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Mdr1 gene-expression in a multidrug-resistant human non-hodgkins-lymphoma xenograft model
1INST GUSTAVE ROUSSY,PHARMACOL CLIN & MOLEC LAB,39 RUE CAMILLE DESMOULINS,F-94805 VILLEJUIF,FRANCE. INST GUSTAVE ROUSSY,DEPT INTERNAL MED,DIV HEMATOL,F-94805 VILLEJUIF,FRANCE. INST GUSTAVE ROUSSY,EXPTL THERAPEUT SECT,F-94805 VILLEJUIF,FRANCE. INST GUSTAVE ROUSSY,CYTOGENET LAB,F-94805 VILLEJUIF,FRANCE. INST GUSTAVE ROUSSY,DEPT HISTOPATHOL,F-94805 VILLEJUIF,FRANCE. HARVARD UNIV,SCH MED,JOINT CTR RADIAT THERAPY,BOSTON,MA 02115.
Abstract:
In order to investigate the biology of tumor cells which express MDR1 gene and to test the activity of different P-glycoprotein blocking agents in vivo, we established a nude mice model. Five Non Hodgkin's Lymphoma (NHL) tumor specimens were xenografted to nude mice. One of them, obtained from a chemotherapy-refractory patient gave rise to a mice transplantable model. This tumor xenograft model, IGR-NHL-90, showed overexpression of the human MDR1 gene. In this tumor model, histology, mitotic index, phenotypic and karyotypic traits remained stable at subsequent passages. The in vitro resistance of vincristine was reversed by verapamil for these NHL tumor cells, suggesting that the MDR1 resistance is a relevant mechanism in this model. In the absence of chemotherapy a higher biological aggressivity of the heterotransplanted NHL was noted in subsequent nude mice passages. This was associated with decreased passage time and higher MDR1 m-RNA transcript levels. Thus IGR-NHL-90 may represent a suitable material to study regulation of MDR1 gene transcription in vivo and also to test the activity of various P-glycoprotein reversing agents with concurrent chemotherapy.
Insights
Researchers developed a nude mice model for Non Hodgkin
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer chemotherapy.
- The MDR1 gene encodes P-glycoprotein, a key efflux pump contributing to drug resistance.
- Developing effective strategies to overcome MDR is crucial for improving patient outcomes.
Purpose of the Study:
- To establish and characterize a preclinical model for studying MDR in Non Hodgkin's Lymphoma (NHL).
- To investigate the role of the MDR1 gene and P-glycoprotein in chemotherapy resistance in vivo.
- To evaluate the efficacy of P-glycoprotein inhibitors in combination with chemotherapy.
Main Methods:
- Xenotransplantation of five NHL tumor specimens into nude mice.
- Establishment of a transplantable MDR1-overexpressing NHL xenograft model (IGR-NHL-90).
- In vitro and in vivo assessments of drug resistance, gene expression, and tumor behavior.
Main Results:
- The IGR-NHL-90 model demonstrated stable histological, phenotypic, and karyotypic traits across passages.
- In vitro vincristine resistance was reversed by verapamil, confirming MDR1 involvement.
- The xenograft exhibited increased biological aggressivity with higher MDR1 mRNA levels in later passages.
Conclusions:
- The IGR-NHL-90 xenograft model is suitable for studying MDR1 gene regulation and P-glycoprotein inhibitor activity in vivo.
- This model provides a platform for testing novel therapeutic strategies against MDR in NHL.
- Understanding MDR mechanisms is vital for developing more effective cancer treatments.
