Treosulfan-induced apoptosis in acute myeloid leukemia cells is accompanied by translocation of protein kinase C delta and enhanced by bryostatin-1

Schmidmaier, Ralf; Oellerich, Mark F.; Baumgart, Joachim; Emmerich, Bertold; Meinhardt, Gerold

doi:10.1016/j.exphem.2003.09.023

Cited by 33 publications

(26 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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).…”

Section: Treosulfan: Clinical Pharmacologymentioning

confidence: 99%

“…4,23 Similar results were shown for acute and chronic myelogenous leukemia, where treosulfan is a potent inducer of cell death, equal or superior to BU. 20,24 Treosulfan has a broad anti-stem-cell effect against both primitive and committed stem cells. 25,26 In contrast to BU, which preferentially depletes primitive stem cells, treosulfan was found to deplete committed progenitors as well as primitive stem cells in vitro.…”

Section: Treosulfan: Clinical Pharmacologymentioning

confidence: 99%

See 1 more Smart Citation

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

Danylesko

Shimoni

Nagler

2011

Bone Marrow Transplant

View full text Add to dashboard Cite

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.

show abstract

Section: Treosulfan: Clinical Pharmacologymentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…None of these substances could reverse CAM-DR (data not shown). Furthermore, expression of proteins important for cell survival and drug resistance was tested by immunoblotting as described previously, 12 such as members of the Bcl-2 family (eg, Bad, Bax, Bcl-2, Bcl-XL, Mcl-1), members of the inhibitor of apoptosis (IAP) family (eg, IAP-1, IAP-2, ILP, survivin), cell-cycle proteins (eg, cyclin D1), members of the PKC family (eg, PKC␣, PKC␤, PKD␦), and other key signaling molecules for apoptosis, survival, and proliferation of multiple myeloma cells (eg, Erk1, Erk2, Akt, PI3-kinase). Myeloma cells were either grown alone or in coculture with HS-5 cells.…”

Section: Targeting Adhesion Molecules May Overcome Cam-drmentioning

confidence: 99%

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

Schmidmaier¹,

Baumann²,

Simsek³

et al. 2004

Blood

Self Cite

107

View full text Add to dashboard Cite

Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting

show abstract

“…All three optical isomers of BDO 2 are genotoxic (2,10,37), and S,S-BDO 2 is the most cytotoxic and genotoxic (38,39); it is believed to be the active form of the anti-tumor agent L-threitol-1,4-bismethanesulfonate (treosulfan) (40)(41)(42). The genotoxicity is probably due to its potential to form DNA-DNA (43)(44)(45)(46) and DNA-protein cross-links (47,48), the latter having been observed in mice (49,50).…”

Section: Introductionmentioning

confidence: 99%

Structure of the 1,4-Bis(2‘-deoxyadenosin-N⁶-yl)-2S,3S-butanediol Intrastrand DNA Cross-Link Arising from Butadiene Diepoxide in the Human N-ras Codon 61 Sequence

Merritt

Nechev

et al. 2007

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The 1,4-bis(2′-deoxyadenosin-N 6 -yl)-2S,3S-butanediol intra-strand DNA cross-link arises from bisalkylation of tandem N 6 -dA sites in DNA by R,R-butadiene diepoxide (BDO 2 ). The oligodeoxynucleotide 5′-d(C 1 G 2 G 3 A 4 C 5 X 6 Y 7 G 8 A 9 A 10 G 11 )-3′·5′-d (C 12 T 13 T 14 C 15 T 16 T 17 G 18 T 19 C 20 C 21 G 22 )-3′ contains the BDO 2 cross-link between the second and third adenines of the codon 61 sequence (underlined) of the human N-ras protooncogene and is named the (S,S)-BD-(61-2,3) cross-link (X,Y = cross-linked adenines). NMR analysis reveals that the cross-link is oriented in the major groove of duplex DNA. Watson-Crick base pairing is perturbed at base pair X 6 ·T 17 , whereas base pairing is intact at base pair Y 7 ·T 16 . The cross-link appears to exist in two conformations, in rapid exchange on the NMR time scale. In the first conformation, the β-OH is predicted to form a hydrogen bond with T 16 O 4 , whereas in the second, the β-OH is predicted to form a hydrogen bond with T 17 O 4 . In contrast to the (R,R)-BD-(61-2,3) cross-link in the same sequence [Merritt, W.K., Nechev, L.V., Scholdberg, T.A., Dean, S.M., Kiehna, S.E., Chang, J.C., Harris, T.M., Harris, C.M., Lloyd, R.S., and Stone, M.P. (2005) Biochemistry 44, 10081-10092], the anti conformation of the two hydroxyl groups at C β and C γ with respect to the C β -C γ bond results in a decreased twist between base pairs X 6 ·T 17 and Y 7 ·T 16 , and an approximate 10° bending of the duplex. These conformational differences may account for the differential mutagenicity of the (S,S)-and (R,R)-BD-(61-2,3) cross-links, and suggest that stereochemistry plays a role in modulating biological responses to these cross-links [Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580.

show abstract

Treosulfan-induced apoptosis in acute myeloid leukemia cells is accompanied by translocation of protein kinase C delta and enhanced by bryostatin-1

Cited by 33 publications

References 42 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

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

Structure of the 1,4-Bis(2‘-deoxyadenosin-N⁶-yl)-2S,3S-butanediol Intrastrand DNA Cross-Link Arising from Butadiene Diepoxide in the Human N-ras Codon 61 Sequence

Contact Info

Product

Resources

About

Treosulfan-induced apoptosis in acute myeloid leukemia cells is accompanied by translocation of protein kinase C delta and enhanced by bryostatin-1

Cited by 33 publications

References 42 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

The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase

Structure of the 1,4-Bis(2‘-deoxyadenosin-N6-yl)-2S,3S-butanediol Intrastrand DNA Cross-Link Arising from Butadiene Diepoxide in the Human N-ras Codon 61 Sequence

Contact Info

Product

Resources

About

Structure of the 1,4-Bis(2‘-deoxyadenosin-N⁶-yl)-2S,3S-butanediol Intrastrand DNA Cross-Link Arising from Butadiene Diepoxide in the Human N-ras Codon 61 Sequence