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Resistance circumvention strategies tested in clinical leukaemia specimens using the MTT colorimetric assay
E Lambert1, J K Rees, P R Twentyman
1Department of Clinical Oncology, University of Cambridge, UK.
Abstract:
We have used a 4-day MTT colorimetric assay to study drug sensitivity of leucocytes from leukaemia patients and from normal donors. Response to Adriamycin, vincristine, aclacinomycin A, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), and melphalan has been determined, together with the effects of the resistance modifiers verapamil, cyclosporin A, and ethacrynic acid. Sensitivity of chronic lymphoblastic leukemia (CLL) lymphocytes to vincristine was much greater than that of normal lymphocytes or of leucocytes from myeloid leukaemia patients. These cells were also more sensitive to melphalan. Verapamil and cyclosporin A at clinically achievable doses of 1 microgram/ml produced significant chemosensitisation in normal and leukaemic specimens, but the sensitisation ratio was greater than or equal to 2 only in a minority of specimens, except in the case of sensitisation to vincristine seen in the majority of CLL specimens. Sensitisation was generally greater in the more chemo-resistant specimens. The ratio of sensitivities of cells to Adriamycin compared with aclacinomycin A was greatest in the more Adriamycin-resistant specimens which supports the idea that cross-resistance between these agents may not be great. This was not, however, true for the ratio of Adriamycin/MX2 sensitivity. Use of the MTT assay may allow the identification of patients who would benefit from treatment with resistance modifiers or with 'low-resistance' anthracyclines.
Insights
This study used an MTT assay to test leukemia drug sensitivity. Chronic lymphoblastic leukemia cells showed higher sensitivity to vincristine and melphalan, suggesting potential for targeted therapies.
Area of Science:
- Hematology
- Pharmacology
- Oncology
Background:
- Leukemia drug resistance poses a significant challenge in treatment.
- Understanding differential drug sensitivity in various leukemia types is crucial for personalized medicine.
Purpose of the Study:
- To evaluate drug sensitivity in leukocytes from leukemia patients and healthy donors.
- To investigate the efficacy of resistance modifiers in overcoming drug resistance.
- To assess the potential of the MTT assay for identifying patients who may benefit from specific treatments.
Main Methods:
- A 4-day MTT colorimetric assay was employed.
- Drug sensitivity to Adriamycin, vincristine, aclacinomycin A, MX2, and melphalan was determined.
- The effects of resistance modifiers (verapamil, cyclosporin A, ethacrynic acid) were assessed.
Main Results:
- Chronic lymphoblastic leukemia (CLL) lymphocytes exhibited significantly greater sensitivity to vincristine and melphalan compared to normal or myeloid leukemia cells.
- Verapamil and cyclosporin A demonstrated chemosensitization, particularly in chemo-resistant specimens and for vincristine in CLL.
- Cross-resistance patterns varied, with lower cross-resistance between Adriamycin and aclacinomycin A than between Adriamycin and MX2.
Conclusions:
- The MTT assay can differentiate drug sensitivity profiles in leukemia subtypes.
- Resistance modifiers show potential for enhancing chemotherapy efficacy, especially in resistant cases.
- Identifying specific drug sensitivities and cross-resistance patterns may guide the selection of anthracyclines and resistance modifiers for improved patient outcomes.