Reactome | Anti-cancer drugs generate DNA interstrand crosslinks

Anti-cancer drugs generate DNA interstrand crosslinks

Stable Identifier

R-HSA-9713785

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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Anti-cancer drugs generate DNA interstrand crosslinks

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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
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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 Souhami, RL, Giacomini, G, Hartley, JM, Whelan, J, Hartley, JA, Gander, M, Spanswick, VJ	Clin Cancer Res	1999
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11262084	Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity Howard, PW, Thurston, DE, Kelland, LR, Jenkins, TC, Adams, LJ, Brooks, NA, Hartley, JA, Gregson, SJ	J Med Chem	2001
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9837991	Gene and human tumour cell line specific differencesin nitrogen mustard induced DNA alkylation and interstrand crosslinking frequencies Souhami, RL, Sunters, A, Hartley, JA, Grimaldi, KA	Nucleic Acids Res	1998
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9474239	Chemical, biochemical and pharmacological activity of the novel sterically hindered platinum co-ordination complex, cis-[amminedichloro(2-methylpyridine)] platinum(II) (AMD473) Abrams, M, Murrer, BA, Kelland, LR, Hartley, JA, Raynaud, F, Grimaldi, K, Holford, J	Anticancer Drug Des	1998
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29992976	Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine Harper, J, Zammarchi, F, Chivers, S, Bingham, JP, Antonow, D, Flynn, MJ, Tiberghien, A, Adams, L, van Berkel, PH, Havenith, CEG, Mao, S, Hartley, JA, Masterson, LA, Reinert, H, Chowdhury, S, Corbett, S, Williams, DG, Howard, PW	Sci Rep	2018
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