Phase I Study of Continuous-Infusion L-S,R-Buthionine Sulfoximine With Intravenous Melphalan

Bailey, Howard; Ripple, G. R.; Tutsch, Kendra D.; Arzoomanian, Rhoda Z.; Alberti, Dona; Feierabend, Chriss; Mahvi, David; Schink, Julian C.; Pomplun, Marcia; Mulcahy, Ríona; Wilding, George

doi:10.1093/jnci/89.23.1789

Cited by 145 publications

(120 citation statements)

References 22 publications

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“…BSO has already been clinically used as a potential sensitizer of L-PAM, an alkylating anticancer agent. 7,8 In our examination, the IC 50 values of L-PAM on PC-3 and DU145 cells were 105.0718.0 and 9.972.3 mM, respectively. Addition of 10 mM BSO decreased these IC 50 values of L-PAM by 1.4-and 1.6-fold in PC-3 and DU145 cells, respectively.…”

Section: Resultsmentioning

confidence: 57%

“…7 Subsequent clinical trials with L-PAM plus BSO, however, did not show therapeutic effects on advanced solid tumors. 8 Our in vitro growth inhibition assays provide experimental evidence for this failure in clinical trials. In prostate cancer cell lines treated with 10 mM BSO, the degree of sensitization was only a 1.4-1.6-fold decrease in IC 50 values of L-PAM.…”

Section: Discussionmentioning

confidence: 93%

“…3 BSO has already warranted its safety in clinical use. 7,8 Owing to their immediate feasibility for clinical use, the combination chemotherapy of As 2 O 3 plus BSO immediately allows many clinicians to examine clinical efficacies. Several in vitro experiments have already examined the efficacy of the combined treatment with As 2 O 3 plus BSO, although the approach is experimental, not therapeutic.…”

Section: Discussionmentioning

confidence: 99%

“…7 However, the combination of BSO with melphalan (L-PAM), an alkylating anticancer agent, has not shown any remarkable therapeutic effect on advanced solid tumors. 7,8 In this study, we tested in vitro and in vivo efficacies of the combination therapy of As 2 O 3 with BSO on androgenindependent prostate cancer cell lines as a model for advanced solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine

et al. 2004

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Clinical application of anticancer agents has been often hampered by toxicity against normal cells, so the achievement of their cancer-specific action is still one of the major challenges to be addressed. Previously, we reported that arsenic trioxide (As 2 O 3 ) could be a promising new drug against not only leukemia but also solid tumors. The cytotoxicity of As 2 O 3 occurred through the generation of reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of As 2 O 3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination therapy of As 2 O 3 with L-buthionine-sulfoximine (BSO), which inhibits a critical step in glutathione synthesis, effectively enhanced in vitro growth inhibition effect of As 2 O 3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and kidney cancers, compared with As 2 O 3 treatment alone. Furthermore, this combination enhanced cytotoxicity to cell lines from prostate cancer with less toxicity to those from normal prostate. In vitro cytotoxic assay using ROSrelated compounds demonstrated that hydrogen peroxide (H 2 O 2 ) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of As 2 O 3 and BSO blocked H 2 O 2 -scavenging systems including glutathione, catalase, and glutathione peroxidase, and that the degree of this blockade was well correlated with intracellular ROS levels and sensitivity to this treatment. Finally, the effectiveness of the combination therapy of As 2 O 3 with BSO was demonstrated with an orthotopic model of prostate cancer metastasis. We propose that the combination therapy of As 2 O 3 with BSO is a valid means of blockade of H 2 O 2 -scavenging system, and that the combination of a ROSgenerating agent with an inhibitor of major scavenging systems is effective in terms of both efficacy and selectivity. Furthermore, because the effective doses of both compounds are within clinically achievable range, this report will lead to immediate benefit for the development of a new cancer therapy.

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Section: Resultsmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine

et al. 2004

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“…Since then, three Phase I clinical trials using BSO in combination with melphalan have been reported [66][67][68]. One Phase I trial showed significant responses to the BSO/melphalan combination [67], and two clinical trials using the same combination are currently being conducted, one at the Phase I level (New Approaches to Neuroblastoma Therapy Consortium, USA.…”

Section: Bso: Animal Studies and Clinical Trialsmentioning

confidence: 99%

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

Leitner

Kachadourian

Day

2007

Biochemical Pharmacology

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The ATP-binding cassette (ABC) class of proteins is one of the most functionally diverse transporter families found in biological systems. Although the abundance of ABC proteins varies between species, they are highly conserved in sequence and often demonstrate similar functions across prokaryotic and eukaryotic organisms. Beginning with a brief summary of the events leading to our present day knowledge of ABC transporters, the purpose of this review is to discuss the potential for utilizing ABC transporters as a means for cellular glutathione (GSH) modulation. GSH is one of the most abundant thiol antioxidants in cells. It is involved in cellular division, protein and DNA synthesis, maintenance of cellular redox status and xenobiotic metabolism. Cellular GSH levels are often altered in many disease states including cancer. Over the past two decades there has been considerable emphasis on methods to sensitize cancer cells to chemotherapeutics and ionization radiation therapy by GSH depletion. We contend that ABC transporters, particularly multi-drug resistant proteins (MRPs), may be used as therapeutic targets for applications aimed at modulation of GSH levels. This review will emphasize MRP-mediated modulation of intracellular GSH levels as a potential alternative and adjunctive approach for cancer therapy.

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Synergism of buthionine sulfoximine and melphalan against neuroblastoma cell lines derived after disease progression

Anderson

Keshelava

Satake

et al. 2000

Med. Pediatr. Oncol.

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Fixed ratio analysis demonstrated BSO/L-PAM synergy (combination index >1) for all cell lines tested. In L-PAM-resistant cell lines, the minimal cytotoxicity observed for BSO combined with nonmyeloablative concentrations of L-PAM was markedly enhanced (>4 logs total cell kill) when BSO was combined with myeloablative concentrations of L-PAM. In alkylator-resistant NB, the optimal use of BSO may require dose escalation of L-PAM to levels requiring AHSCT.

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Phase I Study of Continuous-Infusion L-S,R-Buthionine Sulfoximine With Intravenous Melphalan

Abstract: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.

Cited by 145 publications

References 22 publications

Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine

Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

Synergism of buthionine sulfoximine and melphalan against neuroblastoma cell lines derived after disease progression

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