VAL-083 (dianhydrogalactitol), a DNA-targeting agent that introduces interstrand
DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death, has demonstrated clinical activity against a range of cancers including GBM and ovarian cancer in historical clinical trials.
Complementation of hypersensitivity to DNA interstrand
crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.
The company stated VAL-083 (dianhydrogalactitol) is a "first-in-class", DNA-targeting agent that introduces interstrand
DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death.
These adducts consist of platinum-DNA monoadducts, intrastrand and interstrand
cross-links, and/or DNA-protein cross-links.
The FA pathway is required for the repair of DNA interstrand
crosslinks (ICLs), the hallmark of many cancers and FA.
Excision repair cross-complementation group 1 (ERCC1) is widely recognized as a powerful component of nucleotide excision repair (NER) pathway, which not only involves the repair of interstrand
cross-links in the DNA but also involves the recognition and remove of cytotoxic agents like platinum.
UVB and UVC light induce the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6-4)pyrimidone photoproducts (6-4 PPs), whereas UVA light primarily causes oxidative DNA damage via the formation of 8-oxo-7,8-dihydroguanine (8-oxoG) and cyclobutane thymidine dimers [5, 6], potentially leading to single-strand breaks and other interstrand
cross-links (ICLs) in DNA .
The formaldehyde-induced crosslinks include protein-protein, protein--DNA, and DNA--formaldehyde adducts and interstrand
Processing of a psoralen DNA interstrand
cross-link by XPF-ERCC1 complex in vitro.
Acrolein is known to induce DNA interstrand
cross-links (ICLs; highly toxic DNA lesions) through inhibitory effects on transcription and replication (Kozekov et al.
Furthermore, psoralen can form DNA interstrand
cross-links upon activation with UVA radiation, and the cross-links repair may involve DNA double strand breaks and/or recombination (Finlan et al.
1] This antineoplastic drug inhibits tumour growth through the formation of DNA interstrand
and intrastrand crosslinks, which disrupts the double-stranded DNA helical structure.