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Pharmacologic bone marrow purging: is there any place for etoposide? In vitro comparison with mafosfamide
A Olivieri1, A Poloni, M Montanari
1Clinica di Ematologia, Università di Ancona, Italy.
Abstract:
Residual leukemic cells in a bone marrow graft may increase the risk of relapse after autotransplantation. We have compared the efficacy of etoposide with that of mafosfamide, which has been used mainly for purging in acute leukemias. First, we examined the effects of VP-16 and ASTA-Z on the normal hematopoietic progenitors and on the erythroleukemic cell K562. Subsequently, we evaluated purging activity in cocultures using two different ratios of leukemic contamination. The most effective drug concentrations in inhibiting 100% of K562 growth were 50 micrograms/ml of ASTA-Z and 70 micrograms of VP-16. Residual growth of normal colony-forming units-granulocyte-macrophage (CFU-GM) was 4.8% with VP-16 and 32.5% with ASTA-Z. In treated cocultures, ASTA-Z produced a higher inhibition of the K562 line than VP-16 at both levels of leukemic cell contamination. At 0.5% contamination, VP-16 showed higher toxicity toward normal hematopoietic progenitors than ASTA-Z. At the 5% contamination level, VP-16 completely inhibited colony formation, whereas ASTA-Z spared some normal progenitor cells (21.2%). In conclusion, in our experimental model, VP-16 did not show improved efficacy over ASTA-Z in killing leukemic cells and in sparing normal progenitors.
Insights
Mafosfamide (ASTA-Z) and etoposide (VP-16) were compared for purging leukemic cells in bone marrow grafts. ASTA-Z demonstrated comparable or superior efficacy in eliminating leukemic cells while better sparing normal hematopoietic progenitors.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Residual leukemic cells in bone marrow grafts pose a relapse risk post-autotransplantation.
- Graft purging aims to eliminate contaminating leukemic cells before transplantation.
Purpose of the Study:
- To compare the efficacy of mafosfamide (ASTA-Z) and etoposide (VP-16) for purging leukemic cells from bone marrow grafts.
- To evaluate the toxicity of these agents on normal hematopoietic progenitors.
Main Methods:
- In vitro assessment of VP-16 and ASTA-Z effects on K562 erythroleukemic cells and normal hematopoietic progenitors.
- Coculture experiments with varying ratios of leukemic cell contamination to evaluate purging activity.
Main Results:
- Optimal concentrations for 100% K562 inhibition were 50 µg/mL ASTA-Z and 70 µg/mL VP-16.
- ASTA-Z showed higher K562 inhibition and spared more normal colony-forming units-granulocyte-macrophage (CFU-GM) compared to VP-16.
- VP-16 exhibited greater toxicity to normal progenitors at lower contamination levels (0.5%), while ASTA-Z spared 21.2% of normal progenitors at 5% contamination.
Conclusions:
- VP-16 did not demonstrate superior efficacy over ASTA-Z in eliminating leukemic cells while preserving normal hematopoietic progenitors in this experimental model.
- ASTA-Z appears to be a potentially more favorable agent for graft purging due to its balance of leukemic cell killing and progenitor sparing.