Cytotoxicity of treosulfan and busulfan on pediatric tumor cell lines

Abstract

High-dose chemotherapy of solid tumors aims at eliminating residual or metastatic tumor cells, which remained after conventional treatment. Thus, anticancer drugs used for high-dose chemotherapy should display significant cytotoxicity against the respective tumors. As little data are available about the in-vitro toxicity of busulfan and treosulfan especially on pediatric tumor cell lines, we compared the cytotoxicity of treosulfan and busulfan on four Ewing tumor, four neuroblastoma, two osteosarcoma and two leukemia cell lines in vitro. Growth inhibition of tumor cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide test after 24, 48, 72 and 96 h. Treosulfan and busulfan reduced the growth of all tumor cell lines in a time-dependent and dose-dependent manner. In vitro treosulfan was consistently more cytotoxic than busulfan. Fifty percent growth inhibitions of 608-0.73 micromol/l were determined for treosulfan and of above 5,000-2.81 micromol/l for busulfan. Both drugs exhibited similar cytotoxicity profiles. Busulfan-sensitive/resistant cell lines were also sensitive/resistant to treosulfan. Overall, the leukemia cell lines were most sensitive to busulfan and treosulfan. The Ewing tumor cell lines were the second most sensitive followed by the neuroblastoma cell lines. The osteosarcoma cell lines were the most resistant cell lines. Although the in-vitro stability of both drugs makes direct comparison of their in-vitro toxicity difficult and does not allow any estimation of dosages needed clinically, the in-vitro results indicate substantial cytotoxicity of both drugs on leukemias, Ewing tumors and neuroblastomas. These data suggest further evaluation of treosulfan for high-dose chemotherapy of advanced Ewing tumors, neuroblastomas and high-risk leukemias.

Dehydroalanine Analog of Glutathione: An Electrophilic Busulfan Metabolite That Binds to Human GlutathioneS-Transferase A1-1

“…The concentrations of busulfan fall within the concentration ranges recently used by Lanvers-Kaminsky et al (2006) who found a great variation in cellular susceptibility to this anticancer drug. For example, while growth of leukemia cell lines was inhibited by micromolar concentrations, millimolar concentrations were required to inhibit growth of osteosarcoma cell lines.…”

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike

“…It was found to have therapeutic effects in various in vitro and in vivo models of AML, ALL and multiple myeloma (MM). [17][18][19][20][21] It reduced the viability of human myeloid leukemia cells, even at low concentrations of 10 and 30 mm, by more than 70 and 90%, respectively. 22 Although it is inadequate to correlate in vitro data with plasma levels and response rates in vivo, it is notable that in the in vitro experiments, the concentrations needed to eliminate more than 90% of the leukemia cells were in the range of 100 mM; concentrations that are 10-fold lower than the plasma levels achievable in patients given conventional doses (1 mmol/L).…”

Treosulfan-based preparative regimens for allo-HSCT in childhood hematological malignancies: a retrospective study on behalf of the EBMT pediatric diseases working party

“…It demonstrates cytotoxic/antiproliferative activity against a wide range of hematological malignancies and solid tumors, including important childhood malignancies. [9][10][11][12][13] In addition, TREO reveals an excellent hematopoietic stem cell toxicity and immunosuppressive effects, which are even superior to those of BU. 14,15 As shown in adults, an additional advantage of TREO lies also in its predictable linear pharmacokinetics over a broad i.v.…”