A compound derived from a marine organism defines a new class of anticancer drugs that targets the nucleotide excision repair system of cells.

Ecteinascidin 743 (Et743) is an alkylating agent that tightly binds DNA in the minor groove. It was originally isolated from the Caribbean sea squirt, Ecteinashidia turbinata, shown in the photograph. In Phase II/III trials, the compound has shown remarkable activity against a number of advanced cancers, including sarcomas.

On page 961 of this issue, Takebayashi et al. show that Et743 DNA adducts are recognized by a cell's nucleotide repair system, which ends up killing the cell instead of repairing the damage caused by the adducts. What is particularly interesting, and relevant to cancer therapy, is that the killing is only seen if the repair occurs in transcribed genes.

Nucleotide excision repair (NER) is a mechanism for removing and repairing lesions that distort the DNA helix, such as ultraviolet-light–induced cyclobutane pyrimidine dimers or adducts caused by alkylating anticancer drugs. There are two pathways of NER—one which recognizes damage localized to transcribed regions and the other damage in the global genome. Several proteins that have critical roles in one or both pathways are known.

The link between Et743 and NER was uncovered by the authors by generating two Et743-resistant cell lines and showing that both have defects in the gene encoding xerodema pigmentosum (XPG), an endonuclease involved in NER. Restoring XPG activity in these cells restored their ability to repair DNA damage induced by ultraviolet light and also Et743 sensitivity.

Cell lines deficient in other genes that, similar to XPG, are essential to both trancription-coupled and global genome NER were also found to be resistant to Et743. However, cells deficient in XPC, which encodes a protein that only recognizes damage in the global genome, were sensitive to Et743 killing. This finding suggested that ecteinascidin cytotoxicity is specifically associated with transcription-coupled NER.

In each cell tested, Et743 cytotoxicity correlated with functional transcription-coupled NER activity as well as with the presence of single-stranded DNA breaks in transcribed genes. Based on these observations, the authors suggest that when the NER system detects Et743 adducts in genes it makes single-stranded DNA breaks on either side of the lesion. These breaks are what cause the cells to die.