Epoxide formation from (2S,3S)-threitol 1,4-bismethanesulfonate. Preparation and biological activity of (2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate

Feit, Peter W.; Rastrup-Andersen, Niels; Matagne, Rene

doi:10.1021/jm00300a034

Cited by 66 publications

(46 citation statements)

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“…25 It is easily administered and converted to the active form by nonenzymatic activation. 5 It has myeloablative and immunosuppressive characteristics, but is associated with limited non-hematological toxicity. The combination of fludarabine and treosulfan shares properties of both RIC and myeloablative regimens.…”

Section: Discussionmentioning

confidence: 99%

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

Danylesko

Shimoni

Nagler

2011

Bone Marrow Transplant

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Allogeneic hematopoietic SCT is a curative treatment for a variety of hematological malignancies and genetic diseases. There is a continuous search for novel conditioning regimens that will reduce SCT-related toxicity while retaining maximal antimalignancy effect. Treosulfan (L-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) was initially used in the treatment of certain solid tumors. Preclinical studies showed that it has a myeloablative effect on committed and non-committed stem cells. It has potent immunosuppressive characteristics, more prominent than its related chemotherapy agent BU, which makes it an attractive candidate for the use in conditioning regimens before allo-SCT. It is also associated with a favorable toxicity profile with little extramedullary toxicity. The combination of fludarabine and treosulfan was explored in several studies in patients not eligible for standard myeloablative conditioning, and data are rapidly emerging. This regimen is associated with consistent engraftment. A limited non-relapse mortality (NRM) rate in the range of 9-28% was observed. This rate is promising considering the patients selected and results from low rates of organ toxicity as well as acute and chronic GVHD. The regimen was also associated with low relapse rates of 5-30% depending on disease status at SCT. Together with low NRM rate, this resulted in favorable survival in the range of 40-80%. Promising results were seen in myelodysplastic syndrome (survival 36-70%) and leukemia in remission (60-70%). Randomized prospective studies will be needed to better define the role of treosulfan-based regimens in SCT.

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Section: Discussionmentioning

confidence: 99%

“…4 It is non-enzymatic and occurs under physiological conditions. 5 Both epoxide species are assumed to be responsible for the DNA alkylation, interstrand cross-linking, chromosomal aberration and induction of apoptosis. 6 This is in contrast to BU, which is a direct alkylating agent.…”

Section: Treosulfan: Clinical Pharmacologymentioning

confidence: 99%

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

Danylesko

Shimoni

Nagler

2011

Bone Marrow Transplant

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“…Treosulfan (TREO) (L-threitol-1,4-bis-methanesulfonate) 8 is a structural analog of BU nonenzymatically activated to alkylating monoand diepoxides. It demonstrates cytotoxic/antiproliferative activity against a wide range of hematological malignancies and solid tumors, including important childhood malignancies.…”

Section: Introductionmentioning

confidence: 99%

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

Wachowiak

Sykora²,

Cornish

et al. 2011

Bone Marrow Transplant

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This retrospective analysis evaluated 51 children (0.7-17 years; median eight) with high-risk or advanced hematological malignancies, including 18 (35%) patients undergoing second/third hematopoietic SCT (allo-HSCT), not eligible for standard myeloablative regimens and transplanted from matched sibling (MSD) (n ¼ 24) or matched unrelated (MUD) (n ¼ 27) donors. Preparative regimens were based on treosulfan (TREO) i.v., a structural analog of BU, given at total dose of 30 g/m 2 (n ¼ 21) or 36-42 g/ m 2 (n ¼ 30) in combination with, fludarabine, cyclophosphamide, melphalan and/or VP-16 according to diagnosis, and risk factors. Deaths due to early regimenrelated toxicity (RRT) did not occur. Nonrelapse mortality was 8% at 1 year and 16% after 4 years. Myeloid engraftment was achieved in 94%, complete donor chimerism in 90% of patients. A 4-year incidence of relapse was 24%, and was significantly lower after MUD-HSCT (8%) than after MSD-HSCT (39%), but similar in children undergoing first (28%) or second/third HSCT (17%). A 4-year disease-free survival was 61%, but it was significantly better in myeloid (73%), than in lymphoid malignancies (41%). Thus, children with high-risk and advanced hematological malignancies and high-risk of life-threatening RRT can be transplanted effectively and safely using TREO-based regimens. Particularly favorable results were achieved in myeloid malignancies and in children undergoing second HSCT.

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“…Unlike busulphan, which alkylates as a primary methanesulphonate, treosulfan is a prodrug for epoxy compounds and converts non-enzymatically to L-diepoxybutane via the corresponding monoepoxide under physiological conditions (Feit et al, 1970; Figure 1). The cytotoxicity of treosulfan is assumed to be due to alkylation of DNA and the formation of DNA interstrand cross-links, although this has not been proven.…”

Section: Introductionmentioning

confidence: 99%

DNA alkylation and interstrand cross-linking by treosulfan

1998

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SummaryThe anti-tumour drug treosulfan (L-threitol 1,4-bismethanesulphonate, Ovastat) is a prodrug for epoxy compounds by converting non-enzymatically to L-diepoxybutane via the corresponding monoepoxide under physiological conditions. The present study supports the hypothesis that this conversion of treosulfan is required for cytotoxicity in vitro. DNA alkylation and interstrand cross-linking of plasmid DNA is observed after treosulfan treatment, but this is again produced via the epoxide species. Alkylation occurs at guanine bases with a sequence selectivity similar to other alkylating agents such as the nitrogen mustards. In treosulfan-treated K562 cells, cross-links form slowly, reaching a peak at approximately 24 h. Incubation of K562 cells with preformed epoxides shows faster and more efficient DNA cross-linking.

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Epoxide formation from (2S,3S)-threitol 1,4-bismethanesulfonate. Preparation and biological activity of (2S,3S)-1,2-epoxy-3,4-butanediol 4-methanesulfonate

Cited by 66 publications

References 0 publications

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

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

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

DNA alkylation and interstrand cross-linking by treosulfan

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