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Development of an orthotopic SCID mouse-human tumor xenograft model displaying the multidrug-resistant phenotype
W T Bellamy1, P Mendibles, P Bontje
1Department of Pathology, College of Medicine, University of Arizona, Tucson 85724, USA.
Abstract:
Multiple myeloma is a plasma cell malignancy which is generally incurable in spite of a high initial response to chemotherapy. While animal models of myeloma are known, the recent developments of human xenografts in nude and SCID mice suggests a promising experimental model. The SCID model, in particular, holds promise because these animals readily accept hematopoietic and lymphoid transplantation and do not generally develop graft versus host reaction. We have developed two drug-resistant variants of the human multiple myeloma cell line ARH-77 by in vitro exposure to gradually increasing concentrations of doxorubicin (ARH-D60) or mitoxantrone (ARM-80). When injected into irradiated SCID mice, the ARH-D60 cell line grew in an orthotopic pattern with the development of osteolytic lesions. This is in contrast to the 8226/C1N human myeloma cell line which grows in a disseminated but nonorthotopic manner in the SCID mouse. Both the ARH-D60 and ARM-80 cell lines are resistant to doxorubicin and cross-resistant to mitoxantrone, vinca alkaloids, taxol and m-AMSA while maintaining sensitivity to antimetabolites and alkylating agents. Growth characteristics and cell cycle kinetics, including S-phase, were not altered in the resistant sublines. The ARH-D60 and ARM-80 cell lines both displayed a classic multidrug-resistance (MDR) phenotype which was partially reversed by the addition of verapamil. These two cell lines represent the first MDR human myeloma cell lines which have demonstrated an orthotopic growth pattern in the SCID mouse and thus may be of value in studying the pathophysiology of this disease.
Insights
Researchers developed two multidrug-resistant (MDR) human multiple myeloma cell lines, ARH-D60 and ARM-80, in SCID mice. These cell lines exhibit orthotopic growth and MDR, offering a valuable model for studying multiple myeloma pathophysiology.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Multiple myeloma is a generally incurable plasma cell malignancy with initial chemotherapy response.
- Existing animal models have limitations; human xenografts in immunodeficient mice offer a promising alternative.
- Severe Combined Immunodeficient (SCID) mice are suitable for hematopoietic and lymphoid transplantation without graft-versus-host reactions.
Purpose of the Study:
- To develop and characterize multidrug-resistant (MDR) human multiple myeloma cell lines.
- To evaluate the in vivo growth patterns of these cell lines in SCID mice.
- To establish a novel experimental model for studying multiple myeloma pathophysiology.
Main Methods:
- In vitro development of drug-resistant variants (ARH-D60, ARM-80) from the ARH-77 human multiple myeloma cell line via stepwise drug exposure.
- Injection of cell lines into irradiated SCID mice to assess orthotopic and disseminated growth patterns.
- Phenotypic characterization, including drug resistance profiles, cross-resistance, and multidrug-resistance (MDR) phenotype assessment, with partial reversal by verapamil.
Main Results:
- ARH-D60 cells demonstrated orthotopic growth in SCID mice with osteolytic lesions, unlike the 8226/C1N cell line.
- Both ARH-D60 and ARM-80 cell lines exhibited resistance to doxorubicin and cross-resistance to mitoxantrone, vinca alkaloids, taxol, and m-AMSA.
- A classic multidrug-resistance (MDR) phenotype was observed, partially reversed by verapamil, without altering growth characteristics or cell cycle kinetics.
Conclusions:
- The ARH-D60 and ARM-80 cell lines are the first MDR human myeloma cell lines to show orthotopic growth in SCID mice.
- These cell lines represent a valuable preclinical model for investigating multiple myeloma pathophysiology and drug resistance mechanisms.
- The model may aid in developing novel therapeutic strategies for drug-resistant multiple myeloma.