Etoposide as an in vitro purging agent for the treatment of acute leukemias and lymphomas in conjunction with autologous bone marrow transplantation

N. Ciobanu, Elisabeth M. Paietta, M. Andreeff, P. Papenhausen, P. H. Wiernik

Research output: Contribution to journalArticle

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Abstract

We examined the effects of various concentrations of etoposide (20-125 μM, 2-h incubation) on normal bone marrow and seven malignant cell lines: HL-60, K562, Namalva, MOLT-3, CEM-7, and the Hodgkin's cell lines L428KS and L428KSA. Tumor cell log-kill was dose dependent and greater than 4 for all cell lines but L428KSA (log-kill, 3.73). Median recovery of CFU-GM after purging with 75, 100, and 125 μM etoposide was 3.6%, 1.3%, and 1% of the controls, respectively. After one week of long-term marrow culture (LTMC), recovery increased 10-20 times/105 cells plated, reaching median values of 33.6%, 23.5%, and 20.7% of the controls in samples purged with 75, 100, and 125 μM etoposide, respectively. Flow cytometry for cell-cycle analysis and RNA content, and chromosomal studies of one-week-old LTMC from healthy donors detected no significant abnormalities in purged as compared to control cultures. After 3-4 weeks of LTMC, both control and etoposide-treated cells formed confluent monolayers. Using a panel of seven monoclonal antibodies (S3.13, S16.144, S4.7, S8.6, RIB-19, anti-HLR-DR, and VIL-A1), we investigated the expression of early and late differentiation antigens on LTMC after various cultures times (0, 1, 2, 3, and 4 weeks). None of the early antigens S3.13, S16.144, and S8.6 was significantly reduced following etoposide treatment, either in nonadherent cells collected from the supernatant or in the adherent cell population obtained from trypsinized monolayers. Etoposide treatment dose dependently delayed the expression of RIB-19 (a late myeloid antigen) and, to a lesser extent, of S4.7 (an 'intermediate' myelomonocytic marker). VIL-A1 expression was not affected by etoposide treatment. We conclude that etoposide purging of bone marrow in the 75-125 μM range spares a sufficient number of functionally intact stem cells to allow adequate in vivo reconstitution following autologous transplantation.

Original languageEnglish (US)
Pages (from-to)626-635
Number of pages10
JournalExperimental Hematology
Volume14
Issue number7
StatePublished - 1986

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Autologous Transplantation
Etoposide
Bone Marrow Transplantation
Lymphoma
Leukemia
Bone Marrow
Therapeutics
Cell Line
Bone Marrow Purging
Nuclear RNA
Antigens
Granulocyte-Macrophage Progenitor Cells
In Vitro Techniques
Differentiation Antigens
Hodgkin Disease
Cell Cycle
Flow Cytometry
Stem Cells
Monoclonal Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Etoposide as an in vitro purging agent for the treatment of acute leukemias and lymphomas in conjunction with autologous bone marrow transplantation. / Ciobanu, N.; Paietta, Elisabeth M.; Andreeff, M.; Papenhausen, P.; Wiernik, P. H.

In: Experimental Hematology, Vol. 14, No. 7, 1986, p. 626-635.

Research output: Contribution to journalArticle

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T1 - Etoposide as an in vitro purging agent for the treatment of acute leukemias and lymphomas in conjunction with autologous bone marrow transplantation

AU - Ciobanu, N.

AU - Paietta, Elisabeth M.

AU - Andreeff, M.

AU - Papenhausen, P.

AU - Wiernik, P. H.

PY - 1986

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N2 - We examined the effects of various concentrations of etoposide (20-125 μM, 2-h incubation) on normal bone marrow and seven malignant cell lines: HL-60, K562, Namalva, MOLT-3, CEM-7, and the Hodgkin's cell lines L428KS and L428KSA. Tumor cell log-kill was dose dependent and greater than 4 for all cell lines but L428KSA (log-kill, 3.73). Median recovery of CFU-GM after purging with 75, 100, and 125 μM etoposide was 3.6%, 1.3%, and 1% of the controls, respectively. After one week of long-term marrow culture (LTMC), recovery increased 10-20 times/105 cells plated, reaching median values of 33.6%, 23.5%, and 20.7% of the controls in samples purged with 75, 100, and 125 μM etoposide, respectively. Flow cytometry for cell-cycle analysis and RNA content, and chromosomal studies of one-week-old LTMC from healthy donors detected no significant abnormalities in purged as compared to control cultures. After 3-4 weeks of LTMC, both control and etoposide-treated cells formed confluent monolayers. Using a panel of seven monoclonal antibodies (S3.13, S16.144, S4.7, S8.6, RIB-19, anti-HLR-DR, and VIL-A1), we investigated the expression of early and late differentiation antigens on LTMC after various cultures times (0, 1, 2, 3, and 4 weeks). None of the early antigens S3.13, S16.144, and S8.6 was significantly reduced following etoposide treatment, either in nonadherent cells collected from the supernatant or in the adherent cell population obtained from trypsinized monolayers. Etoposide treatment dose dependently delayed the expression of RIB-19 (a late myeloid antigen) and, to a lesser extent, of S4.7 (an 'intermediate' myelomonocytic marker). VIL-A1 expression was not affected by etoposide treatment. We conclude that etoposide purging of bone marrow in the 75-125 μM range spares a sufficient number of functionally intact stem cells to allow adequate in vivo reconstitution following autologous transplantation.

AB - We examined the effects of various concentrations of etoposide (20-125 μM, 2-h incubation) on normal bone marrow and seven malignant cell lines: HL-60, K562, Namalva, MOLT-3, CEM-7, and the Hodgkin's cell lines L428KS and L428KSA. Tumor cell log-kill was dose dependent and greater than 4 for all cell lines but L428KSA (log-kill, 3.73). Median recovery of CFU-GM after purging with 75, 100, and 125 μM etoposide was 3.6%, 1.3%, and 1% of the controls, respectively. After one week of long-term marrow culture (LTMC), recovery increased 10-20 times/105 cells plated, reaching median values of 33.6%, 23.5%, and 20.7% of the controls in samples purged with 75, 100, and 125 μM etoposide, respectively. Flow cytometry for cell-cycle analysis and RNA content, and chromosomal studies of one-week-old LTMC from healthy donors detected no significant abnormalities in purged as compared to control cultures. After 3-4 weeks of LTMC, both control and etoposide-treated cells formed confluent monolayers. Using a panel of seven monoclonal antibodies (S3.13, S16.144, S4.7, S8.6, RIB-19, anti-HLR-DR, and VIL-A1), we investigated the expression of early and late differentiation antigens on LTMC after various cultures times (0, 1, 2, 3, and 4 weeks). None of the early antigens S3.13, S16.144, and S8.6 was significantly reduced following etoposide treatment, either in nonadherent cells collected from the supernatant or in the adherent cell population obtained from trypsinized monolayers. Etoposide treatment dose dependently delayed the expression of RIB-19 (a late myeloid antigen) and, to a lesser extent, of S4.7 (an 'intermediate' myelomonocytic marker). VIL-A1 expression was not affected by etoposide treatment. We conclude that etoposide purging of bone marrow in the 75-125 μM range spares a sufficient number of functionally intact stem cells to allow adequate in vivo reconstitution following autologous transplantation.

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