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University of Maryland Baltimore

University of Maryland Baltimore Experimental Therapeutics Symposium 2009

Education Health & Medicine Technology

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

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

Shu

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