Anticancer pharmaceutical application of glufosfamide
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A technology of glufosfamide and cancer, applied in the field of glufosfamide, can solve the problems such as no development and listing, no significant increase in overall survival rate, etc.
Inactive Publication Date: 2019-06-04
SHENZHEN ASCENTAWITS PHARM TECH CO LTD
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Problems solved by technology
[0004] US Threshold company obtained the US FDA's fast-track approval qualification in 2004 for the treatment of unresectable locally advanced or metastatic pancreatic cancer that has previously received gemcitabine (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 in 2007 the company announced that there was no significant increase in phase III clinical trials for patients with metastatic pancreatic cancer as second-line treatment Overall survival (Tudor E. Ciuleanua, Alexander V. 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 remapped with gemcitabine, European Journal Of Cancer, 45(2009):1589-1596), that is, the subsequent development of the drug ended in failure because the final phase III clinical trial failed
[0005] In China, Qilu Pharmaceutical Co., Ltd. and Jiangsu Hansoh Pharmaceutical Co., Ltd. also applied for new drugs in 2005, and obtained approval from China Food and Drug Administration. However, there was no subsequent development and listing
Method used
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[0180] In vitro cell experiment
[0181] 1. Materials and methods
[0182] 1.1. Materials and instruments
[0183] AA8 cell line, purchased from American type culture collection (ATCC#CRL-1859);
[0184] UV41 cell line, purchased from American type culture collection (ATCC#CRL-1860);
[0185] MEM-alphamedium medium, purchased from Fisher Reagent Company (Fisher#12-561-056);
[0186] Fetal bovine serum (FBS for short), purchased from ThermoFisher (ThermoFisher#26140-079);
[0187] Penicillin streptomycin solution-double antibody Penn-step, purchased from Hyclone Company (Hyclone#SV30010);
[0188] AlamarBlue reagent was purchased from ThermoFisher (ThermoFisher #DAL1100).
[0189] 1.2. Test compound
[0190] compound
Dissolving solvent
Test concentration (μM / L)
dilute solution
Glufosfamide
DMSO
0.015-1000
Media solution containing 0.5% DMSO
Cisplatin
DMSO
0.003-200
Medium solution containing 0.5% DMSO
[0191]...
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Abstract
Glufosfamide or analogues thereof have specific inhibitory effects on cells with specific gene variations, specifically, DNA repairs damaged cells, the cells or tissues at least have one or more genemutations of 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, PARP or ERCC5. The analogues are esters obtained by esterification reaction of one or more hydroxyl groups in glufosfamide molecules with organic acid and inorganic oxyacid; esters obtained by esterification reaction of one or more hydroxyl groups in glufosfamide molecules with amino acid; and salts obtained by reaction of glufosfamide molecules withan acid. Therefore, provided is medical uses of glufosfamide or the analogues thereof in treatment of tumors and cancer diseases of cancer patients with specific gene variations.
Description
technical field [0001] The present invention relates to glufosfamide, especially the treatment of glufosfamide to cancer or tumor patients with specific gene mutation. Background technique [0002] Glufosfamide (glufosfamide), the chemical name is β-D-glucopyranosyl-N, N'-bis (2-chloroethyl) phosphoramide, and the English name is β-D-Glucopyranosyl-[N, N'- bis[(2-chloroethyl)]phosphoric aciddiamide, a new type of alkylating agent antineoplastic drug, is formed by linking a molecule of isophosphoramide mustard with direct alkylation and a molecule of glucose through glycosidic bonds . Glufosfamide is transported into tumor cells by the sodium-dependent glucose transmembrane transporter SAAT1, and then hydrolyzed by glucosidase to release isophosphoramide mustard to exert its activity. . [0003] The compound was first developed by Asta Medica (Degussa) in Heidelberg, Germany, in cooperation with the Cancer Research Center (DKFZ). In October 2001, Baxter International Baxt...
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