The document discusses mechanisms of tumor suppressor genes and their role in cancer development. It describes how tumor suppressor genes like RB-1, p53, and BRCA1/2 normally regulate cell cycle and DNA repair but are inactivated in cancer through mutations or deletions. Viruses can also interact with cell cycle pathways by binding to proteins like Rb and p53. The document lists several tumor suppressor genes and the cancers they are associated with. It also discusses using oncolytic viruses to selectively target and kill cancer cells.

2. Mechanisms of tumor suppressor genes Ellisen and Haber Sci Med 5-4, 1998, 26-35 Fusie maligne met niet-maligne cel: geen maligne cel 50% van kinderen met familiehistorie retinoblastoma krijgt deze tumor; predestinatie? AMPLIFICATION REARRANGEMENT ACTIVATING MUTATION INACTIVATING MUTATION DELETION LOSS OF FUNCTION GAIN OF FUNCTION NORMAL GENE AT CHROMOSOMAL LOCUS

3. Rb-switch and cell cycle regulation Ellisen and Haber Tumor-associated: - Rb - cyclinD - p16Ink4a - CDK4 Cell cycle activation

4. Rb-switch and cell cycle regulation Ellisen and Haber Tumor-associated: - Rb - cyclinD - p16Ink4a - CDK4 Cell cycle activation

5. Virussen en interactie met celcyclus Ellisen en Haber Humaan papillomavirus (HPV) 16 E6 bindt p53, E7 bindt Rb Sterke associatie van HPV met baarmoederhalskanker Vaccinatie tegen HPV Sinds 2009! Adenovirus E1A bindt Rb, E1B bindt p53 Simian virus 40: SV40 T-antigen T ag bindt p53 en Rb

6. Activatie van p53 door UV Ellisen and Haber DNA-schade wordt gedetecteerd en leidt tot Cel-cyclus blokkade Apoptose UV-ATM-p53  -p21 waf –blok cycline/cdk DNA repair ATM: ataxia telangiectasia: Hersendegeneratie, kanker p21 waf cdk-remmer

7. Activatie van p53 door UV Ellisen and Haber DNA-schade wordt gedetecteerd en leidt tot Cel-cyclus blokkade Apoptose UV-ATM-p53  -p21 waf –blok cycline/cdk DNA repair ATM: ataxia telangiectasia: Hersendegeneratie, kanker p21 waf cdk-remmer

8. Activatie van p53 door UV Ellisen and Haber DNA-schade wordt gedetecteerd en leidt tot Cel-cyclus blokkade Apoptose UV-ATM-p53  -p21 waf –blok cycline/cdk DNA repair ATM: ataxia telangiectasia: Hersendegeneratie, kanker p21 waf cdk-remmer

9. DNA errors Ellisen and Haber Instabiliteit van DNA Verandering van micro-satelliet sequenties Of vice-versa!

10. Species-specific differences Ellisen and Haber Answer: unknown!

11. Tumor suppressor genes Ellisen and Haber RB-1 p53 hMSH-2 BRCA-1/2 VHL WT-1 APC Cell cycle regulation Transcription factor DNA repair DNA repair, cytokinesis (?) RNA stability? Genitourinary,Tc factor Wnt-signaling Retina, lung, breast 50% of all cancers Colon, endometrial Ovary (rare) Breast, ovary (rare) Renal carcinoma Wilms’ tumor Colon carcinoma Retinoblastoma Li-Fraumeni Colon Breast, ovary Von Hippel Lindau WAGR syndrome Adenomatous polyposis coli

12. Cell-specificity Ellisen and Haber Functional redundancy Genen met vergelijkbare functies Cel-specifiek? Schade induceert apoptose, behalve in retina???

13. De adeno-truc: ONYX-015 Ellisen and Haber Gemodificeerd adenovirus kan alleen repliceren –en dus cellen doden– in p53 negatieve cellen

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