In vitro cytotoxicity of VP-16-213 and nitrogen mustard: Agonistic on tumor cells but not on normal human bone marrow progenitors

R. M. Lemoli, S. C. Gulati

Research output: Contribution to journalArticle

Abstract

The possible presence of tumor cells in remission bone marrow (BM) is one of the major problems for the success of autologous BM transplantation (ABMT), because the reinfusion of viable malignant cells may result in relapse. In this study we attempted the purging of the malignant cells by the use of VP-16-123 (VP-16) and nitrogen mustard (NM) either alone or in combination. Four cell lines from various hematological malignancies were utilized: SK-DHL-2 was established from a B-cell diffuse histiocytic lymphoma; RAJI was from an Epstein-Barr virus (EBV)-infected B-cell lymphoma cell line; K-562 were from a chronic myelogenous leukemia (CML) blastic crisis; and HL-60, derived from a human promyeolcytic leukemia, were used in exponential growth phase. Four logs of tumor cell elimination were observed after 1-h incubation of RAJI cells with 25 μg/ml of VP-16. K-562 and SK-DHL-2 cells showed a > 4 logs reduction after 1-h exposure to 75 μg/ml of VP-16, and HL-60 cell line growth was inhibited by 3.2 logs. Under the same conditions (i.e., the treatment with 75 μg/ml), we observed a mean recovery of 2.7% of BM granulocyte-macrophage colonies (granulocyte-macrophage colony-forming units, CFU-GM), 3.2% of erythroid (erythroid burst-forming units, BFU-E), and 2.5% of pluripotent (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) progenitors, respectively. More than 3 logs reduction of leukemia and lymphoma cell lines were reached following 1-h treatment with 1 μg/ml of NM. After exposure to the same concentration of the drug we obtained 2.5% CFU-GM, 1.2% BFU-E, and 2% CFU-GEMM recovery. A drug mixture containing constant doses of VP-16 (10 and 20 μg/ml) and NM (1 μg/ml) reduced HL-60 and SK-DHL-2 cell growth to undetectable levels (i.e., 4 and 5 logs elimination) in the presence of an excess of irradiated BM cells, whereas it did not further affect the recovery of the BM precursors as compared to the single drugs used alone. These results suggest that the combination of these two drugs at the selected dose level could provide a better therapeutic index (i.e., higher tumor cell killing coupled with no additional cytotoxic effect on normal BM cells) than the same chemotherapeutic agent used alone and that this mixture may be useful for the 'ex vivo' treatment of BM grafts.

Original languageEnglish
Pages (from-to)1008-1012
Number of pages5
JournalExperimental Hematology
Volume18
Issue number9
Publication statusPublished - 1990

Fingerprint

Mechlorethamine
Etoposide
Bone Marrow
Granulocyte-Macrophage Progenitor Cells
Erythroid Precursor Cells
Neoplasms
Myeloid Progenitor Cells
Cell Line
B-Cell Lymphoma
Granulocytes
Bone Marrow Cells
Leukemia
Growth
Macrophages
Pharmaceutical Preparations
Megakaryocytes
Lymphoma, Large B-Cell, Diffuse
In Vitro Techniques
Autologous Transplantation
HL-60 Cells

Keywords

  • ABMT
  • agonistic
  • purging

ASJC Scopus subject areas

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

Cite this

In vitro cytotoxicity of VP-16-213 and nitrogen mustard : Agonistic on tumor cells but not on normal human bone marrow progenitors. / Lemoli, R. M.; Gulati, S. C.

In: Experimental Hematology, Vol. 18, No. 9, 1990, p. 1008-1012.

Research output: Contribution to journalArticle

@article{ee012c2cb3ac490ba68cd92e70f650bf,
title = "In vitro cytotoxicity of VP-16-213 and nitrogen mustard: Agonistic on tumor cells but not on normal human bone marrow progenitors",
abstract = "The possible presence of tumor cells in remission bone marrow (BM) is one of the major problems for the success of autologous BM transplantation (ABMT), because the reinfusion of viable malignant cells may result in relapse. In this study we attempted the purging of the malignant cells by the use of VP-16-123 (VP-16) and nitrogen mustard (NM) either alone or in combination. Four cell lines from various hematological malignancies were utilized: SK-DHL-2 was established from a B-cell diffuse histiocytic lymphoma; RAJI was from an Epstein-Barr virus (EBV)-infected B-cell lymphoma cell line; K-562 were from a chronic myelogenous leukemia (CML) blastic crisis; and HL-60, derived from a human promyeolcytic leukemia, were used in exponential growth phase. Four logs of tumor cell elimination were observed after 1-h incubation of RAJI cells with 25 μg/ml of VP-16. K-562 and SK-DHL-2 cells showed a > 4 logs reduction after 1-h exposure to 75 μg/ml of VP-16, and HL-60 cell line growth was inhibited by 3.2 logs. Under the same conditions (i.e., the treatment with 75 μg/ml), we observed a mean recovery of 2.7{\%} of BM granulocyte-macrophage colonies (granulocyte-macrophage colony-forming units, CFU-GM), 3.2{\%} of erythroid (erythroid burst-forming units, BFU-E), and 2.5{\%} of pluripotent (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) progenitors, respectively. More than 3 logs reduction of leukemia and lymphoma cell lines were reached following 1-h treatment with 1 μg/ml of NM. After exposure to the same concentration of the drug we obtained 2.5{\%} CFU-GM, 1.2{\%} BFU-E, and 2{\%} CFU-GEMM recovery. A drug mixture containing constant doses of VP-16 (10 and 20 μg/ml) and NM (1 μg/ml) reduced HL-60 and SK-DHL-2 cell growth to undetectable levels (i.e., 4 and 5 logs elimination) in the presence of an excess of irradiated BM cells, whereas it did not further affect the recovery of the BM precursors as compared to the single drugs used alone. These results suggest that the combination of these two drugs at the selected dose level could provide a better therapeutic index (i.e., higher tumor cell killing coupled with no additional cytotoxic effect on normal BM cells) than the same chemotherapeutic agent used alone and that this mixture may be useful for the 'ex vivo' treatment of BM grafts.",
keywords = "ABMT, agonistic, purging",
author = "Lemoli, {R. M.} and Gulati, {S. C.}",
year = "1990",
language = "English",
volume = "18",
pages = "1008--1012",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "9",

}

TY - JOUR

T1 - In vitro cytotoxicity of VP-16-213 and nitrogen mustard

T2 - Agonistic on tumor cells but not on normal human bone marrow progenitors

AU - Lemoli, R. M.

AU - Gulati, S. C.

PY - 1990

Y1 - 1990

N2 - The possible presence of tumor cells in remission bone marrow (BM) is one of the major problems for the success of autologous BM transplantation (ABMT), because the reinfusion of viable malignant cells may result in relapse. In this study we attempted the purging of the malignant cells by the use of VP-16-123 (VP-16) and nitrogen mustard (NM) either alone or in combination. Four cell lines from various hematological malignancies were utilized: SK-DHL-2 was established from a B-cell diffuse histiocytic lymphoma; RAJI was from an Epstein-Barr virus (EBV)-infected B-cell lymphoma cell line; K-562 were from a chronic myelogenous leukemia (CML) blastic crisis; and HL-60, derived from a human promyeolcytic leukemia, were used in exponential growth phase. Four logs of tumor cell elimination were observed after 1-h incubation of RAJI cells with 25 μg/ml of VP-16. K-562 and SK-DHL-2 cells showed a > 4 logs reduction after 1-h exposure to 75 μg/ml of VP-16, and HL-60 cell line growth was inhibited by 3.2 logs. Under the same conditions (i.e., the treatment with 75 μg/ml), we observed a mean recovery of 2.7% of BM granulocyte-macrophage colonies (granulocyte-macrophage colony-forming units, CFU-GM), 3.2% of erythroid (erythroid burst-forming units, BFU-E), and 2.5% of pluripotent (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) progenitors, respectively. More than 3 logs reduction of leukemia and lymphoma cell lines were reached following 1-h treatment with 1 μg/ml of NM. After exposure to the same concentration of the drug we obtained 2.5% CFU-GM, 1.2% BFU-E, and 2% CFU-GEMM recovery. A drug mixture containing constant doses of VP-16 (10 and 20 μg/ml) and NM (1 μg/ml) reduced HL-60 and SK-DHL-2 cell growth to undetectable levels (i.e., 4 and 5 logs elimination) in the presence of an excess of irradiated BM cells, whereas it did not further affect the recovery of the BM precursors as compared to the single drugs used alone. These results suggest that the combination of these two drugs at the selected dose level could provide a better therapeutic index (i.e., higher tumor cell killing coupled with no additional cytotoxic effect on normal BM cells) than the same chemotherapeutic agent used alone and that this mixture may be useful for the 'ex vivo' treatment of BM grafts.

AB - The possible presence of tumor cells in remission bone marrow (BM) is one of the major problems for the success of autologous BM transplantation (ABMT), because the reinfusion of viable malignant cells may result in relapse. In this study we attempted the purging of the malignant cells by the use of VP-16-123 (VP-16) and nitrogen mustard (NM) either alone or in combination. Four cell lines from various hematological malignancies were utilized: SK-DHL-2 was established from a B-cell diffuse histiocytic lymphoma; RAJI was from an Epstein-Barr virus (EBV)-infected B-cell lymphoma cell line; K-562 were from a chronic myelogenous leukemia (CML) blastic crisis; and HL-60, derived from a human promyeolcytic leukemia, were used in exponential growth phase. Four logs of tumor cell elimination were observed after 1-h incubation of RAJI cells with 25 μg/ml of VP-16. K-562 and SK-DHL-2 cells showed a > 4 logs reduction after 1-h exposure to 75 μg/ml of VP-16, and HL-60 cell line growth was inhibited by 3.2 logs. Under the same conditions (i.e., the treatment with 75 μg/ml), we observed a mean recovery of 2.7% of BM granulocyte-macrophage colonies (granulocyte-macrophage colony-forming units, CFU-GM), 3.2% of erythroid (erythroid burst-forming units, BFU-E), and 2.5% of pluripotent (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) progenitors, respectively. More than 3 logs reduction of leukemia and lymphoma cell lines were reached following 1-h treatment with 1 μg/ml of NM. After exposure to the same concentration of the drug we obtained 2.5% CFU-GM, 1.2% BFU-E, and 2% CFU-GEMM recovery. A drug mixture containing constant doses of VP-16 (10 and 20 μg/ml) and NM (1 μg/ml) reduced HL-60 and SK-DHL-2 cell growth to undetectable levels (i.e., 4 and 5 logs elimination) in the presence of an excess of irradiated BM cells, whereas it did not further affect the recovery of the BM precursors as compared to the single drugs used alone. These results suggest that the combination of these two drugs at the selected dose level could provide a better therapeutic index (i.e., higher tumor cell killing coupled with no additional cytotoxic effect on normal BM cells) than the same chemotherapeutic agent used alone and that this mixture may be useful for the 'ex vivo' treatment of BM grafts.

KW - ABMT

KW - agonistic

KW - purging

UR - http://www.scopus.com/inward/record.url?scp=0025205098&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025205098&partnerID=8YFLogxK

M3 - Article

C2 - 2397748

AN - SCOPUS:0025205098

VL - 18

SP - 1008

EP - 1012

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 9

ER -