Anti-cancer drugs generate DNA interstrand crosslinks

Stable Identifier
R-HSA-9713785
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
General
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

Some of the earliest and still most widely used anti-cancer chemotherapeutics are drugs that induce DNA interstrand crosslinks (ICLs). In addition to inducing ICLs, these drugs also induce other types of DNA damage. ICL-inducing anti-cancer agents can be grouped into monofunctional alkylating agents (chloroethylating nitrosoureas), bifunctional alkylating agents (nitrogen mustards, aziridines and pyrrolobenzodiazepine dimers), platinums, and psoralens (furocoumarins). All ICL-inducing drugs are characterized by the presence of two chemical leaving groups that are lost in the formation of the ICL.

Chloroethylating nitrosoureas are monofunctional alkylating agents that induce DNA crosslinks in two steps: chloroethylation of a nucleophilic site on one strand, followed by displacement of chlorine by a nucleophilic site on the opposite strand, resulting in an ethyl bridge between the strands. Chloroethylating nitrosoureas include the following chemotherapeutic drugs:
carmustine (also known as BCNU) (Kohn 1977: study done on E. coli DNA)
fotemustine (Hayes et al. 1997)
lomustine (also known as CCNU) (Kohn 1977: study done on E. coli DNA)
nimustine (also known as ACNU) (Aida and Bodell 1987).

Nitrogen mustards are alkylating agents that include the following chemotherapeutic drugs:
chlorambucil (Hartley et al. 1999; Wang et al. 2003)
cyclophosphamide (Crook et al. 1986)
ifosfamide (Hartley et al. 1999)
mechlorethamine (Sunters et al. 1998)
melphalan (Parsons 1984)
uramustine (O'Connor and Kohn 1990: study done in mouse cells).

Aziridines are bifunctional alkylating agents that include the following chemotherapeutic drugs:
altretamine (Coley et al. 1995: trimelamol, the compound assayed in the study, contains three carbinolamine moieties, thus representing a bioactivated form of altretamine, also known as HMM)
mitomycin C (also known as MMC), an antitumor antibiotic potent at inducing ICLs (Dorr et al. 1985)
thioTEPA (Cohen et al. 1991: study done in mice).

Pyrrolobenzodiazepine (PBD) dimers are derivatives of naturally occurring anti-tumor antibiotics. While naturally occurring anti-tumor antibiotics anthramycin, DC-81, tomamycin and sibiromycin do not induce ICLs, joining two PBD molecules through their C8 positions via a linker creates potent bifunctional agents able to induce ICLs (Smellie et al. 1994). PBD dimers that have been clinically tested are:
SGD-1882, used to produce talirine (also known as SGD-1910), which can be conjugated with antibodies (Kung Sutherland et al. 2013: direct induction of ICLs by SGD-1882 has not been shown, but addition of SGD-1882 induces appearance of DNA damage response biomarkers consistent with ICL repair)
SG3199 (Hartley et al. 2018), used to produce tesirine (also known as SG3249), which contains a linker added onto SG3199, which enables its conjugation with antibodies (Tiberghien et al. 2016)
SG2000 (also known as SJG-136, Gregson et al. 2001)
Due to their potency, PBD dimers are finding their use in the clinic as antibody-drug conjugates, which allows targeted delivery of these drugs to cancer cells (reviewed in Hartley 2021).

Platinums are platinum (Pt)-containing compounds that include the following chemotherapeutic drugs:
carboplatin (Blommaert et al. 1995)
cisplatin (Plooy et al. 1985, Blommaert et al. 1995)
oxaliplatin (Woynarowski et al. 1998)
picoplatin (also known as AMD473) (Holford, Sharp et al. 1998; Holford, Raynaud et al. 1998)
satraplatin.(Mellish et al. 1995).

For review, please refer to Deans and West 2011, Fu et al. 2012, and Rycenga and Long 2018.

Literature References
PubMed ID Title Journal Year
851960 Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas

Kohn, KW

Cancer Res 1977
7763301 The role of the N-(hydroxymethyl)melamines as antitumour agents: mechanism of action studies

Coley, HM, Brooks, N, Phillips, DH, Hewer, A, Jenkins, TC, Jarman, M, Judson, IR

Biochem Pharmacol 1995
32543981 Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy

Hartley, JA

Expert Opin Biol Ther 2021
10100700 Measurement of DNA cross-linking in patients on ifosfamide therapy using the single cell gel electrophoresis (comet) assay

Hartley, JM, Spanswick, VJ, Gander, M, Giacomini, G, Whelan, J, Souhami, RL, Hartley, JA

Clin Cancer Res 1999
3463409 Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells

Crook, TR, Souhami, RL, McLean, AE

Cancer Res 1986
7599137 Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells

Blommaert, FA, van Dijk-Knijnenburg, HC, Dijt, FJ, den Engelse, L, Baan, RA, Berends, F, Fichtinger-Schepman, AM

Biochemistry 1995
7558420 DNA-binding properties of novel cis- and trans platinum-based anticancer agents in 2 human ovarian carcinoma cell lines

Mellish, KJ, Barnard, CF, Murrer, BA, Kelland, LR

Int J Cancer 1995
11262084 Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity

Gregson, SJ, Howard, PW, Hartley, JA, Brooks, NA, Adams, LJ, Jenkins, TC, Kelland, LR, Thurston, DE

J Med Chem 2001
29679802 The evolving role of DNA inter-strand crosslinks in chemotherapy

Rycenga, HB, Long, DT

Curr Opin Pharmacol 2018
3928152 Formation and repair of DNA interstrand cross-links in relation to cytotoxicity and unscheduled DNA synthesis induced in control and mutant human cells treated with cis-diamminedichloroplatinum(II)

Plooy, AC, van Dijk, M, Berends, F, Lohman, PH

Cancer Res 1985
3469016 Cellular resistance to chloroethylnitrosoureas, nitrogen mustard, and cis-diamminedichloroplatinum(II) in human glial-derived cell lines

Aida, T, Bodell, WJ

Cancer Res 1987
6722805 Dependence on treatment time of melphalan resistance and DNA cross-linking in human melanoma cell lines

Parsons, PG

Cancer Res 1984
3926301 Interactions of mitomycin C with mammalian DNA detected by alkaline elution

Dorr, RT, Bowden, GT, Alberts, DS, Liddil, JD

Cancer Res 1985
9271495 Mechanism of action of fotemustine, a new chloroethylnitrosourea anticancer agent: evidence for the formation of two DNA-reactive intermediates contributing to cytotoxicity

Hayes, MT, Bartley, J, Parsons, PG, Eaglesham, GK, Prakash, AS

Biochemistry 1997
12582240 DNA crosslinking and biological activity of a hairpin polyamide-chlorambucil conjugate

Wang, YD, Dziegielewski, J, Wurtz, NR, Dziegielewska, B, Dervan, PB, Beerman, TA

Nucleic Acids Res 2003
9472630 In vitro circumvention of cisplatin resistance by the novel sterically hindered platinum complex AMD473

Holford, J, Sharp, SY, Murrer, BA, Abrams, M, Kelland, LR

Br J Cancer 1998
9804612 Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA

Woynarowski, JM, Chapman, WG, Napier, C, Herzig, MC, Juniewicz, P

Mol Pharmacol 1998
23770776 SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML

Kung Sutherland, MS, Walter, RB, Jeffrey, SC, Burke, PJ, Yu, C, Kostner, H, Stone, I, Ryan, MC, Sussman, D, Lyon, RP, Zeng, W, Harrington, KH, Klussman, K, Westendorf, L, Meyer, D, Bernstein, ID, Senter, PD, Benjamin, DR, Drachman, JG, McEarchern, JA

Blood 2013
9837991 Gene and human tumour cell line specific differencesin nitrogen mustard induced DNA alkylation and interstrand crosslinking frequencies

Sunters, A, Grimaldi, KA, Souhami, RL, Hartley, JA

Nucleic Acids Res 1998
21701511 DNA interstrand crosslink repair and cancer

Deans, AJ, West, SC

Nat. Rev. Cancer 2011
9474239 Chemical, biochemical and pharmacological activity of the novel sterically hindered platinum co-ordination complex, cis-[amminedichloro(2-methylpyridine)] platinum(II) (AMD473)

Holford, J, Raynaud, F, Murrer, BA, Grimaldi, K, Hartley, JA, Abrams, M, Kelland, LR

Anticancer Drug Des 1998
22237395 Balancing repair and tolerance of DNA damage caused by alkylating agents

Fu, D, Calvo, JA, Samson, LD

Nat. Rev. Cancer 2012
2265064 Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustards

O'Connor, PM, Kohn, KW

Cancer Commun 1990
29992976 Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine

Hartley, JA, Flynn, MJ, Bingham, JP, Corbett, S, Reinert, H, Tiberghien, A, Masterson, LA, Antonow, D, Adams, L, Chowdhury, S, Williams, DG, Mao, S, Harper, J, Havenith, CEG, Zammarchi, F, Chivers, S, van Berkel, PH, Howard, PW

Sci Rep 2018
27882195 Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload

Tiberghien, AC, Levy, JN, Masterson, LA, Patel, NV, Adams, LR, Corbett, S, Williams, DG, Hartley, JA, Howard, PW

ACS Med Chem Lett 2016
1714342 Interaction of N,N',N''-triethylenethiophosphoramide and N,N',N''-triethylenephosphoramide with cellular DNA

Cohen, NA, Egorin, MJ, Snyder, SW, Ashar, B, Wietharn, BE, Pan, SS, Ross, DD, Hilton, J

Cancer Res 1991
Participants
Participates
Inferred From
Authored
Reviewed
Created
Cite Us!