at least BRCA1, BRCA2, FANCA of the patient, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、 Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、 A gene mutation, preferably BRCA1, BRCA2, BARD1, FANCA in Ku80, MHS6, MGMT, PARP and ERCC5, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, one or more genes in XRCC3, XRCC4/XPF are prominent Become.

Technical solution 8:

According to pharmaceutical composition described in technical solution 7, wherein DNA repair enzyme, which is damaged, is

Homologous recombination DNA repair enzyme homologous recombination repair is impaired,

Nucleotide Sequence Analysis enzyme nucleotide excision repair is impaired,

Non-homologous end joining enzyme nonhomologous endjoining is impaired,

Base-excision repair enzymes base excision repair is impaired,

Mismatch repair enzyme mismatch repari is impaired,

Fanconi anaemia approach repair enzyme is one of impaired or more, preferably homologous recombination DNA repair enzyme Homologous recombination repair is impaired, Nucleotide Sequence Analysis enzyme nucleotide excision Repair is impaired.

Technical solution 9:

The pharmaceutical composition according to any one of technical solution 7-8, wherein the drug also contains other anticancers Medicine, antineoplastic and cellular immunotherapy, radiotherapy and operative treatment, other anticarcinogens, antineoplastic include that HDAC inhibits Agent, estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxicity/cell growth inhibition It is agent, antiproliferative, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibitor, inverse Inhibitor, the apoptosis-inducing of transcripting enzyme inhibitor and other angiogenesis inhibitors, cell Proliferation and survival-signal conduction The drug of agent and interference cell cycle checkpoint, PD-1 (immunosupress receptor), PD-L1 (immunosupress receptors ligand) and CTL4 Inhibitor such as (dissolubility T lymphocytes 4).

Technical solution 10:

The pharmaceutical composition according to any one of technical solution 7-9, wherein the tumour, cancer include:

Lung cancer, non-small cell lung cancer, liver cancer, cancer of pancreas, gastric cancer, osteocarcinoma, cancer of the esophagus, mastocarcinoma, prostate cancer, testis Cancer, colon cancer, oophoroma, wing moon bright cancer, cervix cancer, melanoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, Carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinoma, adenocarcinoma cystic, cystocarcinoma, soft cancer, bronchiolar carcinoma, bone cell cancer, epithelioma, Cholangiocarcinoma, choriocarcinoma, embryo cancer, spermatogonium cancer, Willms cancer, spongiocyte cancer, astrocytoma, medulloblast Tumor, craniopharyngioma, ependymoma, pinealoma, hemocytoblastoma, acoustic neuromas, meningioma, neuroblastoma, at view Nerve-cell tumor, retinoblastoma, neurofibroma, fibrosarcoma, desmocytoma, fibroma, adenofibroma, fibre Tie up chondroma, inocystoma, fibromyxoma, fibro-osteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, mucus Cystoma, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, sarcolipoma, rouge Fat tumor, lipoadenoma, lipoblastoma, lipochondroma, adipofibroma, lipoangioma, myxolioma, chondrosarcoma, Chondroma, chondromyoma, chordoma, chorioadenoma, chorioepithelium tumor, chorioblastoma, osteosarcoma, osteoblast Tumor, osteochondrofibroma, osteochondrosarcoma, osteochondroma, osteocystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, blood vessel Sarcoma, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angioceratoma, angioglioma, blood vessel Endothelioma, angiofibroma, angiomyoma, angiolipoma, hematolymphangioma, angiolipoleiomyoma, blood vessel flesh rouge Tumor, angiomyoneuroma aglomus tumor, angiomyxoma, angioreticuloendothelioma, lymphangioendothelial sarcoma, lymph granulation tumor, lymphangioma, lymph Tumor, lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, endothelium Tumor, endothelioblastoma, synovialoma, synovial sarcoma, celiothelioma, mesocytoma, ewing's tumor, liomyoma, leiomyosarcoma, It is leiomyoblastoma, leiomyofibroma, rhabdomyoma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphatic leukaemia, acute Myelomatosis, chronic disease cell, polycythemia, lymthoma, carcinoma of endometrium, glioma, colorectal cancer, thyroid gland Cancer, bladder transitional cell carcinoma and Huppert's disease, preferably oophoroma, cervical carcinoma, prostate cancer, cancer of pancreas, breast cancer.

Technical solution 11:

The pharmaceutical composition according to any one of technical solution 7-10, wherein the analog refers to: Portugal's phosphinylidyne The pharmaceutical salt of amine, solvate, hydrate, stereoisomer, inclusion compound or prodrug (such as ester), are particularly preferred as

A, hydroxyl in glufosfamide molecule or more hydroxyl and organic acid, inorganic oxacid pass through esterification Obtained ester；

B, the ester that hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification；

C, glufosfamide molecule reacts resulting salt with acid.

Technical solution 12:

The pharmaceutical composition according to any one of technical solution 7-11, wherein patient refers to the mankind Humanbeings patient and the mammal mammals patient in addition to the mankind.

Technical solution 13:

Glufosfamide or its analog are used to treat tumour, the cancer of the impaired patient of DNA repair enzyme, and the patient's is swollen Tumor, cancerous tissue at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、 MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、Ku80、 A gene mutation, preferably BRCA1, BRCA2, BARD1, FANCA in MHS6, MGMT, PARP or ERCC5, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, it is one or more in XRCC3, XRCC4/XPF.

Technical solution 14:

It is used to treat the impaired tumour of DNA repair enzyme, cancer according to glufosfamide described in technical solution 13 or its analog Disease, wherein DNA repair enzyme, which is damaged, is

Homologous recombination DNA repair enzyme homologous recombination repair is impaired,

Nucleotide Sequence Analysis enzyme nucleotide excision repair is impaired,

Non-homologous end joining enzyme nonhomologous endjoining is impaired

Base-excision repair enzymes base excision repair is impaired,

Mismatch repair enzyme mismatch repari is impaired,

Fanconi anaemia approach repair enzyme is one of impaired or more, preferably homologous recombination DNA repair enzyme Homologous recombination repair is impaired, Nucleotide Sequence Analysis enzyme nucleotide excision Repair is impaired.

Technical solution 15:

The glufosfamide according to any one of technical solution 13-14 or its analog are for treating DNA repair enzyme Impaired tumour, cancer, wherein glufosfamide or its analog also with other anticarcinogens, antineoplastic and cellular immunotherapy, Radiotherapy and operative treatment are used in combination to be treated, other anticarcinogens, antineoplastic include hdac inhibitor, estrogen Receptor modulators, androgen receptor modifier, retinoid receptor modulators, cytotoxicity/cytostatic agent, antiproliferative Agent, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase suppression Inhibitor, cell death inducer and the interference of preparation and other angiogenesis inhibitors, cell Proliferation and survival-signal conduction The drug of cell cycle checkpoint, PD-1 (immunosupress receptor), PD-L1 (immunosupress receptors ligand) and CTL4 (dissolubility T Lymphocyte 4) etc. inhibitor.

Technical solution 16:

The glufosfamide according to any one of technical solution 13-15 or its analog are for treating DNA repair enzyme Tumour, the cancer of impaired patient, wherein the tumour, cancer include:

Lung cancer, non-small cell lung cancer, liver cancer, cancer of pancreas, gastric cancer, osteocarcinoma, cancer of the esophagus, mastocarcinoma, prostate cancer, testis Cancer, colon cancer, oophoroma, wing moon bright cancer, cervix cancer, melanoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, Carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinoma, adenocarcinoma cystic, cystocarcinoma, soft cancer, bronchiolar carcinoma, bone cell cancer, epithelioma, Cholangiocarcinoma, choriocarcinoma, embryo cancer, spermatogonium cancer, Willms cancer, spongiocyte cancer, astrocytoma, medulloblast Tumor, craniopharyngioma, ependymoma, pinealoma, hemocytoblastoma, acoustic neuromas, meningioma, neuroblastoma, at view Nerve-cell tumor, retinoblastoma, neurofibroma, fibrosarcoma, desmocytoma, fibroma, adenofibroma, fibre Tie up chondroma, inocystoma, fibromyxoma, fibro-osteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, mucus Cystoma, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, sarcolipoma, rouge Fat tumor, lipoadenoma, lipoblastoma, lipochondroma, adipofibroma, lipoangioma, myxolioma, chondrosarcoma, Chondroma, chondromyoma, chordoma, chorioadenoma, chorioepithelium tumor, chorioblastoma, osteosarcoma, osteoblast Tumor, osteochondrofibroma, osteochondrosarcoma, osteochondroma, osteocystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, blood vessel Sarcoma, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angioceratoma, angioglioma, blood vessel Endothelioma, angiofibroma, angiomyoma, angiolipoma, hematolymphangioma, angiolipoleiomyoma, blood vessel flesh rouge Tumor, angiomyoneuroma aglomus tumor, angiomyxoma, angioreticuloendothelioma, lymphangioendothelial sarcoma, lymph granulation tumor, lymphangioma, lymph Tumor, lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, endothelium Tumor, endothelioblastoma, synovialoma, synovial sarcoma, celiothelioma, mesocytoma, ewing's tumor, liomyoma, leiomyosarcoma, It is leiomyoblastoma, leiomyofibroma, rhabdomyoma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphatic leukaemia, acute Myelomatosis, chronic disease cell, polycythemia, lymthoma, carcinoma of endometrium, glioma, colorectal cancer, thyroid gland Cancer, bladder transitional cell carcinoma and Huppert's disease, preferably oophoroma, cervical carcinoma, prostate cancer, cancer of pancreas, breast cancer.

Technical solution 17:

The glufosfamide according to any one of technical solution 13-16 or its analog are for treating DNA repair enzyme Impaired tumour, cancer, wherein the analog refers to: the pharmaceutical salt of glufosfamide, solvate, hydrate, three-dimensional different Structure body, inclusion compound or prodrug (such as ester), are particularly preferred as

A, hydroxyl in glufosfamide molecule or more hydroxyl and organic acid, inorganic oxacid pass through esterification Obtained ester；

B, the ester that hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification；

C, glufosfamide molecule reacts resulting salt with acid.

Technical solution 18:

The glufosfamide according to any one of technical solution 13-17 or its analog are for treating DNA repair enzyme Impaired tumour, cancer, wherein tumour or cancer refer to mankind human beings and the mammal mammals in addition to the mankind Tumour or cancer.

Technical solution 19:

Use the preparation containing glufosfamide or its analog as the impaired tumour for the treatment of DNA repair enzyme, the medicine of cancer patient Product, the patient tumors, cancerous tissue at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、 Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPF、ERCC1、ERCC2、ERCC3、ERCC4、 A gene mutation, preferably BRCA1, BRCA2, BARD1, FANCA in XRCC1, Ku80, MHS6, MGMT, PARP or ERCC5, RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, one or more genes in XRCC3, XRCC4/XPF are prominent Become.

Technical solution 20:

Use the preparation containing glufosfamide or its analog impaired as treatment DNA repair enzyme according to technical solution 19 The tumour of patient, cancer drug, wherein DNA repair enzyme, which is damaged, is

Homologous recombination DNA repair enzyme homologous recombination repair is impaired,

Nucleotide Sequence Analysis enzyme nucleotide excision repair is impaired,

Non-homologous end joining enzyme nonhomologous endjoining is impaired,

Base-excision repair enzymes base excision repair is impaired,

Mismatch repair enzyme mismatch repair is impaired,

Fanconi anaemia approach repair enzyme is one of impaired or more, preferably homologous recombination DNA repair enzyme Homologous recombination repair is impaired, Nucleotide Sequence Analysis enzyme nucleotide excision Repair is impaired.

Technical solution 21:

Use the preparation containing glufosfamide or its analog as treatment according to any one of technical solution 19-20 DNA repairs the drug of the tumour of impaired patient, cancer, wherein the preparation containing glufosfamide or its analog also includes it His anticarcinogen, antineoplastic and cellular immunotherapy, radiotherapy and operative treatment, other anticarcinogens, antineoplastic include Hdac inhibitor, estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxicity/cell Growth inhibitor, antiproliferative, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, hiv protease Inhibitor, the cell of inhibitor, reverse transcriptase inhibitor and other angiogenesis inhibitors, cell Proliferation and survival-signal conduction The drug of inducer of apoptosis and interference cell cycle checkpoint, PD-1 (immunosupress receptor), PD-L1 (match by immunosupress receptor Body) and the inhibitor such as CTL4 (dissolubility T lymphocyte 4).

Technical solution 22:

Use the preparation containing glufosfamide or its analog as treatment according to any one of technical solution 19-21 The drug of the tumour of the impaired patient of DNA repair enzyme, cancer, wherein the tumour, cancer include:

Lung cancer, non-small cell lung cancer, liver cancer, cancer of pancreas, gastric cancer, osteocarcinoma, cancer of the esophagus, mastocarcinoma, prostate cancer, testis Cancer, colon cancer, oophoroma, wing moon bright cancer, cervix cancer, melanoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, Carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinoma, adenocarcinoma cystic, cystocarcinoma, soft cancer, bronchiolar carcinoma, bone cell cancer, epithelioma, Cholangiocarcinoma, choriocarcinoma, embryo cancer, spermatogonium cancer, Willms cancer, spongiocyte cancer, astrocytoma, medulloblast Tumor, craniopharyngioma, ependymoma, pinealoma, hemocytoblastoma, acoustic neuromas, meningioma, neuroblastoma, at view Nerve-cell tumor, retinoblastoma, neurofibroma, fibrosarcoma, desmocytoma, fibroma, adenofibroma, fibre Tie up chondroma, inocystoma, fibromyxoma, fibro-osteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, mucus Cystoma, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, sarcolipoma, rouge Fat tumor, lipoadenoma, lipoblastoma, lipochondroma, adipofibroma, lipoangioma, myxolioma, chondrosarcoma, Chondroma, chondromyoma, chordoma, chorioadenoma, chorioepithelium tumor, chorioblastoma, osteosarcoma, osteoblast Tumor, osteochondrofibroma, osteochondrosarcoma, osteochondroma, osteocystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, blood vessel Sarcoma, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angioceratoma, angioglioma, blood vessel Endothelioma, angiofibroma, angiomyoma, angiolipoma, hematolymphangioma, angiolipoleiomyoma, blood vessel flesh rouge Tumor, angiomyoneuroma aglomus tumor, angiomyxoma, angioreticuloendothelioma, lymphangioendothelial sarcoma, lymph granulation tumor, lymphangioma, lymph Tumor, lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, endothelium Tumor, endothelioblastoma, synovialoma, synovial sarcoma, celiothelioma, mesocytoma, ewing's tumor, liomyoma, leiomyosarcoma, It is leiomyoblastoma, leiomyofibroma, rhabdomyoma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphatic leukaemia, acute Myelomatosis, chronic disease cell, polycythemia, lymthoma, carcinoma of endometrium, glioma, colorectal cancer, thyroid gland Cancer, bladder transitional cell carcinoma and Huppert's disease, preferably oophoroma, cervical carcinoma, prostate cancer, cancer of pancreas, breast cancer.

Technical solution 23:

Use the preparation containing glufosfamide or its analog as treatment according to any one of technical solution 19-22 The drug of the impaired tumour of DNA repair enzyme, cancer, wherein the analog refers to: the pharmaceutical salt of glufosfamide, solvation Object, hydrate, stereoisomer, inclusion compound or prodrug (such as ester), are particularly preferred as

A, hydroxyl in glufosfamide molecule or more hydroxyl and organic acid, inorganic oxacid pass through esterification Obtained ester；

B, the ester that hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification；

C, glufosfamide molecule reacts resulting salt with acid.

Technical solution 24:

Use the preparation containing glufosfamide or its analog as treatment according to any one of technical solution 19-23 The drug of the impaired tumour of DNA repair enzyme, cancer.

Technical solution 25:

A method of tumour, the cancer of the impaired patient of DNA repair enzyme being treated, this method includes to the disease The patient takes the pharmaceutical preparation containing glufosfamide or its analog, and the tumour or cancerous tissue of the patient is at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、 XRCC2, XRCC3, XRCC4/XPFERCC1, ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP or ERCC5 In a gene mutation, preferably BRCA1, BRCA2, BARD1, FANCA, RAD51D, RAD51C, RAD52, RAD54, RAD55, One or more gene mutations in RAD57, XRCC3, XRCC4/XPF.

Technical solution 26:

According to treatment method described in technical solution 25, wherein DNA repair enzyme, which is damaged, is

Homologous recombination DNA repair enzyme homologous recombination repair is impaired,

Nucleotide Sequence Analysis enzyme nucleotide excision repair is impaired,

Non-homologous end joining enzyme nonhomologous endjoining is impaired,

Base-excision repair enzymes base excision repair is impaired,

Mismatch repair enzyme mismatch repair is impaired,

Fanconi anaemia approach repair enzyme is one of impaired or more, preferably homologous recombination DNA repair enzyme Homologous recombination repair is impaired, Nucleotide Sequence Analysis enzyme nucleotide excision Repair is impaired.

Technical solution 27:

The treatment method according to any one of technical solution 25-26, wherein the pharmaceutical preparation also contains other Anticarcinogen, antineoplastic and cellular immunotherapy, radiotherapy and operative treatment, other anticarcinogens, antineoplastic include HDAC Inhibitor, estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxicity/cell growth Inhibitor, antiproliferative, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibit Inhibitor, the Apoptosis of agent, reverse transcriptase inhibitor and other angiogenesis inhibitors, cell Proliferation and survival-signal conduction The drug of inducer and interference cell cycle checkpoint.

Technical solution 28:

The treatment method according to any one of technical solution 25-27, wherein the tumour, cancer include:

Lung cancer, non-small cell lung cancer, liver cancer, cancer of pancreas, gastric cancer, osteocarcinoma, cancer of the esophagus, mastocarcinoma, prostate cancer, testis Cancer, colon cancer, oophoroma, wing moon bright cancer, cervix cancer, melanoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, Carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinoma, adenocarcinoma cystic, cystocarcinoma, soft cancer, bronchiolar carcinoma, bone cell cancer, epithelioma, Cholangiocarcinoma, choriocarcinoma, embryo cancer, spermatogonium cancer, Willms cancer, spongiocyte cancer, astrocytoma, medulloblast Tumor, craniopharyngioma, ependymoma, pinealoma, hemocytoblastoma, acoustic neuromas, meningioma, neuroblastoma, at view Nerve-cell tumor, retinoblastoma, neurofibroma, fibrosarcoma, desmocytoma, fibroma, adenofibroma, fibre Tie up chondroma, inocystoma, fibromyxoma, fibro-osteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, mucus Cystoma, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, sarcolipoma, rouge Fat tumor, lipoadenoma, lipoblastoma, lipochondroma, adipofibroma, lipoangioma, myxolioma, chondrosarcoma, Chondroma, chondromyoma, chordoma, chorioadenoma, chorioepithelium tumor, chorioblastoma, osteosarcoma, osteoblast Tumor, osteochondrofibroma, osteochondrosarcoma, osteochondroma, osteocystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, blood vessel Sarcoma, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angioceratoma, angioglioma, blood vessel Endothelioma, angiofibroma, angiomyoma, angiolipoma, hematolymphangioma, angiolipoleiomyoma, blood vessel flesh rouge Tumor, angiomyoneuroma aglomus tumor, angiomyxoma, angioreticuloendothelioma, lymphangioendothelial sarcoma, lymph granulation tumor, lymphangioma, lymph Tumor, lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, endothelium Tumor, endothelioblastoma, synovialoma, synovial sarcoma, celiothelioma, mesocytoma, ewing's tumor, liomyoma, leiomyosarcoma, It is leiomyoblastoma, leiomyofibroma, rhabdomyoma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphatic leukaemia, acute Myelomatosis, chronic disease cell, polycythemia, lymthoma, carcinoma of endometrium, glioma, colorectal cancer, thyroid gland Cancer, bladder transitional cell carcinoma or Huppert's disease, preferably oophoroma, cervical carcinoma, prostate cancer, cancer of pancreas, breast cancer.

Technical solution 29:

The treatment method according to any one of technical solution 25-28, wherein the analog refers to: Portugal's phosphinylidyne The pharmaceutical salt of amine, solvate, hydrate, stereoisomer, inclusion compound or prodrug (such as ester), are particularly preferred as

A, hydroxyl in glufosfamide molecule or more hydroxyl and organic acid, inorganic oxacid pass through esterification Obtained ester；

B, the ester that hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification；

C, glufosfamide molecule reacts resulting salt with acid.

Technical solution 30:

The treatment method according to any one of technical solution 25-29, wherein patient refers to mankind humanbeings Patient and the mammal mammals patient in addition to the mankind.

Term is explained:

BRCA1, BRCA2, i.e. Breast Cancer 1,2 genes.

FANCA, that is, Fanconi anemia complememtation group A gene FANCD1, FANCD2 are Fanconi anemia group D1,2protein gene.

ATM, ataxia-telangiectasia mutated gene Ataxia Telangiectasia-Mutated gene.

ATR, ATM-Rad3-Related gene.

CHEK1, CHEK2, Checkpoint kinase 1,2 genes.

CTP, Cytidine Triphosphate gene.

1 gene of BARD1, BRCA1-associated RING domainprotein.

1 gene of BRIP1, BRCA1-interacting protein.

RAD51D, RAD51C, RAD52, RAD54, RAD55, RAD57, i.e. Restriction-siteassociated The relevant DNA gene in DNA, that is, restriction site 51D, 51C, 52,54,55,57.

FAM175, family with sequence similarity 175member gene.

1 gene of NBN, Nijmegen breakage syndrome.

Rad50, DNArepairprotein RAD50 gene.

11 gene of MRE11, Mismatch Repair Endonuclease.

P53, Tumorproteinp53 gene.

No. 1 gene of NBS1, Nijmegenbreakage syndrome.

A homologous gene of XRS2, mankind Nbs1.

XRCC1, XRCC2, XRCC3, the gene of DNArepairprotein XRCC1,2,3.

ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, Excision RepairCross-Complementation 1,2,3,4,5 gene of group.

Ku80, the gene of encoded K u80 albumen.

6 gene of MHS6, MutS homolog.

MGMT, Methylguanine Methyltransferase gene.

The poly- adenosine diphosphate of PARP, polyADP-ribose polymerase-ribose polymerase gene.

Obviously, the present invention also provides a kind of specific treatment methods of disease, i.e., first the subject or patient are carried out more than The gene diagnosis of gene is tested, i.e., using corresponding BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、 Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、 The gene diagnosis reagent or gene diagnosis method or gene sequencing of Ku80, MHS6, MGMT, PARP or ERCC5 gene differentiated, To filter out the patient for said gene mutation occur, it is administered or treats.

Further, in order to which the anti cancer target for reinforcing glufosfamide or its analog acts on, enhancing grape can be used in combination Saccharide transporter expression drug, preparation or simultaneously to the patient carry out enhancing glucose transporter expression treatment, more into One step, the drug that can directly take glufosfamide or its analog and above-mentioned enhancing glucose transporter expression are compound Compound preparation.

In order to detect above-mentioned BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、 MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、Ku80、 It is abnormal whether MHS6, MGMT, PARP or ERCC5 gene occur being mutated etc., and the present invention also provides corresponding detection reagent, the examinations Agent includes corresponding BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、 NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、Ku80、MHS6、MGMT、 The protein of PARP or ERCC5 gene coding or the inhibitor and other suitable adjuvants of enzyme, by observing the correspondence when test Inhibitor differentiates whether the cell corresponding BRCA1, BRCA2, FANCA occurs to the function and effect of the cell, FANCD1, FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、 RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、 ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP or ERCC5 gene mutation or defect.

Obviously, for glufosfamide as a kind of broad spectrum anticancer agent, tumour, the cancer that can be treated are very extensive, including but Be not limited to above: lung cancer, non-small cell lung cancer, liver cancer, cancer of pancreas, gastric cancer, osteocarcinoma, cancer of the esophagus, mastocarcinoma, prostate cancer, Carcinoma of testis, colon cancer, oophoroma, wing moon bright cancer, cervix cancer, melanoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, sweat gland Cancer, carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinoma, adenocarcinoma cystic, cystocarcinoma, soft cancer, bronchiolar carcinoma, bone cell cancer, epithelium Cancer, cholangiocarcinoma, choriocarcinoma, embryo cancer, spermatogonium cancer, Willms cancer, spongiocyte cancer, astrocytoma, at nerve channel Cytoma, craniopharyngioma, ependymoma, pinealoma, hemocytoblastoma, acoustic neuromas, meningioma, neuroblastoma, At optic cell tumor, retinoblastoma, neurofibroma, fibrosarcoma, desmocytoma, fibroma, fiber gland Tumor, inochondroma, inocystoma, fibromyxoma, fibro-osteoma, fibromyxosarcoma, fibropapilloma, mucus meat Tumor, myxocystoma, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, rouge It is sarcoma, lipoma, lipoadenoma, lipoblastoma, lipochondroma, adipofibroma, lipoangioma, myxolioma, soft Osteosarcoma, chondroma, chondromyoma, chordoma, chorioadenoma, chorioepithelium tumor, chorioblastoma, osteosarcoma, at Osteocyte tumor, osteochondrofibroma, osteochondrosarcoma, osteochondroma, osteocystoma, osteodentinoma, osteofibroma, bone fibres meat Tumor, angiosarcoma, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angioceratoma, nervus vasculairs colloid Tumor, nemendothelioma, angiofibroma, angiomyoma, angiolipoma, hematolymphangioma, angiolipoleiomyoma, blood Pipe myolipoma, angiomyoneuroma aglomus tumor, angiomyxoma, angioreticuloendothelioma, lymphangioendothelial sarcoma, lymph granulation tumor, lymphatic vessel Tumor, lymthoma, lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblast It is tumor, endothelioma, endothelioblastoma, synovialoma, synovial sarcoma, celiothelioma, mesocytoma, ewing's tumor, liomyoma, smooth The white blood of muscle tumor, leiomyoblastoma, leiomyofibroma, rhabdomyoma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphoblastic Disease, acute myelogenous leukemia, chronic disease cell, polycythemia, lymthoma, carcinoma of endometrium, glioma, Colon and rectum Cancer, thyroid cancer, bladder transitional cell carcinoma and Huppert's disease.

Preferably as one kind to above-mentioned 30 technical solutions, the analog refers to:

A, hydroxyl in glufosfamide molecule or more hydroxyl and organic acid, inorganic oxacid pass through esterification Obtained ester, organic acid can be carboxylic acid (- COOH), sulfonic acid (- SO3H), sulfinic acid (RSOOH), thionothiolic acid (RCOSH)；

B, the ester that hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification, ammonia Base acid can be the a-amino acid hydrolyzed via protein or others β-, γ-... w- amino acid naturally, further Preferably a-amino acid；

C, glufosfamide molecule reacts resulting salt with acid progress acid-base reaction, and acid can be organic acid or inorganic acid, has Machine acid can be carboxylic acid (- COOH), sulfonic acid (- SO3H), sulfinic acid (RSOOH), thionothiolic acid (RCOSH), and inorganic acid is sulfuric acid, salt Acid, phosphoric acid, hydrobromic acid etc..

Glufosfamide of the invention or its analog and other anticancers or chemotherapeutant, immunization therapy drug group It closes, it is clear that should be able to also reach the purpose of the present invention, should also be protected.The non-limiting example of this reagent can be found in swollen The cancer theory and practice of tumor, V.T.Devita and S.Hellman (editor), the 6th edition (on 2 15th, 2001), LippincottWilliams&Wilkins publishing house.Those skilled in the art can with the special characteristic of drug with it is related Based on cancer (or other indications), which kind of combination for recognizing reagent be can be used.Be incorporated as compound come using anticancer agent, It is including but not limited to following: estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cell toxicant Agent, microtubule inhibitors/stabilizer, Topoisomerase inhibitors, antisense RNA and DNA oligonucleotides, antimetabolite are coupled to carefully The antibody or radioactivity isoreagent, HMG-CoA reductase inhibitor, inhibitors of prenyl transferases, farnesyl- of cytotoxic agents Protein transferase inhibitors, angiogenesis inhibitors, kinase inhibitor, COX2 inhibitor, integrin blockers agent, PPAR swash Dynamic agent, MDR inhibitor and immunotherapy medicaments.Other anticancer agents also include hypoxia activatable agent, proteasome inhibitor, ubiquitin Inhibitor, HDM2 inhibitor, TNF activator, BUB-R inhibitor, CENP-E inhibitor and interferon (such as alpha-interferon).This Kind anticancer agent can be small molecule or biological agent (such as the agent of RNA antisense and antibody).

Hdac inhibitor is histon deacetylase (HDAC) inhibitor, comprising:

A, fatty acid, such as butyrate, phenyl butyrate and valproic acid；

B, hydroxamate can inhibit the natural hydroxamic acid of HDACs, SAHA and TSA structure as TSA is the 1st be found Similar, being approved 1st can be used for clinical preparation；

C, cyclic peptide, such as natural products depsipeptide FK-228, apicidin and ring hydroxamic acid；

D, benzamides, such as MS-275, MGCD0103.

" estrogenic agents " refer to the compound that can be interfered or estrogen is inhibited to be bound to receptor herein, regardless of machine What is made as.The example of estrogenic agents includes but is not limited to tamosifen (tamoxifen), Raloxifene (raloxifene), idoxifene (Idoxifene), LY353381, LY117081, Toremifene (toremifne), fulvestrant (fulvestrant), arna support department azoles (anastrozole) and column arrange azoles (letrazole).

" androgen receptor modifier " refers to the compound that can be interfered or androgen is inhibited to be bound to receptor, and tube mechanism is not What.The example of androgen receptor modifier includes Tamsulosin (finasteride) and other 5α-reductase inhibitor, Ni Lu Meter Te (nilutamide), Drogenil (flutamide), Bicalutamide (bicalutamide), Liarozole (liarozole) And abiraterone (abiraterone) acetate.

" retinoid receptor modulators " refer to the compound that can be interfered or retinoid is inhibited to be bound to receptor, regardless of machine What is made as.The example of this retinoid receptor modulators includes bexarotene (bexarotene), vitamin A acid (tretinoin), 13CRA, RETINOIC ACID, difluoromethylornithine, ILX23-7553, trans--N- (4 '-hydroxyphenyl) regards yellow amide and N-4- carboxyphenyl retinamide.

The example of cytotoxic agent include but is not limited to sertenef, cachexia toxin, ifosfamide (ifosfamide), he Sonermin (tasonermin), Lonidamine (lonidamine), carbon chloramines platinum, hexamethyl melamine (altretamine), Po Nimo Take charge of spit of fland (prednimustine), mitolactol, Ranimustine (ranimustine), Fotemustine TM (fotemustine), Nedaplatin (nedaplatin), oxalic acid platinum, Temozolomide (temozolomide), cyclophosphamide, Eptaplatin amine (heptaplatin), estramustine (estramustine), Improsulfan (improsulfan) toluene fulfonate, chloroethene ring phosphinylidyne Amine, Nimustine (nimustine), chlorodibromide history pyridine (dibrospidium chloride), Pumitepa (pumitepa), sieve bar platinum amine (lobaplatin), sand urge platinum amine (satraplatin), Pu Feiluo mycin (profiromycin), cisplatin, more grams of Suo Hong rhzomorphs, Pumitepa (irofulven), western phosphamide (dexifosfamide), cis--amine dichloride base (2- methvl-pyridinium) platinum, benzyl guanine, glufosfamide (glufosfamide), GPX100, four chlorinations (trans-, trans-, trans-)-bis--μ-(hexane -1,6- diamines)-μ-[diamines-platinum (II)] bis- [diamines (chloro) platinum (II)], two A Jidingji spermine (diarizidinylspermine), arsenic trioxide, 1- (11- dodecylamino -10- hydroxyundecyl) -3,7-dimethylxanthine, the red rhzomorph of azoles (zorubicin), Yi Dahong Rhzomorph, daunorubicin, double peaces urge (bisantrene), mitogen flavones (mitoxantrone), Pi Lahong rhzomorph (pirarubicin), Pi Nahuaide (pinafide), the red rhzomorph of Wa Er, the red rhzomorph of Ah nurse (amrubicin), anti-new primary Lars Anxin (deansino) -3 '-morpholinyl -13- deoxidation -10- hydroxyl carminomycin, Anna is removed in eastern (antineoplaston), 3 ' - Mycin (annamycin) plus drawing red rhzomorph (galarubicin), also Li Nahuaide (elinafide), MEN10755,4- piptonychia Oxygroup -3- deamination -3- '-aziridino -4- methyl sulphonyl-daunorubicin (referring to WO 00/50032), methotrexate, Ji His shore (gemcitabine) of west and its mixture.

Microtubule inhibitors/microtubule stabilization agent example include taxol (paclitaxel), Vincamine sulfate, 3 ', 4 '-two -4 '-deoxidations -8 of the dehydrogenation ' raw element of-positive grey born of the same parents in Changchun, many thanks his rope (docetaxel), vincristine, vincaleukoblastinum, Wei Nuoruibin (vinorelobine), benefit sit plain (rhizoxin), Duola's statin, rice fertile albumen (mivobulin), isethionic acid Salt, Ou Li statin (auristatin), Xi Maduoting (cemadotin), RPR109881, BMS184476, Wen Fuluning (vinflunine), cryptophycin, 2,3,4,5,6- five fluoro- N- (fluorine-based -4- anisyl of 3-) benzsulfamides, dehydration catharanthus roseus Alkali, N, N- dimethyl-L-valyl base-L- valyl-N-methyl-L- valyl base-L- dried meat aminoacyl-L-PROLINE- Tert-butylamides, TDX258, Ai Boxi ketone (epothilone) (see, e.g. United States Patent (USP) US6,284,781 and US6,288, And BMS 188,797 237).

Some examples of Topoisomerase inhibitors are Hycamtin (topotecan), Hai Kata amine (hycaptamine), Irinotecan (irinotecan), rubitecan (rubitecan) etc..

The example of antimetabolite include: 5 FU 5 fluorouracil, enocitabine (enocitabine), Mifurol Tab (carmofur), Tegafur (tegafur), Pentostatin (pentostatin), doxifluridine (doxifluridine), Trimetrexate (trimetrexate), fludarabine (fludarabine), capecitabine (capecitabine), Galocitabine (galocitabine), cytarabine Ou Kefusite (ocfosfate), Fu Tiabin (fosteabine) sodium hydrate, thunder For Qu Sai (raltitrexed), bar mentions Cui Xi and obtain (paltitrexid), Emitefur (emitefur), Tiazofurine (tiazofurin), Tiazofurine (decitabine), nolatrexed (nolatrexed), pemetrexed (pemetrexed), Buddhist nun's letter Rabin (nelzarabine), 2 '--2 '-methylene cytidines of deoxidation, 2 '-fluorine-based -2 '-deoxycytidines of methylene, N- [5- (2,3- dihydro-benzofuranyl) sulfonyl]-N '-(3,4- dichlorophenyl) urea, N6- [4- deoxidation -4- [N2- [2 (E), 4 (E)-tetradecadiene acyl groups] sweet amino acylamino-]-L- glyceryl-B-L- sweet dew-heptan pyranose] adenine, A Puli Fixed (aplidine), also (ecteinascidin), troxacitabine (troxacitabine), 4- [2- amino -4- oxygen are determined in day west Generation -4,6,7,8- tetrahydro -3H- pyrimido [5,4-b] [Isosorbide-5-Nitrae] thiazine -6- bases-(S)-ethyl] -2,5- thiophene acyl group-L- paddy ammonia Acid, aminopterin-induced syndrome, 5 FU 5 fluorouracil, alanosine, 11- acetyl group -8- (carbamyl oxygroup methyl) -4- formyl Base methoxyl group -14- oxygen -1, the 11- diaza Fourth Ring -6- (7.4.1.0.0)-ten four -2,4,6- triolefin -9- base acetates, bitter horse Beans alkali (swainsonine), Lometrexol (lometrexol), dexrazoxane (dexrazoxane), methioninase, 2 '-cyanogen Base -2 '-'-deoxy-n 4- palmityl -1-B-D- arabino-furanosylcytosine and 3- aminopyridine -2- carboxylic aldehyde contracting amino sulphur Urea.

" HMG-CoA reductase inhibitor " refers to the inhibitor of 3- hydroxy-3-methyl glutaryl base-CoA reductase.It can make With the example of HMG-CoA reductase inhibitor, including but not limited to Lovastatin (lovastatin) (referring to United States Patent (USP) 4, 231,938,4,294,926 and 4,319,039), Simvastatin (simvastatin) (referring to United States Patent (USP) 4,444,784,4, 820,850 and 4,916,239), Pravastatin (pravastatin) (referring to United States Patent (USP) 4,346,227,4,537,859,4, 410,629,5,030,447 and 5,180,589), fluvastatin (fluvastatin) (referring to United States Patent (USP) 5,354,772,4, 5,356,896) and Atorvastatin 911,165,4,929,437,5,189,164,5,118,853,5,290,946 and (atorvastatin) (referring to United States Patent (USP) 5,273,995,4,681,893,5,489,691 and 5,342,952).In this article One word of HMG-CoA reductase inhibitor used, be include all pharmaceutically acceptable lactones and open-acid forms (that is, its Middle lactonic ring is opened to form free acid), and the salt and ester shape of the compound with HMG-CoA reductase inhibitory activity Formula, therefore, the utilization of this salt, ester, open acid and lactone form is comprised in the scope of the present invention.

" prenyl-protein inhibitors " refer to a kind of compound, can inhibit any or any group The prenyl-protein transferase of conjunction, including farnesyl protein transferase (FPTase), geranyl geranyl- Protein transferase type I (GGPTase- I) and geranyl geranyl-- II (GGPTase- of protein transferase type II, also referred to as Rab GGPTase).

The example of farnesyl protein transferase inhibitors includes that ([[[(11R) -3,10- bis- is bromo- by 4- by 2- by 4- by SARASARTM 8- chloro-6,11-dihydro -5H- benzo [5,6] cycloheptyl [1,2-b] pyridine -11- base -] -1- piperidyl] -2- oxoethyl] -1- piperazine Pyridine carboxylic acid amides, for pico farad Buddhist nun primary (tipifarnib) etc..

" angiogenesis inhibitors " refer to the compound that can inhibit neovascularization, and tube mechanism is not why.Angiogenesis suppression The example of preparation includes but is not limited to tyrosinase inhibitor, such as tyrosinase receptor Flt-1-1 (VEGFR1) and Flk-1/KDR (VEGFR2) inhibitor, epidermis derives, fibroblast derives or the inhibitor of blood platelet institute derivative growth factor, MMP (matrix metallo-proteinase) inhibitor, integrin blockers agent, white blood cell cerebroysin -12, the more sulfate of pentosan, epoxy Change enzyme inhibitor, including non-steroid anti-inflammatory agent (NSAID), such as aspirin and brufen (ibuprofen), and selection Property Cyclooxygenase-2 Inhibitor, such as the Thebe Sai Laku (celecoxib) and the Thebe Luo Feiku (rofecoxib)

Other examples of angiogenesis inhibitors include but is not limited to pQE30/en, by carat because of (ukrain), ranpirnase (ranpirnase), IM862, carbamic acid 5- methoxyl group -4- [2- methyl -3- (3- methyl-2-butene base) Oxyranyle] - 1- oxygen spiral shell [2,5] octyl- 6- base (chloro acetyl group) ester, acetyl group dinaline (dinanaline), 5- amino -1- [[3,5- bis- Chloro- 4- (4- chloro benzoyl) phenyl] methyl] -1H-1,2,3- triazole -4- carboxylic acid amides, CM101, squalamine, windmill he Spit of fland, RPI4610, NX31838, sulphation sweet dew pentose phosphate ester, 7,7- (bis- [imino group-N- methyl -4, the 2- pyrrolo-es of carbonyl - Carbonylimino [N- methyl -4,2- pyrroles]-carbonylimino]-bis--(1,3- napadisilate) and 3- [(2,4- dimethyl pyrazoles Cough up -5- base) methylene] -2- dihydroindolone (SU5416).

It adjusts or inhibits angiogenesis and the other therapeutic agents used can also be merged with glufosfamide or its analog, including It can adjust or inhibit the reagent of blood coagulation Yu plasmin action system.It can adjust or inhibit blood coagulation molten with fibrin The example of this reagent of enzyme effect approach, including but not limited to heparin is (referring to Thromb.Haemost.80:10-23 (1998)), (also referred to as active thrombin activatable plasmin acts on for low molecular weight heparin and carboxypeptidase U inhibitor The inhibitor of inhibitor [TAFIa]).The example of TAFIa inhibitor has been described in PCT publication WO03/013,526.

The example of kinase inhibitor includes: that can inhibit cell surface receptor and these surface receptor downstream informations transduction stepwise The reagent of reaction.This reagent can inhibition of cell proliferation and existence.It includes inhibitor (such as the lucky phytin Buddhist nun primary of EGFR (gefitinib) with supple and graceful Luo Tinibai (erlotinib)), to the inhibitor of the antibody (such as C225) of EGFR, ERB-2 (such as Trastuzumab (trastuzumab)), the suppression of the inhibitor of IGFR, the inhibitor of cytokine receptor, the inhibitor of MET, PI3K Preparation (such as LY294002), serine/threonine kinase (the including but not limited to inhibitor of Akt, such as in WO 02/ 083064, described in WO 02/083139, WO 02/083140 and WO 02/083138 those), the inhibitor of Raf enzyme (such as BAY-43-9006), inhibitor (such as the Wyeth CCI- of the inhibitor (such as CI-1040 and PD-098059) of MEK, mTOR And the inhibitor of C-ab1 kinases 779).Other kinase inhibitors include that can inhibit to be related to those of protein of cell cycle.Its Including aurora body kinase inhibitor, CDK inhibitor (such as flavones pyridine alcohol, CYC202, BMS387032 and pole shape kinase inhibition Agent).These also include that can interfere cell cycle outpost and pass through so that cancer cell injures the reagent of agent sensitization to DNA.This examination Agent includes the inhibitor of such as ART, ATM, Chk1 and Chk2.

" integrin blockers agent ", which refers to, selectively antagonism, inhibition or to be neutralized physiology ligand to be bound to α v β 3 whole Join the compound of albumen, understand selectively antagonism, inhibition or neutralizes the chemical combination that physiology ligand is bound to 5 integrin of α v β Object, meeting antagonism, inhibition or neutralization physiology ligand are bound to the compound of both 3 integrin of α v β and 5 integrin of α v β, And it can antagonism, inhibition or the rendered compound in the specific integrin activity in microvascular endothelial cells of neutralization.This term Also refer to the antagonist of α v β 6, α v β 8,1 β 1 of α, 2 β 1 of α, 5 β 1 of α, 6 β 1 of α and alpha 6 beta 4 integrin.This term also refers to α v β 3, α v β 5, α V β 6, α v β 8,1 β 1 of α, 2 β 1 of α, 5 β 1 of α, 6 β 1 of α and alpha 6 beta 4 integrin any combination of antagonist.

Combination with the compound other than anticancer compound is also included in the methods of the invention.For example, glufosfamide Or its analog and PPAR- γ (i.e. PPAR-gamma) agonist and PPAR- δ (i.e. PPAR-delta) agonist are (collectively referred to as " PPAR agonist ") combination, can be used for treating certain malignant disorders.PPAR- γ and PPAR- δ are respectively core peroxide Enzyme body proliferation peroxisome proliferator-activated receptor gamma and δ.PPAR- γ is in the performance on endothelial cell and its is related to angiogenesis, has been reported in (referring to J.Cardiovasc.Pharmacol.1998 in document；31:909-913；J.Biol.Chem.1999；274:9116- 9121；Invest.Ophthalmol Vis.Sci.2000；41:2309-2317).Recently, PPAR- gamma agonist has been found It can inhibit in vitro to respond the angiogenesis of VEGF；Troglitazone (troglitazone) and rosiglitazone (rosiglitazone) maleate can inhibit development of the retina neovascular nucleus formation in mouse (Arch.Ophthamol.2001；119:709-717).PPAR- gamma agonist and PPAR- γ/alfa agonists example include but It is not limited to thiazole pyridine diketone (such as DRF2725, CS-011, troglitazone (troglitazone), rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone)), fenofibrate (fenofibrate), Gemfibrozil (gemfirozil), clofibrate (clofirate).

Glufosfamide or its analog can also and be administered with the inhibitor of one or more intrinsic multiple drug resistances (MDR), special It is not to convey the sub- related MDR of protein expression with high level.This MDR inhibitor includes the inhibition of p- glycoprotein (P-gp) Agent, such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar (valspodar)).

Other anticancer agents also include hypoxia activatable agent (such as Tirapazamine (tirapazamine)), proteasome inhibition Agent (such as actacystin replaces left rice (bortezomib) with rich), ubiquitin inhibitor, HDM2 inhibitor, TNF activator, BUB-R Inhibitor, CENP-E inhibitor and interferon-' alpha '.

Immunotherapy medicaments include but is not limited to PD-1 inhibitor (such as Keytruda), PD-L1 inhibitor (such as Tecentriq, Imfinzi) and CTLA4 inhibitor (such as Yervoy).

The action and effect of invention

It is experimentally confirmed, glufosfamide or its analog have specific inhibition for the cell that specific gene makes a variation Effect, is specifically exactly the impaired cell of DNA repair enzyme, which is at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2、ATM、ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、 RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、 A gene mutation Genetic Mutant Cell in ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP or ERCC5.

Detailed description of the invention

Fig. 1 is cell survival rate of the AA8 cell after the glufosfamide for applying various concentration in the embodiment of the present invention Curve graph；

Fig. 2 is cell survival rate of the UV41 cell after the glufosfamide for applying various concentration in the embodiment of the present invention Curve graph；

Fig. 3 is cell survival rate curve of the AA8 cell after the cis-platinum for applying various concentration in the embodiment of the present invention Figure；And

Fig. 4 is cell survival rate curve of the UV41 cell after the cis-platinum for applying various concentration in the embodiment of the present invention Figure.

Specific embodiment

Isolated cells experiment

1, material and method

1.1, material and instrument

AA8 cell strain is purchased from American Type Culture collection warehousing American type culture collection (ATCC#CRL-1859)；

UV41 cell strain is purchased from American Type Culture collection warehousing American type culture collection (ATCC#CRL-1860)；

MEM-alphamedium culture medium is purchased from Fisher Reagent Company (Fisher#12-561-056)；

Fetal calf serum Fetal bovine serum (abbreviation FBS) is purchased from ThermoFisher company (ThermoFisher#26140-079)；

The dual anti-Penn-step of Penicillin Streptomycin Solution-is purchased from Hyclone company (Hyclone#SV30010)；

AlamarBlue reagent is purchased from ThermoFisher company (ThermoFisher#DAL1100).

1.2, compound is tested

Compound	Dissolution solvent	Test concentrations (μM/L)	Dilute solution
				Glufosfamide	DMSO	0.015-1000	Culture medium solution containing 0.5%DMSO
Cis-platinum	DMSO	0.003-200	Culture medium solution containing 0.5%DMSO

1.3, experimental condition

1.3.1, cell culture

AA8 and UV41 cell is cultivated in the MEM-alpha culture medium with 10%FBS and 1%Penn-strep.

1.3.2, experiment condition

In order to carry out proliferation assay, by AA8 and UV41 cell with 4000 cells/wells in 96 holes, black, clear bottom group It knits in culture plate and is inoculated with.Cell is in 37 DEG C and 5%CO₂Lower overnight incubation.Then by compound processing 72 of the cell in 1.2 sections Hour.The total volume of every hole culture medium is 200ul.After processing, cell Proliferation is measured using AlamarBlue fluorescent quantitation method Rate.AlamarBlue measurement is to detect metabolic activity based on the growth of detection fluorescence and colorimetric.Specifically, The active constituent resazurin of AlamarBlue reagent is blue and hardly fluoresces.After entering cell, resazurin quilt It is reduced to resorufin, this is a kind of red and high fluorescent compound.Lasting cell growth maintains the environment of reproducibility, Therefore the integral fluorescence and color of the medium of cell peripheral are increased.

The fluorescence intensity of experiment display AlamarBlue reagent is directly proportional to cell quantity.In order to carry out AlamarBlue survey It is fixed, 20ulAlamarBlue reagent is added to each hole and is incubated for 4 hours in 37 DEG C of incubators.Use BioTek Synergy ^TM2 microplate reader measure fluorescence intensity under 530nm excitation and 590nm transmitting.

2, experimental result.It is resulting that the experimental data are shown in the following table shown in 1- table 4.

Table 1, glufosfamide are to the proliferation experiment data of AA8 cell

Table 2, glufosfamide are to the proliferation experiment data of UV41 cell

Table 3, cis-platinum are to the proliferation experiment data of A8 cell

* this group of data are bad value, are kicked except without statistics calculating.

Table 4, cis-platinum are to the proliferation experiment data of UV41 cell

3, data are analyzed

Each concentration of cell proliferation test will be done in parallel three times.Experiment number is analyzed using GraphPad Prism software According to.In the case where no compound, fluorescence intensity (Ft) is defined as 100%.In the case where no cell, fluorescence intensity (Fb) it is defined as 0%.Cell percentages %=(F-Fb)/(Ft- in the survival of each compound is calculated according to the following formula Fb), wherein fluorescence intensity of the F=in the presence of compound.

Using nonlinear regression analysis, by the concentration of compound-survivaling cell percentage experimental data, that is, response curve Drafting pattern, cell survival rate are Y-axis, and the concentration value of compound is X-axis, and the corresponding concentration of 50% maximum activity is set to IC₅₀, such as Shown in Fig. 1 to Fig. 4.

Finally glufosfamide and cis-platinum are acquired to IC50 value such as the following table 5 of AA8, UV41 cell.

The IC50 value of table 5, glufosfamide AST1001 and cis-platinum cisplatin to AA8, UV41 cell

4, experiment conclusion

UV41 cell strain is the derivative for being CHO-AA8 cell line, and from the ultraviolet sensitivity system of AA8, which is Homologous recombination DNA caused by DNA ERCC4/XPF gene mutation repair homologous recombination repair enzyme by The cell strain that damage and Nucleotide Sequence Analysis nucleotide excision repair enzyme are damaged.DNA repair enzyme is impaired specific For further include non-homologous end joining be damaged nonhomologous end joining, base excision repair base One during excision repair is impaired, mispairing reparation mismatch repari is impaired, fanconi anaemia approach reparation is impaired Kind or more situation.

There is document to show UV41 cell strain for AA8, be there are the cell of Nucleotide Sequence Analysis enzyme defect, It is sensitive to large volume adduct mutagen, belongs to excision and repairs supplementation group 4, UV41 it is extremely sensitive to DNA crosslinking agent (referring to Thompson LH,et al.Repair of DNA adducts in asynchronous CHO cells and the role ofrepair in cell killing and mutation induction in synchronous cells treated with 7-bromomethylbenz[a]anthracene.Somatic CellMol.Genet.10:183-194, 1984.PubMed:6584989；Thompson LH,et al.Genetic diversity ofUV-sensitive DNArepair mutants ofChinese hamster ovary cells.Proc.Natl.Acad.Sci.USA 78: 3734-3737,1981.PubMed:6943579；Hoy CA,et al.Defective DNA cross-link removal in Chinese hamster cell mutants hypersensitive to bifunctional alkylating agents.CancerRes.45:1737-1743,1985.PubMed:3919945；Busch D,et al.Summary of complementation groups of UV-sensitive CHO cell mutants isolated by large- scale screening.Mutagenesis 4:349-354,1989.PubMed:2687628；Bessho T,et al.Initiation of DNA interstrand cross-link repair in humans:the nucleotide excision repair system makes dual incisions 5"to the cross-linked base and removes a 22-to 28-nucleotide-long damage-free strand.Mol.Cell.Biol.17:6822- 6830,1997.PubMed:9372913；Thompson LH,et al.Hypersensitivity to mutation and sister-chromatid-exchange induction in CHO cell mutants defective in incising DNA containing UV lesions.Somatic Cell Genet.8:759-773,1982.PubMed:7163954)。 The DNA repair enzyme of UV41 cell is impaired to lead to BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、 Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、 A gene or multiple genes mutate in Ku80, MHS6, MGMT, PARP or ERCC5.

By the IC50 value of contrast table 5 it is found that glufosfamide is prominent for normal AA8 cell and AA8 cell generation gene UV41 cell after becoming has selective inhibitory, and the inhibitory activity IC50 to normal cell is 23 μM, to the thin of mutation Born of the same parents' (cancer cell or tumour cell) but have up to 32.8 times i.e. 0.7 μM of inhibitory activity.

That is, glufosfamide has the cell that specific gene makes a variation the inhibiting effect of specificity, specifically Be exactly the impaired cell of DNA repair enzyme, which is at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR、CHEK1、CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、 FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、 A Genetic Mutant Cell in ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP or ERCC5, therefore glufosfamide or its is similar Object can treat DNA and repair impaired tumour, cancer, and the preparation containing glufosfamide or its analog can be used to repair as treatment DNA The drug of the tumour of impaired patient, cancer, glufosfamide or its analog can be used to treat the impaired tumour of DNA repair enzyme, Cancer, the tumour for treating the impaired patient of DNA repair enzyme, the pharmaceutical composition of cancer containing glufosfamide or its analog are by this Disclosed in invention, the application of glufosfamide or its analog in the drug of tumour, cancer that preparation treatment DNA repair enzyme is damaged Also presently disclosed.

Further, glufosfamide is the isophosphoramide mustard for having direct alkanisation by a molecule and a molecule Portugal Grape sugar is transported under the action of the glucose transmembrane transporter SAAT1 of sodium dependence by the connected formation of glycosidic bond Into tumour cell, activity is then played by hydrolysis release isophosphoramide mustard, that is to say, that glufosfamide is different phosphinylidyne The prodrug of amine.The more general normal cell of growth and breeding due to cancer cell is more vigorous, to the benefit of glucose etc. With also more with demand, that is to say, that tumour cell has the high unique property utilized to glucose, and (glucose transport carries Body gene expression is high), this local concentration that will lead to the glufosfamide of the tumor presence of patient's body is enriched with, and can be selected Glufosfamide is improved targeted to tumor locus to property the effect that tumour is killed.

So glufosfamide is as targeting prodrug, it is only high in glucose transporters and glucoside expression of enzymes More toxin (isophosphoramide mustard) with lethality could be discharged in cancer cell, and in normal cell, due to grape Sugar transport carrier is low or without expression, and prodrug can not discharge toxin, so inactive or toxicity is low.

Claims (10)

1. the application of glufosfamide or its analog in the impaired tumour of patient of preparation treatment DNA reparation, the drug of cancer, Tumour or cancerous tissue at least BRCA1, BRCA2, FANCA of the patient, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、 Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、 A gene mutation in Ku80, MHS6, MGMT, PARP and ERCC5.

2. application according to claim 1, wherein DNA reparation, which is damaged, is

Homologous recombination DNA repair homologous recombination repair it is impaired,

Nucleotide Sequence Analysis nucleotide excision repair is impaired,

Homologous end connect impaired nonhomologous endjoining,

Base excision repair base excision repair is impaired,

Mispairing repair mismatch repari it is impaired,

Fanconi anaemia approach reparation is one of impaired or more.

3. application described in any one of -2 according to claim 1, wherein the patient is that glucose transporter expression is positive Patient.

4. the treatment DNA containing glufosfamide or its analog repairs tumour, the pharmaceutical composition of cancer of impaired patient, the trouble Tumour or cancerous tissue at least BRCA1, BRCA2, FANCA of person, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、 MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、Ku80、 A gene mutation in MHS6, MGMT, PARP and ERCC5.

5. glufosfamide or its analog are used to treat tumour, cancer that DNA repairs impaired patient, the tumour or cancer of the patient Tissue at least BRCA1, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、 NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、Ku80、MHS6、MGMT、 A gene mutation in PARP and ERCC5.

6. use the preparation containing glufosfamide or its analog to repair the drug of the tumour of impaired patient, cancer as treatment DNA, Tumour or cancerous tissue at least BRCA1, BRCA2, FANCA of the patient, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2、CTP、BARD1、BRIP1、PALB2、RAD51D、RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、 Rad50、MRE11、p53、NBS1、XRS2、XRCC2、XRCC3、XRCC4/XPFERCC1、ERCC2、ERCC3、ERCC4、XRCC1、 A gene mutation in Ku80, MHS6, MGMT, PARP and ERCC5.

7. a kind of tumour, method of cancer treated DNA and repair impaired patient, this method include to described in the disease Patient takes the pharmaceutical preparation containing glufosfamide or its analog, tumour or the cancerous tissue at least BRCA1 of the patient, BRCA2, FANCA, FANCD1, FANCD2, ATM, ATR, CHEK1, CHEK2, CTP, BARD1, BRIP1, PALB2, RAD51D, RAD51C、RAD52、RAD54、RAD55、RAD57、FAM175、NBN、Rad50、MRE11、p53、NBS1、XRS2、XRCC2、 One in XRCC3, XRCC4/XPFERCC1, ERCC2, ERCC3, ERCC4, XRCC1, Ku80, MHS6, MGMT, PARP and ERCC5 Gene mutation.

8. treatment method according to claim 7, wherein the pharmaceutical preparation also contains other anticarcinogens, antineoplastic, Other described anticarcinogens, antineoplastic include hdac inhibitor, estrogenic agents, androgen receptor modifier, class view Pigment receptor modulators, cytotoxicity/cytostatic agent, antiproliferative, Prenyl-protein inhibitors, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitor and other angiogenesis inhibitors, cell increase Grow the inhibitor, cell death inducer and the drug for interfering cell cycle checkpoint with survival-signal conduction.

9. the treatment method according to any one of claim 7-8, wherein the tumour, cancer include:

Lung cancer, non-small cell lung cancer, liver cancer, cancer of pancreas, gastric cancer, osteocarcinoma, cancer of the esophagus, mastocarcinoma, prostate cancer, carcinoma of testis, knot Intestinal cancer, oophoroma, wing moon bright cancer, cervix cancer, melanoma, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, sebaceous glands Cancer, papillary carcinoma, papillary adenocarcinoma, adenocarcinoma cystic, cystocarcinoma, soft cancer, bronchiolar carcinoma, bone cell cancer, epithelioma, bile duct Cancer, choriocarcinoma, embryo cancer, spermatogonium cancer, Willms cancer, spongiocyte cancer, astrocytoma, medulloblastoma, Craniopharyngioma, ependymoma, pinealoma, hemocytoblastoma, acoustic neuromas, meningioma, neuroblastoma, at optic nerve Cytoma, retinoblastoma, neurofibroma, fibrosarcoma, desmocytoma, fibroma, adenofibroma, fiber are soft Osteoma, inocystoma, fibromyxoma, fibro-osteoma, fibromyxosarcoma, fibropapilloma, myxosarcoma, mucous bursa Tumor, myxochondroma, myxochondrosarcoma, myxochondrofibrosarcoma, myxadenoma, myxoblastoma, sarcolipoma, fat It is tumor, lipoadenoma, lipoblastoma, lipochondroma, adipofibroma, lipoangioma, myxolioma, chondrosarcoma, soft Osteoma, chondromyoma, chordoma, chorioadenoma, chorioepithelium tumor, chorioblastoma, osteosarcoma, osteoblastoma, Osteochondrofibroma, osteochondrosarcoma, osteochondroma, osteocystoma, osteodentinoma, osteofibroma, the fibrosarcoma of bone, blood vessel meat It is tumor, hemangioma, angiolipoma, angiochondroma, hemangioblastoma, angioceratoma, angioglioma, intravascular Rind gall, angiofibroma, angiomyoma, angiolipoma, hematolymphangioma, angiolipoleiomyoma, angiomyoliopma, Angiomyoneuroma aglomus tumor, angiomyxoma, angioreticuloendothelioma, lymphangioendothelial sarcoma, lymph granulation tumor, lymphangioma, lymthoma, Lymphomyxoma, lymphosarcoma, lymphangiofibroma, lymphocytoma, lymphoepithelioma, lymphoblastoma, endothelioma, at Endothelial cell tumor, synovialoma, synovial sarcoma, celiothelioma, mesocytoma, ewing's tumor, liomyoma, leiomyosarcoma, Cheng Ping Sliding myomata, leiomyofibroma, rhabdomyoma, rhabdomyosarcoma, rhabdomyomyxoma, acute lymphatic leukaemia, Acute Meyloid Property leukaemia, chronic disease cell, polycythemia, lymthoma, carcinoma of endometrium, glioma, colorectal cancer, thyroid cancer, Bladder transitional cell carcinoma or Huppert's disease.

10. the treatment method according to any one of claim 7-9, wherein the analog refers to:

A, hydroxyl in glufosfamide molecule or more hydroxyl is obtained with organic acid, inorganic oxacid by esterification Ester；

B, the ester that hydroxyl in glufosfamide molecule or more hydroxyl and amino acid are obtained by esterification；

C, glufosfamide molecule reacts resulting salt with acid.