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Research Team: Asso.Prof. Đỗ Thị Hồng Tươi Dr. Trương Công Trị MSc. Trần Thị Như Nguyện

UNIVERSITY OF MEDICINE AND PHARMACY AT HO CHI MINH CITY Faculty of Pharmacy. Research Team: Asso.Prof. Đỗ Thị Hồng Tươi Dr. Trương Công Trị MSc. Trần Thị Như Nguyện Pharm. Trần Thị Phương Uyên MSc. Nguyễn Bá Thọ.

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Research Team: Asso.Prof. Đỗ Thị Hồng Tươi Dr. Trương Công Trị MSc. Trần Thị Như Nguyện

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  1. UNIVERSITY OF MEDICINE AND PHARMACY AT HO CHI MINH CITY Faculty of Pharmacy • Research Team: Asso.Prof. Đỗ ThịHồngTươi • Dr. Trương Công Trị • MSc. Trần Thị Như Nguyện • Pharm. Trần Thị Phương Uyên • MSc. NguyễnBáThọ ESTABLISHMENT A SUBCUTANEOUS TUMOR MODEL BY HepG2 CELL LINE IN MICE TO STUDY ANTI-TUMOR EFFECTOF LIPOSOME PACLITAXEL

  2. INTRODUCTION Hepatocellular carcinoma (HCC): one of the leading causes of cancer deaths (ranked 3rdfor men, 6th for women) (Ferlay, Bray, 2010) - 2007, over 700.000 cases in the world - 2008, over 725.000 (Southeast Asia: 75.000 new cases) - Vietnam: high percentage of HCC patients, high cost of medications (imported) Paclitaxel: - Antiproliferation & death induction against human HCC(in vitro); - Combination withDOX reduced HCC tumor size(in vivo) - Poor solubility and permeabilitypoor bioavailability - Liposomal paclitaxel: enhance solubility, permeability and targeting specificity Establish a model of HCC using HepG2 cell line in mice Study the anti-tumor effect of liposome paclitaxel formulation

  3. METHODS - RESULTS s.c. injectionon nude/SCID mice In vivo model of HCC (xenograft model) Culturing HepG2 cell line Treatment Immunodeficiency induced by CYP

  4. METHODS - RESULTS Studying immunodeficiency-induced model on Swiss albino CYP i.p. cyclophosphamid 100mg/kg; 0,1ml/10g DOX i.p. doxorubicine 10mg/kg i.p. saline • Collect blood from tail vein every 1 – 2 days • Count leucocytes (Neubauer chamber) CYP CYP maleSwiss albino 8-10 week 32 ± 2 g n = 6 day 1 day 3 CYP CYP CYP day 1 day 3 day 5 DOX CYP day 1 day 3 Monitor mortality rate and ability to maintain immunodeficiency

  5. METHODS - RESULTS Studying immunodeficiency-induced model on Swiss albino I.p. CYP day 1, 3, 5: weak, ruffled fur, slow movement, 2/6 blind. 1 dead on day 7. Sharp decrease in leucocytes, lowest on day 6, followed by a slight recovery of 23% on day 21. I.p. DOX & CYP:weak, ruffled fur, slow movement. 1 dead on day 5 and another on day 6. Lowest number of leucocytes is recorded on day 5, followed by a rapid recovery of 87% on day 21.

  6. METHODS - RESULTS Studying immunodeficiency induced model on Swiss albino Ip CYP day 1, 3: weak, ruffled fur, normal movement, 0 dead. Total leucocytes were lowest on day 5, then recovered by 33% on day 21. Choose this protocol for the study of HCC induction

  7. METHODS - RESULTS Establish a model of HCC in SCID mice Pathology control (iv, NaCl 0.9%) Control n= 6 (PBS, sc) CYP Collect tumors i.p. 100mg/kg n = 36 HCC-induced n= 30 (HepG2, sc) Treatment (5-FU, iv 20mg/kg) Day 1 & 3 5 12 =>16 19 • Results (Mean ± SEM) analyzed by student’t test/Mann-Whitney • p < 0,05

  8. METHODS - RESULTS Establish a model of HCC in SCID mice Day 12, visible tumors on 17/30 mice (56.7%) Pathology control 5-FU treatment

  9. METHODS - RESULTS Establish a model of HCC in SCID mice % difference in tumor size d12 d14 d16 d18 Pathology control Treatment

  10. METHODS - RESULTS Establish a model of HCC in SCID mice

  11. METHODS - RESULTS Establish a model of HCC in SCID mice

  12. METHODS - RESULTS Study the anti-tumor effect of liposome paclitaxel formulation Ip CYP Mice with sc tumors Sc 106 HepG2 cells/mouse Day 12 Size mesuring Combination Pathology Treatment Positive control NaCl 0,9%0.1 ml/10 g PXT-Monta 1.5 10 mg/kg 5-FU20 mg/kg • 5-FU 20 mg/kg • PXT-Monta 10 mg/kg iv once a day, for 5 continuous days Day 19: Tumors collecting, sample preparing, histology analyzing Percentage of difference (%) = (Vafter – Vbefore)/Vbefore x 100

  13. METHODS - RESULTS Study the anti-tumor effect of liposome paclitaxel formulation Day 12: 14/20 mice with (efficiency of 77.78%)

  14. METHODS - RESULTS Study the anti-tumor effect of liposome paclitaxel formulation

  15. METHODS - RESULTS Study the anti-tumor effect of liposome paclitaxel formulation 5-FU + PTX-Monta PTX-Monta 5-FU Pathology control

  16. METHODS - RESULTS Study the anti-tumor effect of liposome paclitaxel formulation Pathology control 5-FU PTX-Monta 5-FU + PTX-Monta

  17. METHODS - RESULTS Study the anti-tumor effect of liposome paclitaxel formulation 5-FU Pathology 5-FU + PTX-Monta PTX-Monta

  18. METHODS - RESULTS Study the anti-tumor effect of liposome paclitaxel formulation Pathology 5-FU PTX-Monta 5-FU + PTX-Monta

  19. CONCLUSIONS • Evaluated and chose the suitable immunodeficiency-induced model of CYP 100 mg/kg, i.p. on day 1, 3. • Successfully establish a model of HCC in male immunodeficientSwiss albinoby s.c. injection of 106human HepG2 cells per mouse. • In vivo antitumor effect + Liposomal PTX decreased tumor size less than5-FU did. + Combination of liposomal PTX and 5-FU are more efficient in decreasing tumor size than single therapies. + Histology: tumors in combination groupare the most likely to have necrosisand less likely to have cell abnormalities than 2 single therapy groups.

  20. THANK YOU FOR YOUR ATTENTION

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