The molecular target to the medicine is the new medicine which in the molecular biology, in the molecular genetics rationale appears, because of its precise target to the therapeutic action, is opposite in the traditional chemotherapy medicine has many superiority, has formed a treatment tumor new domain, has provided one untoward effect small method for the tumor treatment. In the recent 20 years, along with science of medicine's development, are published unceasingly massively take the tumour cell level expression as the target new anti-tumor medicine, and move toward gradually clinical, mainly include the cell signal transduction member viagra
, the newborn blood vessel cialis
, the target bear the medicine to the end grain of enzyme inhibitor as well as in view of the tumor the reversal medicinal preparation. The attack tumor's target spot has various, at present studies mature mainly has tumour cell surface target (antigen or immune body), like cell membrane differentiation related antigen (CD13, CD20, CD22, CD33, CD52, CD117 and so on), cell signal transduction member like epidermis growth factor (EGF) and acceptor (EGFR) and blood vessel bast growth factor (VEGF) and on acceptor's tyrosine activating enzyme, as well as law Niji transferase, matrix metal proteinase and so on. åä¸²1
The molecular target still did not have the unification at present to the medicine the taxonomic approach. According to affects a target difference, may divide into the following 4 kinds.
* protein kinase
In cell's split up signal conduction factor, includes the massive protein kinase family. In the cell signal conduction process, the protein tyrosine activating enzyme is very important, it may catalyze on ATP the phosphorus acid radical to shift to many important protein tyrosine residue on causes its phosphorylation, causes to conduct leg's activation, affects the cell to grow, the multiplication and the differentiation, but in many tumour cells tyrosine activating enzyme activeness exceptionally elevates. Surpasses 50% cancer gene and the product has the protein tyrosine activating enzyme activeness, their unusual expression will cause the tumor the occurrence. In addition, this enzyme's unusual expression also with the tumor shift, the tumor newborn blood vessel production, the tumor bears the medicine to the chemotherapy to concern. The research can block or the beautification causes disease's selective protein kinase inhibitor abnormally by the signal conduction, was considered that is the hopeful medicine development way. At present, had already discovered some protein kinase inhibitor and in view of the different protein kinase ATP union position spot small molecular therapeutical agent, and entered the clinical research, like tyrosine activating enzyme inhibitor and so on.
* tumor blood vessel production factor
The positive and negative regulation's balancing control tumor blood vessel's production, is promoting the tumor growth and the shift from this, develops the blood vessel production inhibitor is the tumor studies one of most active domains. In clinical trial's blood vessel production inhibitor has the following 4 kinds.
① The adjustment matrix responded that suppresses medicine which the basilar membrane degrades: Marimastat, BMS-275291 and so on.
Matrix proteinase (MMP) is one kind of protein hydroltyic enzyme, may cause the extracellular matrix to degrade, it in the tumor infiltration, the shift and the vascularization process plays the crucial role. Matrix proteinase inhibitor (MMPI) may through suppress the metal proteinase to play the anti-tumor growth and the shift role. BMS-275291 is one kind of MMPI, it uses in the later period non-cellule lung cancer jointly with the chemotherapy the treatment, at present enteredⅡ/ⅢTime clinical trial; Col-3 is MMP-2 and the MMP-9 inhibitor (Ⅰ/ⅡTime clinical); AE941 is MMP-2, MMP-9 and the MMP-12 inhibitor, it may seal up VEGF and its acceptor's union,ⅡTime clinical trial treatment multiple myeloma, ⅢThe time clinical trial uses in the kidney cancer and the non-cellule lung cancer treatment.
② Suppresses endothelial cell's medicine directly: Sha Li amine (Thalidomide), phagocidin derivative (TNP470), graciousness (Endostatin) and so on.
TNP 470 are first enters the clinical trial to damp the blood vessel medicine, it has the intense inhibitory action to the endothelial cell multiplication and the newborn vascularization, it and lucky west his shore or along platinum union use, ⅢThe time clinical used in entity lump treatments and so on cervical cancer, stomach cancer, prostate gland cancer, breast cancer and lung cancer demonstrates the obvious anti-tumor activeness.
Endocardial blood vessel production inhibiting factor: Blood vessel chalone (angiostatin) and bast chalone (endostatin) has the intense inhibitory action to the mouse tumor newborn blood vessel production, and had not discovered that bears the medicine phenomenon, uses these two kind of inhibiting factor to be possible jointly to eradicate mouse in vivo thoroughly the transplant lump, but clinical waits for further confirming. At present two medicines have carried on the clinical trial in US. åä¸²2
③ Suppresses the endothelial cell specificity conformity element the medicine: Vitaxin/Î±VÎ²3 humanized monoclonal antibody, EMD121974/Î±VÎ²3 small molecular antagonist compound. Tumour cell's coherence is playing the great importance in the tumor attack and the shift the role. The adherency member like conformity element may promote the tumor shift, moreover it may also start certain cell escape mechanism suppressor cell to perish weakly. Therefore suppressed the adherency member/conformity element signal conduction to be possible to play the anti-tumor role. Vitaxin is one kind of anti-Î±VÎ²3 monoclonal antibody,Ⅰ/ⅡThe time clinical trial uses in treating the later period Rectal Cancer; EMD121974 is a anti-Î±VÎ²3 small member, enteredⅢTime clinical trial, also has the very good curative effect.
④ Suppresses medicine which the angiogenesis factor activates: VEGF monoclonal antibody and so on. åä¸²9
In recent years the anti-tumor blood vessel medicine research development is rapid, the world probably had 75 kind of anti-blood vessel medicines to enter the clinical trial stage, the majority has been inⅠTime orⅡTime clinical trial stage, but has 12 kinds to enter or to complete at leastⅢTime clinical trial.
Had discovered that before the specificity regulation epidermis special acceptor tyrosine activating enzyme the ligand protein is a kind, blood vessel production factor, if VEGF/the VEGFR system, were considered that is the tumor medicine very good function target spot.
VEGFs is a kind of protein, for highly special blood vessel endothelial cell mitosis original, through activates after the acceptor union plays the role. VEGF may promote endothelial cell's mitosis, the extension cell's survival time, enhances in the matrix degeneration process to need the enzyme the expression, increases the blood vessel permeability and so on. VEGF surpasses 2mm to the volume the entity lump fast growth display function.
VEGFR is kind of important tyrosine activating enzyme, many research indicated that its signal transduction way being out of balance in the tumor occurrence, the growth and the shift has the influential role. VEGFR mainly has VEGFR-1 (Flt-1), VEGFR-2 (the KDR /Flt-1) and VEGFR-3 (Flt-4), is the tyrosine activating enzyme acceptor. VEGF through and two kind of cross bast cell membrane acceptor union display biology function.
●DNA analysis situs isomerase
Eukaryotic cell's DNA analysis situs isomerase in DNA duplication, duplication, reorganization as well as in forms in the correct chromosomic structure, the chromosome separation, the concentration to play the influential role. The analysis situs isomerase inhibitor already became the anti-tumor medicine research to develop one of most important target. åä¸²5
The DNA replication is the key which the tumour cell multiplies. Suppresses DNA to direct the enzyme, causes directs the synthesis to be blocked, the DNA replication receives suppresses, the tumour cell cannot multiply, thus achieves the anti-tumor the goal. Therefore, DNA directs the enzyme is a anti-tumor medicine research ideal target spot.
The mitotic cycle regulation, perishes, the differentiation and so on massive biological process to rely on weakly in the different protein regulation expresses and degrades, many reactant decline function is completes through the pan-element dependent hydrolisis destruction. Had discovered that many levels may regulate in the entire pan-element process, seeks the target the different factor medicine to have to this way in the very good prospect. In the tumor treatment, the pan-element - proteinase way inhibitor may take one kind of new anti-tumor medicine.
Histone acetylize is the gene expression main adjustment factor, it activates the gene expression through the change transcription factor and DNA close. The histone went to the acetylize enzyme (histone deacetylase, HDA) the gene expression inhibitory action to provide the new target for the tumor treatment. The HDA inhibitor can cause the mitotic cycle to block with perishes weakly the gene activation, this function may use in the tumor the treatment.