PMID- 9357970
OWN - NLM
STAT- MEDLINE
DCOM- 19971120
LR  - 20151119
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 25
IP  - 12
DP  - 1997 Nov
TI  - Pharmacological purging of minimal residual disease from peripheral blood stem 
      cell collections of acute myeloblastic leukemia patients: preclinical studies.
PG  - 1261-9
AB  - In this paper we describe an experimental model for ex vivo purging of 
      contaminating tumor cells from peripheral blood stem cell (PBSC) collections 
      obtained from patients with acute myeloblastic leukemia (AML). We studied the 
      combination of the alkylating agent nitrogen mustard (NM; concentrations ranging 
      from 0.25 to 1.25 microg/mL) and etoposide (VP-16; constant dose of 20 
      microg/mL), and the conventional cyclophosphamide (Cy)-derivative mafosfamide 
      (concentrations: 20-175 microg/mL). THE AIMS OF OUR STUDY WERE: 1) To compare the 
      toxicity of the purging protocols on bone marrow (BM) and circulating trilineage 
      precursors collected from normal donors after priming with granulocyte 
      colony-stimulating factor (G-CSF) or after complete remission (CR) consolidation 
      chemotherapy and G-CSF (leukemic patients); 2) to demonstrate the survival of 
      very primitive hematopoietic progenitors (LTC-IC) in the peripheral blood (PB) 
      and the BM after pharmacological treatment; and 3) to evaluate the antineoplastic 
      efficacy of purging protocols on PBSC collections using 3 well-established 
      leukemic cell lines. Our results demonstrated that the toxicity on BM and PB 
      progenitor cells could be correlated with the complete killing of committed 
      granulocyte-macrophage colony-forming units (CFU-GMs) and erythroid precursors 
      (BFU-Es), a condition reached at the concentration of 1.5 microg/mL of NM (in 
      addition to 20 microg/mL of VP-16) and 175 microg/mL of mafosfamide. Notably, 
      early and late megakaryocyte progenitor cells (CFU-MKs and BFU-MKs, respectively) 
      showed higher sensitivity to NM/VP-16, but not to mafosfamide, than did CFU-GMs 
      and BFU-Es. The dose of NM capable of inhibiting 95% of CFU-MKs and BFU-MKs 
      (ID95) was 0.75 microg/mL. After incubation with the same dose of NM, the 
      recovery of CFU-GMs and BFU-Es was 20 +/- 8% SD and 25 +/- 10% SD, respectively 
      (p < 0.05). Long-term liquid cultures showed the recovery of primitive 
      hematopoietic cells after incubation with the highest concentrations of NM/VP-16 
      and mafosfamide, with no significant differences between PB and BM samples. Under 
      the same experimental conditions, we observed a more than 5-log reduction of 
      contaminating leukemic cell lines (i.e., K-562, KG-1, and HL-60). In conclusion, 
      we demonstrated that NM/VP-16 and mafosfamide purging agents are capable of 
      killing leukemic cell lines that contaminate leukapheresis products from patients 
      with AML, whereas an acceptable proportion of primitive LTC-IC is spared. 
      Moreover, despite the different kinetic and functional profile of mobilized and 
      steady-state BM progenitors, we did not observe any difference in toxicity of 
      antineoplastic agents on hematopoietic cells at different levels of 
      differentiation. These data suggest that pharmacological strategies developed for 
      eliminating minimal residual disease (MRD) from BM autografts can be effectively 
      and safely applied to circulating stem cell harvests.
FAU - Motta, M R
AU  - Motta MR
AD  - Institute of Hematology and Oncology, University of Bologna, Italy.
FAU - Mangianti, S
AU  - Mangianti S
FAU - Rizzi, S
AU  - Rizzi S
FAU - Ratta, M
AU  - Ratta M
FAU - Campanini, E
AU  - Campanini E
FAU - Fortuna, A
AU  - Fortuna A
FAU - Fogli, M
AU  - Fogli M
FAU - Tura, S
AU  - Tura S
FAU - Lemoli, R M
AU  - Lemoli RM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Antineoplastic Agents)
RN  - 50D9XSG0VR (Mechlorethamine)
RN  - 5970HH9923 (mafosfamide)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 8N3DW7272P (Cyclophosphamide)
SB  - IM
MH  - Antineoplastic Agents/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Bone Marrow Cells/drug effects
MH  - Cyclophosphamide/administration & dosage/*analogs & derivatives
MH  - Etoposide/*administration & dosage
MH  - Hematopoietic Stem Cells/*pathology
MH  - Humans
MH  - Leukemia, Myeloid, Acute/blood/*drug therapy/pathology
MH  - Mechlorethamine/*administration & dosage
MH  - Neoplasm, Residual/*drug therapy
MH  - Tumor Cells, Cultured/drug effects
EDAT- 1997/11/14 00:00
MHDA- 1997/11/14 00:01
CRDT- 1997/11/14 00:00
PHST- 1997/11/14 00:00 [pubmed]
PHST- 1997/11/14 00:01 [medline]
PHST- 1997/11/14 00:00 [entrez]
PST - ppublish
SO  - Exp Hematol. 1997 Nov;25(12):1261-9.