1 / 23

Impact of DNA Repair Mechanisms on Resistance to alkylating therapeutic agents

Impact of DNA Repair Mechanisms on Resistance to alkylating therapeutic agents. NH 2. NH 2. C. O. C. O. N. N. N. N. N. N. CH 3. CH 3. N. NH 2. N. N. H. O. C. O. N. N. N. N. CH 3. CH 3. N. TMZ. MTIC. DITC. NH 2. CH 3. O. C. O. N. N. N. N. N. H 2 N. N.

violet
Download Presentation

Impact of DNA Repair Mechanisms on Resistance to alkylating therapeutic agents

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Impact of DNA Repair Mechanisms on Resistance to alkylating therapeutic agents

  2. NH2 NH2 C O C O N N N N N N CH3 CH3 N NH2 N N H O C O N N N N CH3 CH3 N TMZ MTIC DITC

  3. NH2 CH3 O C O N N N N N H2N N CH3 N N H TMZ O6mG CH3 O N MTIC N H2N N N N7mG

  4. Repair Pathways Responsible for Processing Methyl DNA Adducts TMZ MGMT & MMR O6mG (6%) N7mG (70%) N3mA (9%) BER

  5. Direct Repair of O6mG Mediated by AGT AGT

  6. The Correlation of MGMT Activity to the Drug Resistance 1500 100 10 1 0.1 0 1000 Tumor Volume (mm3) BCNU 30 mg/kg 500 0 0 10 20 30 40 50 60 Days 0.1 % 1 % 10 % 100 % Cancer Res. 1997

  7. MGMT MGMT O Cys Cys N HN S S H2N N N Reaction of O6-benzylguanine and AGT Protein - O N N H2N N N O6-benzylguanine (BG) Guanine

  8. AGT AGT O6-Methylating Agent MGMT Repair Mismatch Repair Cytotoxicity Cell Survival

  9. MutH

  10. Resistance of MMR Deficient Colon Cancer Cells to TMZ SW480 (MMR+) HCT 15 (MSH6 mut) HCT 116 (MLH1 mut) 100 100 100 +BG +BG 10 10 10 +BG 1 1 1 0 500 1000 1500 2000 0 500 1000 1500 2000 0 500 1000 1500 2000 TMZ(µM) Cancer Res. 1996

  11. Repair Pathways Responsible for Processing Methyl DNA Adducts TMZ MGMT & MMR O6mG (6%) N7mG (70%) N3mA (9%) BER

  12. MPG Methoxyamine XRCC1 PARP b DNA pol XRCC1 XRCC1 LigaseIII BER pathway N7mG AP site APE

  13. 5’ P P P 3’ O C H 5’ 5’ P P P P P P 3’ 3’ O CH3 HN H HO C Methoxyamine binds to aldehyde group in an AP site MPG MX APE

  14. U UDG MX NHOCH3 MX bound AP Site is Resistant to Cleavage by AP-endonuclease + - + - APE AP site 40 mer 20 mer AP-MX site AP-MX Site AP Site

  15. 5’ 5’ OH OH O NH-O- CH3 CH3 O N 3’ 3’ AP site AP site-MX 6 5 4 Unit of Density 3 2 2 1 r = 0.993 0 0 0.375 0.75 1.5 3 6 AP-DNA substrate (g) 5’ 5’ O H OH OH Strepta.HRP N O Strep HRP N NH2 O O N O H 3’ 3’ AP site-ARP AP site

  16. Control TMZ (175µM) TMZ (175µM)+MX(25 mM) TMZ (350µM) 10 TMZ (350µM)+MX(25 mM) 7.5 TMZ (750µM) 5 TMZ (750µM)+MX(25 mM) 2.5 r = 0.995 0 0 94 187 375 750 1500 TMZ(µM) T T M M Z Z 1 1 4 4 T T M M Z Z + + M M X X 1 1 2 2 1 1 0 0 MX-AP 8 8 6 6 4 4 2 2 0 0 0 0 1 1 8 8 7 7 3 3 7 7 5 5 7 7 5 5 0 0 1 1 5 5 0 0 0 0 T T M M Z Z ( ( u u M M ) ) AP sites (unit of density)

  17. Methoxyamine Interrupt BER Pathway MX APE O CH3 HN H HO C 5’ P P P 3’ Block DNA Synthesis Chromosomal Aberration Apoptosis Cell Death

  18. SW480 Tumor Growth in Nude Mice Clin. Cancer Res. 2002

  19. Inhibition of SW480 Tumor Growth By BG plus MX and TMZ in Nude Mice

  20. HCT116 Tumor Growth in Nude Mice 2000 Control TMZ (120 mg/kg) 1500 BG (30 mg/kg)+TMZ MX (0.2 mg/kg) 1000 MX+TMZ 500 0 0 5 10 15 20 25 30 Days

  21. Compared to TMZ alone, the combination of MX+TMZ has No additive toxicity, Compared to BG+TMZ, the combination of MX+TMZ has No toxic death Less body weight loss Less myelosuppression

  22. Blocking BER efficiently potentiate TMZ-antitumor Effect bypassing MMR and p53 genetic status.

  23. Liu & Gerson. Clin Cancer Res 2006;12:328-331

More Related