Shu

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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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Shu

  1. 1. Drug Transport Mechanisms of Cancer Therapeutics Yan Shu Department of Pharmaceutical Sciences School of Pharmacy University of Maryland at Baltimore
  2. 2. Drug Transport Mechanisms <ul><li>Uptake mechanisms: </li></ul><ul><li>Offer potentials for drug targeting </li></ul>Diffusion Influx transporter Efflux transporter Endocytosis (e.g. receptor-mediated) <ul><li>Efflux mechansims: </li></ul><ul><li>Drug resistance </li></ul>Intracellular transport? Diffusion Exocytosis Efflux transporter
  3. 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. 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. 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. 6. Modulation of Brain Tumor Permeability by NO Donors in Rats Bearing Brain Tumors Yin et al, Clin Cancer Res 2008
  7. 7. Sildenafil Increases Drug Uptake in a Lung Cancer Cell Line K ca Caveolin-1 DAPI Merge
  8. 8. Vardenafil Increases Drug Concentrations in a Lung Cancer and Enhances Herceptin Efficacy
  9. 9. Membrane Transporters Involved in Drug Response MATE1-2 MATE Family
  10. 10. Organic Cation Transporters Are Oxaliplatin Transporters Zhang et al, Cancer Res 2007
  11. 11. Oxaliplatin and OCT1 Polymorphisms <ul><li>Platinum-DNA adduct formation </li></ul><ul><li>Oxaliplatin cytotoxicity </li></ul>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
  12. 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. 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

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