DNA alkylation and interstrand cross-linking by treosulfan

Hartley, John A.; O’Hare, Caroline; Baumgart, Joachim

doi:10.1038/sj.bjc.6690043

Cited by 103 publications

(70 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The formation of DNA interstrand cross-links has been demonstrated for many bifunctional electrophiles (1), including such potent anticancer agents as the nitrogen mustards, exemplified by HN2 (9,10), and treosulfan, which is converted in vivo to DEB (41). Moreover, interstrand cross-linking has been found to correlate with mustard cytotoxicity (42).…”

Section: Discussionmentioning

confidence: 99%

DNA Interstrand Cross-Linking by Epichlorohydrin

Romano

Newman

Zahran

et al. 2007

Chem. Res. Toxicol.

View full text Add to dashboard Cite

Epichlorohydrin (ECH), an important industrial chemical, is a bifunctional alkylating agent with the potential to form DNA cross-links. Occupational exposure to this suspect carcinogen leads to chromosomal aberrations, and ECH has been shown previously to undergo reaction with DNA in vivo and in vitro.We used denaturing polyacrylamide gel electrophoresis to monitor the possible formation of interstrand cross-links within DNA oligomers by ECH and the related compound, epibromohydrin (EBH). Although both compounds did indeed form cross-links between deoxyguanosine residues, EBH was a more efficient cross-linker than ECH. The optimal pH for cross-linking also varied, with ECH more efficient at pH 5.0 and EBH more efficient at pH 7.0. Both agents were relatively flexible in the sequences targeted, with comparable efficiencies for 5′-GGC and 5′GC sites. Furthermore, interstrand cross-linking by the two optical isomers of ECH correlated with their relative cytotoxicities, with R-ECH about twice as potent as S-ECH.

show abstract

Section: Discussionmentioning

confidence: 99%

DNA Interstrand Cross-Linking by Epichlorohydrin

Romano

Newman

Zahran

et al. 2007

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…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. Also in contrast to BU, treosulfan is soluble in water and therefore can be easily applied i.v.…”

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

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

“…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

DNA alkylation and interstrand cross-linking by treosulfan

Cited by 103 publications

References 9 publications

DNA Interstrand Cross-Linking by Epichlorohydrin

DNA Interstrand Cross-Linking by Epichlorohydrin

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

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

DNA alkylation and interstrand cross-linking by treosulfan

Cited by 103 publications

References 9 publications

DNA Interstrand Cross-Linking by Epichlorohydrin

DNA Interstrand Cross-Linking by Epichlorohydrin

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

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