Small molecule drugs – optimizing DNA damaging agent-based therapeutics

DNA-targeted chemotherapies remain fundamental in clinical management of both common solid tumours and hematologic malignancies. Recent studies indicate that novel combinations of cytotoxic chemotherapy may have significant activity even in tumours regarded as being resistant to conventional chemotherapy. In addition, the search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues. Trabectedin, bendamustine and the pyrrolobenzodiazepine dimer SG2000 exemplify three different classes of DNA targeted agent undergoing clinical evaluation. Increasingly, DNA damaging drugs are being used in combination with novel agents such as small molecule inhibitors or antibodies targeting receptor tyrosine kinases. Understanding the mechanistic basis for interactions of these novel targeted agents with DNA-interactive drugs will inform design of optimal combinations for future studies and is critical to maximize benefit in the clinic.

► There remains potential to improve clinical combinations of chemotherapeutic agents.
► Trabectedin modulates oncogenic transcription factors.
► Drugs such as bendamustine may have unexpected disease-specific activity.
► Pyrrolobenzodiazepine dimers represent a novel class of DNA interactive drugs.
► Understanding the interactions of targeted and DNA-interactive agents is critical.