腫瘤的生物治療

1、癌癥的生物治療,癌癥的傳統(tǒng)治療方法： 手術(shù)治療 放射治療 化學(xué)治療 癌癥的生物治療方法： 基因治療免疫治療細(xì)胞治療 抗體治療分子靶向治療,癌癥治療現(xiàn)狀,,Progress in Gene Therapy of Liver Cancers,May 4, 2007,,,Genetic Material,Gene Transfer

2、(vectors),Biological Effect,Target Cell,Gene Therapy,,Multistage model of carcinogenesis,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Chemical,Radiation,Virus,,,,,,Normal cell,Preneoplastic

3、 lesion,Malignant tumor,Metastasis,Positive,OncogenesGrowth factors,ProteasesAdhesion receptorsMotility cytokines,Negative,Tumor suppressor genesGrowth inhibitors,Metastasis suppressor genes,Gene therapy strategi

4、es for treatment of liver tumors,Gene Therapy for HCC,1. Gene Replacement Wild-type p532. Antisense Strategies Antisense RNA, Ribozymes, siRNA,shRNA,miRNA against Oncogenes and Growth Factor (ras,

5、 myc, BCL-2, IGF-2, TGF-a)3. Anti-angiogenic therapy,Tumor Suppressor Genes,GenesLocationCancers,,p5317p13Small cell lung cancer Colorectal carcinoma Hepatocellular carcinoma breast cancer

6、Leukemia,RB113q14Retinoblastoma Small cell lung cancer Osteosarcoma Breast cancer,WT111p13Wilm’s tumor Nephroblastoma,DCC18q21Colerectal carcinoma,,NF117qNeurofibromas,APC5q21

7、Colorectal carcinoma,Antitumoral mechanisms induced by tumor suppressor genes,,,,,,,,Nat. Bio. Tech. 2004,,,Antitumoral mechanisms induced by inhibition of oncogenes,Mechanisms of inhibition of oncogenes by shRNA and m

8、iRNA,Co-expression of shRNA and therapeutic genes for therapy of cancer,Mechanisms of Drug Sensitivity by HSV-tk,Ganciclovir (GCV),MonophosphateGCV,Triphosphate GCV,DNA,DNA polymerase,Chain termination,Cell d

9、eath,replication,,,,,,,,,,,CMV-HSV-tk-pA,,,AdCMVtk,,Bystander effect induced by suicide gene,,,,,,,,,,,,,,Introduction of HSV-tk in tumor cells,,,,,,,,,,,,,,Ganciclovir,Effect 1:Death of tranduced cells,Effect 2:Death

10、of nearby cells,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Can cancer be treated by targeting MET signal transduction pathway,,Involvement of cytokines and growth factors in pathogenesis of cancer,Hepatocyte growth factor (HGF),MET

11、 (c-met),,Hepatocyte growth factor (HGF),MET (c-met),HGF,The signaling pathways for MET-dependent invasive growth,Expression of c-met in HCC,Ueki T Hepatology. 1997 Mar;25(3):619-23.,HGF-dependent invasive growth and ang

12、iogenesis,,MET overexpressionOverexpressed receptors, located at the cell surface, undergo spontaneous dimerization and subsequent activationMET gene amplificationenhanced MET transcription by oncogenestransient MET

13、overexpression by hypoxia-activated transcriptionMET structural alterationschromosomal translocation point mutationHGF-dependent autocrine/paracrine activationHGF-independent mechanisms,Mechanisms of Met activati

14、on in cancer,Strategies to target Met signaling,A lesson from anti-angiogenic therapy of cancer via a gene transfer approach,Angiogenesis Formation of new blood vessel from a pre-existing vascular network.,Most solid tu

15、mors (< 1 mm 3) receive blood supply from normal tissue to support of nutrients, oxygen etc. Oxygen diffusion is limited to 100 to 200 mm between capillary and perfused cells. This corresponds to 3 to 5 cellular line

16、s around a vessel If tumors are more than this size, they need their own vascularization.,The role of angiogenesis in tumor growth,Balance of angiogenic and anti-angiogenic factors in tumor progression,,,,,,,,,,,,,,,,,,

17、,,,,,,,,,,,,,,angiogenesis,+,-,The switch from a quiescient, dormant tumor stage to tumor neo-vascularization is regulated by an alteration of the balance of positive and negative regulators of angiogenesis,,,Endogenous

18、regulators of Angiogenesis:,Stimulating factors,Inhibitory factors,aFGF/bFGF VEGF IL-8 TNF-alpha TGF-alpha/beta Angiogenin Heparinase etc.,Angiostatin (K1-3; K4; K5) Endostatin PEDF IFN-alpha/beta IL-12 PF4

19、Thrombospondin etc.,Characteristics/Advantages of an antiangiogenic antitumor therapy,keep the tumor in a dormant stage /no elimination of all of the tumor cells prevention of metastasis no/few side effects because o

20、f minor physiological role of angiogenesis in the adult combination with other therapies (surgery/chemotherapy etc.),Anti-angiogenic factors,1. Angiostatin (1994)2. Endostatin (1997)3. Pigment epithelium derived fact

21、or (PEDF) (1999),Vector construction,Summary,1. Three vectors have been constructed2. Transgenes have been expressed 3. The expressed factors have biological effect4. They have anti-tumor effect5. They induce inhibit

22、ion of angiogenesis in vivo,Gene transfer-mediated anti-angiogenic therapy,Adenovirus:Angiostatin, endostatin, PF-4, soluble Flt-1 Retrovirus: PF-4, dominant-negative FLK-1 mutant receptorAAV: angiostatin, e