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GST-P1 or not to be? TS to be?

GST-P1 or not to be? TS to be?. Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris Comprehensive Cancer Center USC Keck School of Medicine. Peripheral Neurotoxicity. Mechanism not well understood

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GST-P1 or not to be? TS to be?

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  1. GST-P1 or not to be? TS to be? Heinz-Josef Lenz, MD Associate Professor of Medicine Co-Director, Colorectal Center Co-Director, GI Oncology Program USC/Norris Comprehensive Cancer Center USC Keck School of Medicine

  2. Peripheral Neurotoxicity • Mechanism not well understood • Dorsal root ganglia neuronopathy • Axonopathy • Agents implicated: cisplatin, oxaliplatin, taxanes, 5-FU (rare) • Various mechanisms proposed: Sodium, Calcium Channels, DNA repair, Homocystein pathway, Cox-2

  3. Oxaliplatin-related peripheral neuropathy • It has 2 components: • acute neurotoxicity: axonopthay • chronic neurotoxicity: dorsal root ganglia

  4. Mechanism of action of oxaliplatin on Na+ channels (Axonopathy) oxaliplatin + Hg2+ TTX EXTRA Membrane Na+ oxalate ATP ATP INTRA Ca2+ Dach-Pt

  5. Inward Na+current inhibition by oxaliplatin in patch clamp technique Inward Na+current Action potential

  6. Sodium channels • Sodium channels regulate excitability of nerve and muscle cells (Ca dependent) • At least seven different Na+ channels expressed in sensory neurons • Oxaliplatin increases nerve refractory time through its effect in Na+ channels

  7. Neurotoxicity as reason for treatment discontinuation 35 30 CaMg 25 no CaMg 20 % of drop outs for neurotoxicity 15 10 5 0 85 100 130 oxaliplatin dosage (mg/m2) Gamelin et al, Clin Cancer Res 2004

  8. Folate-Homocysteine • Elevated homocysteine  neuronal damage • NMDA receptor stimulation  Ca influx  reactive oxygen species (ROS)  neural apoptosis • Oxidative damage to endothelial cells • High Thymidylate synthase  low Homocysteine levels

  9. DNA repair • ↓ ERCC1, XRCC1, XPD function  ↑ susceptibility of dorsal root ganglia to platinum-damage  peripheral neuropathy • Oxidative Stress leading to damage of dorsal root ganglia (MnSOD, GST)

  10. USC Data on 130 patients treated with CIFOX prospectively in second line

  11. Lipid peroxidation DNA damage

  12. Polymorphisms and Treatment Discontinuation Due to Neurotoxicity *Chi-square P-value

  13. Cumulative Oxaliplatin-Dose and Early Neurotoxicity P = 0.143 Chi-Square P = 0.030* *Fisher’s exact P-value = 0.036

  14. Future: Neurotoxicity • To understand the mechanisms of the acute and chronic neurotoxicity • To investigate the role of oxidative stress such as GST-P1 in neurotoxicity and how to prevent it (antioxidants?)

  15. Is TS prognostic, predictive or both? • Prognostic markers (survival, recurrence) • Not applicable for individual patients • Usually used high/low, presence/absence • Predictive markers (response, survival, toxicity) • Used for an individual patient • Usually absolute number Iqbal et al. Curr Gastroenterol Rep. 2003;5:399-405.

  16. Metabolism and mechanism of action of 5-Fluorouracil (5-FUra) 5-FUra dThd phosphorylase H2FUra DPD a-F-b-ala FdUrd FdUMP DNA dUMP dTMP thymidylate synthase

  17. Assessment of TS Expression DNA mRNA Protein Iqbal et al. Curr Gastroenterol Rep. 2003;5:399-405.

  18. TS and Adjuvant Chemotherapy Evaluation by IHC

  19. TS Protein Expression • 5 studies have evaluated TS in adjuvant chemotherapy for CRC • 4/5 studies consistently show TS as an independent prognosticator of DFS and OS • Conclusions • Patients with high TS who received chemotherapy did as well as patients with low TS with or without chmotx. • The advantage to receiving adjuvant ctx for patients with low TS was less than for patient with high TS • Patients with low TS have a better outcome • The benefit of adjuvant chemotherapy demonstrated in patients with high TS

  20. Thymidylate Synthase Expression and Prognosis in Colorectal Cancer: A Systematic Review and Meta-Analysis: 13 studies with 887 patients MCRC7 studies 2610 patients LCRC Popat et al J Clin Onc February 2004, 529-536

  21. Popat et al J Clin Onc February 2004, 529-536

  22. TS IHC versus RT-PCR The value of TS expression in predicting poor OS seems strongest in studies using RTPCR and not IHC. Popat et al J Clin Onc February 2004, 529-536

  23. TS Repeat Polymorphisms in 221 patients with Dukes C Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30-1.25, P = 0.18) Patients with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52-0.82, P = 0.005).

  24. Low TS High TS

  25. 5-FU NO 5-FU

  26. It all makes sense again? • High TS associated with poor outcome • High TS does not benefit from 5-FU adjuvant chemotherapy • Consistent with data from meta analysis and data from TS polymorphisms and gene expression data. • Controversial data due to difference in technologies, cut off levels, patients populations

  27. Overall Survival by TS Intensity (Stage II) SURVIVAL (Probability Rate) High TS Low TS P=0.47 Years since surgery

  28. Overall Survival by Treatment within high TS Staining Tumours (Stage IIIC) SURVIVAL (Probability Rate) 5-FU No 5-FU P=0.12 YEARS SINCE SURGERY

  29. The is a partial list of some common external causes of free radicals: • Toxins • carbon tetrachloride • paraquat • benzo(a)pyrene • aniline dyes • Toluene • Drugs • Adriamycin,bleomycin,nitrofurantoin • chlorpromazine • Air pollution: Primary sources • carbon monoxide, nitric oxide • passive tobacco smoke • Ingested substances • alcohol • smoked and barbecued food • peroxidized fats in meat and cheese • deep-fried foods • trans fats in processed foods

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