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Drug Transport Mechanisms of Cancer Therapeutics Yan Shu Department of Pharmaceutical Sciences School of Pharmacy University of Maryland at Baltimore
Drug Transport Mechanisms ,[object Object],[object Object],Diffusion Influx transporter Efflux transporter Endocytosis (e.g. receptor-mediated) ,[object Object],[object Object],Intracellular transport? Diffusion Exocytosis Efflux transporter
Signal Pathways in Determining Brian Tumor Permeability B2R: bradykinin receptor 2; NOS: nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: cGMP-dependent protein kinase; PDE5: phosphodiesterase type 5 sGC Calmodulin NOS PKG K Ca  Channel [Ca 2+ ]i  [cGMP]  PDE5 [NO] 5’GMP IBTX, CTX, TEA NS1619, NS004 L-Arg L-Cit HOE140 Levitra, Viagra, Zaprinast Rp-8BR-cGMP Brain Tumor permeability   B2R Bradykinin L-NMMA 2-APB ? LY83583
Modulation of Brain Tumor Permeability by PDE5 Inhibitors Tumor Permeability Survival Tumor Size BK: bradykinin; SIL:sildenafil; VAR: vardenafil; TAD: tadalafil Black et al, Brain Res 2008
Increased Vesicle Formation in Brain Tumors by Vardenafil (Levitra) a, Normal tissue/PBS;  b, Tumor tissue/PBS  c. Tumor tissue/Levitra 1 hour;  d, Tumor tissue/Levitra 2 hours;  e, Tumor tissue/Levitra 3 hours
Modulation of Brain Tumor Permeability by NO Donors in Rats Bearing Brain Tumors Yin et al, Clin Cancer Res 2008
Sildenafil Increases Drug Uptake in a Lung Cancer Cell Line K ca Caveolin-1 DAPI Merge
Vardenafil Increases Drug Concentrations in a Lung Cancer and Enhances Herceptin Efficacy
Membrane Transporters Involved in Drug Response MATE1-2 MATE Family
Organic Cation Transporters Are Oxaliplatin Transporters Zhang et al, Cancer Res 2007
Oxaliplatin and OCT1 Polymorphisms ,[object Object],[object Object],Patients with variant OCT1 may have different response to oxaliplatin in comparison to the patients with reference OCT1 Platinum-DNA adducts (pmols / ug DNA) Mock 0.00 0.05 0.10 0.15 0.20 0.25 Ref S14F R61C G220V G401S V408M 420Del G465R IC 50  of oxaliplatin ( µ M) 0.0 0.5 1.0 1.5 2.0 2.5 mock Ref S14F R61C G220V G401S V408M 420Del G465R
Cisplatin-responsive and –resistant  Human Cervical Cancer Cells OCT3 expression in KB-3-1 and KB-CP20 cells 2D-Gel shows differences in protein expression between KB-3-1 and KB-CP20 cells KB-3-1 KB-CP20
Qing Li, MD, PhD Cedars-Sinai Medical Center, Los Angeles Keith L. Black, MD  Dali Yin, MD Jinwei Hu, MD Bindu Konda, MS Andres Espinoza, MD   Acknowledgement

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Shu

  • 1. Drug Transport Mechanisms of Cancer Therapeutics Yan Shu Department of Pharmaceutical Sciences School of Pharmacy University of Maryland at Baltimore
  • 2.
  • 3. Signal Pathways in Determining Brian Tumor Permeability B2R: bradykinin receptor 2; NOS: nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: cGMP-dependent protein kinase; PDE5: phosphodiesterase type 5 sGC Calmodulin NOS PKG K Ca Channel [Ca 2+ ]i [cGMP] PDE5 [NO] 5’GMP IBTX, CTX, TEA NS1619, NS004 L-Arg L-Cit HOE140 Levitra, Viagra, Zaprinast Rp-8BR-cGMP Brain Tumor permeability  B2R Bradykinin L-NMMA 2-APB ? LY83583
  • 4. Modulation of Brain Tumor Permeability by PDE5 Inhibitors Tumor Permeability Survival Tumor Size BK: bradykinin; SIL:sildenafil; VAR: vardenafil; TAD: tadalafil Black et al, Brain Res 2008
  • 5. Increased Vesicle Formation in Brain Tumors by Vardenafil (Levitra) a, Normal tissue/PBS; b, Tumor tissue/PBS c. Tumor tissue/Levitra 1 hour; d, Tumor tissue/Levitra 2 hours; e, Tumor tissue/Levitra 3 hours
  • 6. Modulation of Brain Tumor Permeability by NO Donors in Rats Bearing Brain Tumors Yin et al, Clin Cancer Res 2008
  • 7. Sildenafil Increases Drug Uptake in a Lung Cancer Cell Line K ca Caveolin-1 DAPI Merge
  • 8. Vardenafil Increases Drug Concentrations in a Lung Cancer and Enhances Herceptin Efficacy
  • 9. Membrane Transporters Involved in Drug Response MATE1-2 MATE Family
  • 10. Organic Cation Transporters Are Oxaliplatin Transporters Zhang et al, Cancer Res 2007
  • 11.
  • 12. Cisplatin-responsive and –resistant Human Cervical Cancer Cells OCT3 expression in KB-3-1 and KB-CP20 cells 2D-Gel shows differences in protein expression between KB-3-1 and KB-CP20 cells KB-3-1 KB-CP20
  • 13. Qing Li, MD, PhD Cedars-Sinai Medical Center, Los Angeles Keith L. Black, MD Dali Yin, MD Jinwei Hu, MD Bindu Konda, MS Andres Espinoza, MD Acknowledgement