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Newer cancer therapies immunotherapy angiotherapy gene therapy

Newer cancer therapies immunotherapy angiotherapy gene therapy. Angiotherapy. Key differences in tumour vasculature. Different flow characteristics / blood volume Microvasculature permeability Increased fractional volume of extravascular, extracellular space. Angiogenesis-overview.

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Newer cancer therapies immunotherapy angiotherapy gene therapy

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  1. Newer cancer therapiesimmunotherapyangiotherapy gene therapy

  2. Angiotherapy

  3. Key differences in tumour vasculature Different flow characteristics / blood volume Microvasculature permeability Increased fractional volume of extravascular, extracellular space

  4. Angiogenesis-overview • Balance between inhibitory factors (endostatin) and angiogenic factors (VEGF, bFGF) • angiogenic factors stimulate MMPs and plasminogen activators • Degradation of basement membrane Invasion and differentiation of endothelial cells in surrounding tissues

  5. BLOOD FLOW Before treatment after treatment

  6. MMPIs • Disappointing results with matrix metalloproteinase inhibitors • Poor survival rate in phase III clinical trials against renal cell carcinoma

  7. Newer cancer therapiesgene therapy

  8. Gene therapy Antisense therapy (suppress gene expression)Gene augmentation (supplement defective gene)

  9. Antisense therapy compensates for genetic mutations that produce destructive proteins Main strategies involved are 1) short stretches of synthetic DNA that target the mRNA transcripts of abnormal proteins preventing its translation OR small RNA molecules (siRNA) used to degrade aberrant RNA transcripts

  10. Antisense therapy 2) provide a gene for a protein (intracellular antibody) that can block the activity of the mutant protein 3) design hybrids of DNA / RNA that might direct repair of the mutant gene

  11. Gene augmentation most therapies simply add a useful gene into a selected cell type to compensate for the missing or flawed version or even instil an entirely new version. Direct approach inducing cancer cells to make a protein that will kill the cell. Indirect approach stimulating an immune response against selected cells or eliminating the blood supply.

  12. delivery 3 challenges in gene therapy delivery delivery • Package the gene • Protect the gene • deliver to the nucleus and release in an active form Vectors ‘Trojan horses’ that sneak the gene into the cell

  13. Carrier molecules designed specifically to enter cells & deposit therapeutic genes Vectors can be viral or non-viral Vectors

  14. METHODS OF VECTOR DELIVERY

  15. Viral vector strategy Replication & virulence genes can be substituted with therapeutic genes

  16. Retroviral vectors designed to enter cell and deposit genesProblems of retroviral therapy includeLack of cell specificity:Promiscuous: depositing genes into several cell types resulting in reduced target efficiency and unwanted physiological effectsRandom splicing into host DNA resulting in normal gene disruption and/or alteration in gene function

  17. Adenoviral vectors do not insert into genome temporary lack of specificity strong immune response

  18. Adeno-associated viral vectors Integrate into genome but small in size Nature Reviews Genetics 1; 91-99 (2000);

  19. Conditionally replicating viruses

  20. Advantagesnon-toxicno immune response Non-viral Vectors

  21. Non-viral Vectors liposomes (lipoplexes)

  22. Non-viral Vectors amino acid polymers: cationic polymers e.g. B-cyclodextrins

  23. naked DNA artificial human chromosomes Non-viral Vectors Gene gun

  24. Tumour-suppressor gene delivery Nature Reviews Cancer (2001) Vol 1; 130-141

  25. Delivery of agents that block oncogene expression Nature Reviews Cancer (2001) Vol 1; 130-141

  26. Suicide gene delivery Nature Reviews Cancer (2001) Vol 1; 130-141

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