Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line

C. P. Anderson, R. C. Seeger, Noriko Satake, H. L. Monforte-Munoz, N. Keshelava, H. H. Bailey, C. P. Reynolds

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable. Patients and Methods: The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM. Results: CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 μmol/L) maximally depleted CHLA-171 glutathione to 36% of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 μmol/L; peak plasma concentration in the patient equals 3.9 μmol/L) and moderately resistant to BSO (LD90 = 509 μmol/L; steady-state concentration in the patient equals 397 μmol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 μmol/L) and levels of L-PAM (10-40 μmol/L) clinically achievable only with hematopoietic stem cell support. Conclusions: The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM.

Original languageEnglish (US)
Pages (from-to)500-505
Number of pages6
JournalJournal of Pediatric Hematology/Oncology
Volume23
Issue number8
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Buthionine Sulfoximine
Melphalan
Neuroblastoma
Cell Line
Alkylating Agents
Glutathione
Hereditary Sensory and Autonomic Neuropathies
Pharmaceutical Preparations
Therapeutics
Hybridomas
P-Glycoprotein
Surface Antigens
HLA Antigens
Hematopoietic Stem Cells
Treatment Failure
Microscopy
RNA

Keywords

  • Alkylator resistance
  • Buthionine sulfoximine
  • Melphalan
  • Myeloablative therapy
  • Neuroblastoma
  • P-glycoprotein

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Oncology
  • Hematology

Cite this

Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line. / Anderson, C. P.; Seeger, R. C.; Satake, Noriko; Monforte-Munoz, H. L.; Keshelava, N.; Bailey, H. H.; Reynolds, C. P.

In: Journal of Pediatric Hematology/Oncology, Vol. 23, No. 8, 2001, p. 500-505.

Research output: Contribution to journalArticle

Anderson, C. P. ; Seeger, R. C. ; Satake, Noriko ; Monforte-Munoz, H. L. ; Keshelava, N. ; Bailey, H. H. ; Reynolds, C. P. / Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line. In: Journal of Pediatric Hematology/Oncology. 2001 ; Vol. 23, No. 8. pp. 500-505.
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abstract = "Background: Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable. Patients and Methods: The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM. Results: CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 μmol/L) maximally depleted CHLA-171 glutathione to 36{\%} of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 μmol/L; peak plasma concentration in the patient equals 3.9 μmol/L) and moderately resistant to BSO (LD90 = 509 μmol/L; steady-state concentration in the patient equals 397 μmol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 μmol/L) and levels of L-PAM (10-40 μmol/L) clinically achievable only with hematopoietic stem cell support. Conclusions: The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM.",
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T1 - Buthionine sulfoximine and myeloablative concentrations of melphalan overcome resistance in a melphalan-resistant neuroblastoma cell line

AU - Anderson, C. P.

AU - Seeger, R. C.

AU - Satake, Noriko

AU - Monforte-Munoz, H. L.

AU - Keshelava, N.

AU - Bailey, H. H.

AU - Reynolds, C. P.

PY - 2001

Y1 - 2001

N2 - Background: Alkylator resistance contributes to treatment failure in high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete glutathione and synergistically enhance in vitro sensitivity to the alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines, but optimal use of this combination needs to be defined because clinical responses have been less frequent and not durable. Patients and Methods: The authors established and characterized a neuroblastoma cell line (CHLA-171) from a patient who died of progressive disease after treatment with BSO and low-dose L-PAM. Results: CHLA-171 lacks MYCN amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell surface antigen expression (human leukocyte antigen class I weakly positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2 (anti-ganglioside GD2 antibody) strongly positive) characteristic of neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000 μmol/L) maximally depleted CHLA-171 glutathione to 36% of baseline. The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in combination, was measured by digital image microscopy (DIMSCAN) over a range of drug concentrations and compared with drug levels obtained in the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was highly resistant to L-PAM (LD90 = 42 μmol/L; peak plasma concentration in the patient equals 3.9 μmol/L) and moderately resistant to BSO (LD90 = 509 μmol/L; steady-state concentration in the patient equals 397 μmol/L). Treatment with a 10:1 (BSO:L-PAM) fixed ratio combination synergistically overcame resistance (3-4 logs of cell kill, combination index <1) at clinically achievable levels of BSO (100-400 μmol/L) and levels of L-PAM (10-40 μmol/L) clinically achievable only with hematopoietic stem cell support. Conclusions: The in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy may be optimally effective for drug-resistant neuroblastoma using myeloablative doses of L-PAM.

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KW - Myeloablative therapy

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