Sapacitabine for cancer

Abstract

Introduction: Sapacitabine is an orally bioavailable nucleoside analog prodrug that is in clinical trials for hematologic malignancies and solid tumors. The active metabolite of sapacitabine, CNDAC (2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosylcytosine), exhibits the unique mechanism of action of causing single-strand breaks (SSBs) after incorporation into DNA, which are converted into double-strand breaks (DSBs) when cells enter a second S-phase. CNDAC-induced DSBs are predominantly repaired through homologous recombination (HR). Cells deficient in HR components are greatly sensitized to CNDAC. Therefore, sapacitabine could be specifically effective against tumors that are deficient in this repair pathway.

Areas covered: This review summarizes results from supporting evidence for the mechanisms of action of sapacitabine, its preclinical activities and the current results of clinical trials in a variety of cancers. The novel action mechanism of sapacitabine is discussed, with a view to validate it as a chemotherapeutic drug targeting malignancies with defects in HR.

Expert opinion: Knowledge of CNDAC mechanism identifies tumors that may be sensitized to sapacitabine, thus enabling a personalized treatment strategy. It also creates the opportunity to overcome resistance to current front-line therapies and identify synergistic interactions with known anticancer drugs. The results of such investigations may provide rationales for the design of sapacitabine-based clinical trials.

Keywords::

• ATM
• BRCA2
• CNDAC
• homologous recombination
• leukemia and lymphoma
• nucleotide excision repair
• Rad51
• sapacitabine
• solid tumor
• Xrcc3

Acknowledgements

The authors are grateful to Dr. David Blake, Cyclacel Pharmaceuticals, Ltd., for critical reading of the manuscript.

Declaration of interests

Investigations from the authors' laboratories were supported by Grants CA28596, CA81534 and CA100532 from the National Cancer Institute, Department of Health and Human Services. The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Notes

This box summarizes key points contained in the article.