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Mafosfamide induces less sister chromatid exchange in Ph-positive cells than in normal bone marrow
R Becher1, G Becker, C G Schmidt
1Dept. of Internal Medicine, University Hospital, Essen, FRG.
Abstract:
The frequency of induced sister chromatid exchange (SCE) is a sensitive tool for the monitoring of DNA damage and has been shown to indicate chemotherapy resistance. Mafosfamide is presently used for the purging of bone marrow in autologous bone marrow transplantation in the treatment of acute leukemia. We studied the SCE-inducing effect of mafosfamide on leukemic cells of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) as a model for leukemic cells. Corresponding data from normal bone marrow were analyzed for comparison. A positive linear correlation (r = 0.99, P = 0.0005) was found between the dose of mafosfamide and induced SCE in Ph-positive CML and normal bone marrow. The concentration of mafosfamide used was 0.1, 0.2, 0.4, and 0.8 micrograms/ml. Additionally, we analyzed five cases of CML and six cases of normal bone marrow. A significant difference in the frequency of induced SCE/metaphase was found between CML and normal bone marrow even after addition of 0.8 micrograms/ml mafosfamide. Also, spontaneous SCE was significantly lower in CML. Our data indicate a lower sensitivity of the leukemic cells to mafosfamide as shown by the induction of a lower frequency of SCE events.
Insights
Mafosfamide induces sister chromatid exchange (SCE) in leukemia cells, but chronic myeloid leukemia (CML) cells show lower sensitivity. This DNA damage response suggests potential chemotherapy resistance in CML patients.
Area of Science:
- Cytogenetics
- Molecular Biology
- Cancer Research
Background:
- Sister chromatid exchange (SCE) frequency is a sensitive indicator of DNA damage and chemotherapy resistance.
- Mafosfamide is utilized for bone marrow purging in autologous bone marrow transplantation for acute leukemia treatment.
Purpose of the Study:
- To investigate the SCE-inducing effect of mafosfamide on Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) cells.
- To compare the sensitivity of CML cells to mafosfamide-induced SCE with that of normal bone marrow cells.
Main Methods:
- Culturing Ph+ CML and normal bone marrow cells.
- Treating cells with varying concentrations of mafosfamide (0.1, 0.2, 0.4, 0.8 µg/ml).
- Analyzing induced sister chromatid exchange (SCE) frequency per metaphase.
Main Results:
- A strong positive linear correlation (r=0.99) was observed between mafosfamide dose and induced SCE in both CML and normal bone marrow.
- Leukemic CML cells exhibited a significantly lower frequency of induced SCE compared to normal bone marrow cells, even at the highest mafosfamide concentration.
- Spontaneous SCE rates were significantly lower in CML cells than in normal bone marrow cells.
Conclusions:
- Leukemic cells from CML patients demonstrate reduced sensitivity to mafosfamide-induced DNA damage, as evidenced by lower SCE induction.
- This differential sensitivity may have implications for mafosfamide's efficacy in CML treatment and warrants further investigation.