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3-D Tumor Model for In Vitro Evaluation of Anticancer Drugs
Periodical: Mol Pharm ISBN: 1543-8384 (Print)
Number: 5
Date: 2008/08/06
Language: Eng
Pages: 849-862
Authors:Horning, J. L., Sahoo, S. K., Vijayaraghavalu, S., Dimitrijevic, S., Vasir, J. K., Jain, T. K., Panda, A. K., Labhasetwar, V.
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Abstract
The efficacy of potential anticancer drugs during preclinical development is generally tested in vitro using cancer cells grown in monolayer; however, a significant discrepancy in their efficacy is observed when these drugs are evaluated in vivo. This discrepancy, in part, could be due to the three-dimensional (3-D) nature of tumors as compared to the two-dimensional (2-D) nature of monolayer cultures. Therefore, there is a need for an in vitro model that would mimic the 3-D nature of tumors. With this objective, we have developed surface-engineered, large and porous biodegradable polymeric microparticles as a scaffold for 3-D growth of cancer cells. Using the MCF-7 cell line as model breast cancer cells, we evaluated the antiproliferative effect of three anticancer drugs: doxorubicin, paclitaxel and tamoxifen in 3-D model vs in 2-D monolayer. With optimized composition of microparticles and cell culture conditions, a density of 4.5 x 10 (6) MCF-7 cells/mg of microparticles, which is an 18-fold increase from the seeding density, was achieved in six days of culture. Cells were observed to have grown in clumps on the microparticle surface as well as in their interior matrix structure. The antiproliferative effect of the drugs in 3-D model was significantly lower than in 2-D monolayer, which was evident from the 12- to 23-fold differences in their IC 50 values. Using doxorubicin, the flow cytometry data demonstrated approximately 2.6-fold lower drug accumulation in the cells grown in 3-D model than in the cells grown as 2-D monolayer. Further, only 26% of the cells in 3-D model had the same concentration of drug as the cells in monolayer, thus explaining the reduced activity of the drugs in 3-D model. The collagen content of the cells grown in 3-D model was 2-fold greater than that of the cells grown in 2-D, suggesting greater synthesis of extracellular matrix in 3-D model, which acted as a barrier to drug diffusion. The microarray analysis showed changes in several ge
The efficacy of potential anticancer drugs during preclinical development is generally tested in vitro using cancer cells grown in monolayer; however, a significant discrepancy in their efficacy is observed when these drugs are evaluated in vivo. This discrepancy, in part, could be due to the three-dimensional (3-D) nature of tumors as compared to the two-dimensional (2-D) nature of monolayer cultures. Therefore, there is a need for an in vitro model that would mimic the 3-D nature of tumors. With this objective, we have developed surface-engineered, large and porous biodegradable polymeric microparticles as a scaffold for 3-D growth of cancer cells. Using the MCF-7 cell line as model breast cancer cells, we evaluated the antiproliferative effect of three anticancer drugs: doxorubicin, paclitaxel and tamoxifen in 3-D model vs in 2-D monolayer. With optimized composition of microparticles and cell culture conditions, a density of 4.5 x 10 (6) MCF-7 cells/mg of microparticles, which is an 18-fold increase from the seeding density, was achieved in six days of culture. Cells were observed to have grown in clumps on the microparticle surface as well as in their interior matrix structure. The antiproliferative effect of the drugs in 3-D model was significantly lower than in 2-D monolayer, which was evident from the 12- to 23-fold differences in their IC 50 values. Using doxorubicin, the flow cytometry data demonstrated approximately 2.6-fold lower drug accumulation in the cells grown in 3-D model than in the cells grown as 2-D monolayer. Further, only 26% of the cells in 3-D model had the same concentration of drug as the cells in monolayer, thus explaining the reduced activity of the drugs in 3-D model. The collagen content of the cells grown in 3-D model was 2-fold greater than that of the cells grown in 2-D, suggesting greater synthesis of extracellular matrix in 3-D model, which acted as a barrier to drug diffusion. The microarray analysis showed changes in several ge
Keywords
Animals, Chick Embryo, Cross-Linking Reagents, dosage/*chemistry/metabolism/*pharmacology, Dose-Response Relationship, Drug, Fibrin/pharmacology, Ganglia, Spinal/drug effects/pathology/physiopathology, Hyaluronic Acid/administration &, Hydrogels/pharmacology, Male, Neurites/*drug effects/pathology, Rats, Rats, Sprague-Dawley, Recovery of Function, Spinal Cord Injuries/pathology/*physiopathology, Sulfhydryl Compounds/metabolism, Tissue Engineering/methods
Animals, Chick Embryo, Cross-Linking Reagents, dosage/*chemistry/metabolism/*pharmacology, Dose-Response Relationship, Drug, Fibrin/pharmacology, Ganglia, Spinal/drug effects/pathology/physiopathology, Hyaluronic Acid/administration &, Hydrogels/pharmacology, Male, Neurites/*drug effects/pathology, Rats, Rats, Sprague-Dawley, Recovery of Function, Spinal Cord Injuries/pathology/*physiopathology, Sulfhydryl Compounds/metabolism, Tissue Engineering/methods
3DCellculture.com's MAMI
search attributes
CellLine: MCF-7
Morphology: Cancerous
Origin: Breast
Species: Human
Scaffold Form: bead/microsphereMorphology: Cancerous
Origin: Breast
Species: Human
Scaffold Material: Chitosan
Scaffold Material: PVA/Polyvinyl alcohol