Mechanisms of tumor suppressor genes Ellisen and Haber Sci Med 5-4, 1998, 26-35 <ul><li>Fusie maligne met niet-maligne cel...
Rb-switch and cell cycle regulation   Ellisen and Haber Tumor-associated: - Rb  - cyclinD - p16Ink4a - CDK4 Cell cycle act...
Rb-switch and cell cycle regulation   Ellisen and Haber Tumor-associated: - Rb  - cyclinD - p16Ink4a - CDK4 Cell cycle act...
Virussen en interactie met celcyclus Ellisen en Haber <ul><li>Humaan papillomavirus (HPV) 16 </li></ul><ul><ul><li>E6 bind...
Activatie van p53 door UV   Ellisen and Haber <ul><li>DNA-schade wordt gedetecteerd en leidt tot </li></ul><ul><ul><li>Cel...
Activatie van p53 door UV   Ellisen and Haber <ul><li>DNA-schade wordt gedetecteerd en leidt tot </li></ul><ul><ul><li>Cel...
Activatie van p53 door UV   Ellisen and Haber <ul><li>DNA-schade wordt gedetecteerd en leidt tot </li></ul><ul><ul><li>Cel...
DNA errors   Ellisen and Haber <ul><li>Instabiliteit van DNA </li></ul><ul><ul><li>Verandering van micro-satelliet sequent...
Species-specific differences  Ellisen and Haber <ul><li>Answer: unknown! </li></ul>
Tumor suppressor genes   Ellisen and Haber <ul><li>RB-1 </li></ul><ul><li>p53 </li></ul><ul><li>hMSH-2 </li></ul><ul><li>B...
Cell-specificity   Ellisen and Haber <ul><li>Functional redundancy </li></ul><ul><ul><li>Genen met vergelijkbare functies ...
De adeno-truc: ONYX-015 Ellisen and Haber <ul><li>Gemodificeerd adenovirus kan alleen repliceren –en dus cellen doden– in ...
A selected list of oncolytic viruses in clinical trials  the Scientist May 2007 ============== Jennerex  (JX-594) Phase I/...
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GKA deel 1 college 8

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GKA deel 1 college 8

  1. 2. Mechanisms of tumor suppressor genes Ellisen and Haber Sci Med 5-4, 1998, 26-35 <ul><li>Fusie maligne met niet-maligne cel: geen maligne cel </li></ul><ul><li>50% van kinderen met familiehistorie retinoblastoma krijgt deze tumor; predestinatie? </li></ul>AMPLIFICATION REARRANGEMENT ACTIVATING MUTATION INACTIVATING MUTATION DELETION LOSS OF FUNCTION GAIN OF FUNCTION NORMAL GENE AT CHROMOSOMAL LOCUS
  2. 3. Rb-switch and cell cycle regulation Ellisen and Haber Tumor-associated: - Rb - cyclinD - p16Ink4a - CDK4 Cell cycle activation
  3. 4. Rb-switch and cell cycle regulation Ellisen and Haber Tumor-associated: - Rb - cyclinD - p16Ink4a - CDK4 Cell cycle activation
  4. 5. Virussen en interactie met celcyclus Ellisen en Haber <ul><li>Humaan papillomavirus (HPV) 16 </li></ul><ul><ul><li>E6 bindt p53, E7 bindt Rb </li></ul></ul><ul><ul><li>Sterke associatie van HPV met baarmoederhalskanker </li></ul></ul><ul><ul><ul><li>Vaccinatie tegen HPV </li></ul></ul></ul><ul><ul><ul><ul><li>Sinds 2009! </li></ul></ul></ul></ul><ul><li>Adenovirus </li></ul><ul><ul><li>E1A bindt Rb, E1B bindt p53 </li></ul></ul><ul><li>Simian virus 40: SV40 </li></ul><ul><ul><li>T-antigen T ag bindt p53 en Rb </li></ul></ul>
  5. 6. Activatie van p53 door UV Ellisen and Haber <ul><li>DNA-schade wordt gedetecteerd en leidt tot </li></ul><ul><ul><li>Cel-cyclus blokkade </li></ul></ul><ul><ul><li>Apoptose </li></ul></ul><ul><li>UV-ATM-p53  </li></ul><ul><ul><li>-p21 waf –blok cycline/cdk </li></ul></ul><ul><ul><li>DNA repair </li></ul></ul><ul><li>ATM: ataxia telangiectasia: </li></ul><ul><ul><li>Hersendegeneratie, kanker </li></ul></ul><ul><li>p21 waf cdk-remmer </li></ul>
  6. 7. Activatie van p53 door UV Ellisen and Haber <ul><li>DNA-schade wordt gedetecteerd en leidt tot </li></ul><ul><ul><li>Cel-cyclus blokkade </li></ul></ul><ul><ul><li>Apoptose </li></ul></ul><ul><li>UV-ATM-p53  </li></ul><ul><ul><li>-p21 waf –blok cycline/cdk </li></ul></ul><ul><ul><li>DNA repair </li></ul></ul><ul><li>ATM: ataxia telangiectasia: </li></ul><ul><ul><li>Hersendegeneratie, kanker </li></ul></ul><ul><li>p21 waf cdk-remmer </li></ul>
  7. 8. Activatie van p53 door UV Ellisen and Haber <ul><li>DNA-schade wordt gedetecteerd en leidt tot </li></ul><ul><ul><li>Cel-cyclus blokkade </li></ul></ul><ul><ul><li>Apoptose </li></ul></ul><ul><li>UV-ATM-p53  </li></ul><ul><ul><li>-p21 waf –blok cycline/cdk </li></ul></ul><ul><ul><li>DNA repair </li></ul></ul><ul><li>ATM: ataxia telangiectasia: </li></ul><ul><ul><li>Hersendegeneratie, kanker </li></ul></ul><ul><li>p21 waf cdk-remmer </li></ul>
  8. 9. DNA errors Ellisen and Haber <ul><li>Instabiliteit van DNA </li></ul><ul><ul><li>Verandering van micro-satelliet sequenties </li></ul></ul><ul><ul><li>Of vice-versa! </li></ul></ul>
  9. 10. Species-specific differences Ellisen and Haber <ul><li>Answer: unknown! </li></ul>
  10. 11. Tumor suppressor genes Ellisen and Haber <ul><li>RB-1 </li></ul><ul><li>p53 </li></ul><ul><li>hMSH-2 </li></ul><ul><li>BRCA-1/2 </li></ul><ul><li>VHL </li></ul><ul><li>WT-1 </li></ul><ul><li>APC </li></ul><ul><li>Cell cycle regulation </li></ul><ul><li>Transcription factor </li></ul><ul><li>DNA repair </li></ul><ul><li>DNA repair, cytokinesis (?) </li></ul><ul><li>RNA stability? </li></ul><ul><li>Genitourinary,Tc factor </li></ul><ul><li>Wnt-signaling </li></ul><ul><li>Retina, lung, breast 50% of all cancers </li></ul><ul><li>Colon, endometrial </li></ul><ul><li>Ovary (rare) </li></ul><ul><li>Breast, ovary (rare) </li></ul><ul><li>Renal carcinoma </li></ul><ul><li>Wilms’ tumor </li></ul><ul><li>Colon carcinoma </li></ul><ul><li>Retinoblastoma </li></ul><ul><li>Li-Fraumeni </li></ul><ul><li>Colon </li></ul><ul><li>Breast, ovary </li></ul><ul><li>Von Hippel Lindau </li></ul><ul><li>WAGR syndrome </li></ul><ul><li>Adenomatous polyposis coli </li></ul>
  11. 12. Cell-specificity Ellisen and Haber <ul><li>Functional redundancy </li></ul><ul><ul><li>Genen met vergelijkbare functies </li></ul></ul><ul><ul><li>Cel-specifiek? </li></ul></ul><ul><li>Schade induceert apoptose, behalve in retina??? </li></ul>
  12. 13. De adeno-truc: ONYX-015 Ellisen and Haber <ul><li>Gemodificeerd adenovirus kan alleen repliceren –en dus cellen doden– in p53 negatieve cellen </li></ul>
  13. 14. A selected list of oncolytic viruses in clinical trials the Scientist May 2007 ============== Jennerex (JX-594) Phase I/II Thymidine kinase deletion prevents replication in cells with low nucleotide pool. Vaccinia Neotropix (SVV-001) Phase I Naturally targets certain tumor cells Seneca Valley Virus Oncolytics (Reolysin) Phase I/II Naturally unable to infect cells with active PKR Reovirus Wellstat (PV701) ]; Hadassah Medical Organization (MTH-68H) Phase I Naturally unable to replicate in interferon-responsive cells Newcastle disease virus Mayo Clinic (MV-CEA) Phase I Engineered to target CD46 on tumor cells Measles virus BioVex (OncoVEXGM-CSF) Phase II ICP34.5 deletion restricts replication to cells with active replication Herpes simplex virus 1 Viralytics (A21) Phase I Targets DAF/intercellular adhesion molecule 1, which is overexpressed in cancer Coxsackie virus Onyx (O15) Phase III (canceled) Sunway Biotech of China (H101) Phase III E1B deletion restricts replication to cells with aberrant mRNA transport Adenovirus Companies/Institutions (candidate) Human trial status Selective targeting method Virus

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