Mechanism-Based Drug Combinations with the DNA Strand-Breaking Nucleoside Analog CNDAC.

Abstract

CNDAC (2'-C-cyano-2'-deoxy-1-β-d-arabino-pentofuranosyl-cytosine, DFP10917) and its orally bioavailable prodrug, sapacitabine, are undergoing clinical trials for hematologic malignancies and solid tumors. The unique action mechanism of inducing DNA strand breaks distinguishes CNDAC from other deoxycytidine analogs. To optimize the clinical potentials of CNDAC, we explored multiple strategies combining CNDAC with chemotherapeutic agents targeting distinct DNA damage repair pathways that are currently in clinical use. The ability of each agent to decrease proliferative potential, determined by clonogenic assays, was determined in paired cell lines proficient and deficient in certain DNA repair proteins. Subsequently, each agent was used in combination with CNDAC at fixed concentration ratios. The clonogenicity was quantitated by median effect analysis, and a combination index was calculated. The c-Abl kinase inhibitor imatinib had synergy with CNDAC in HCT116 cells, regardless of p53 status. Inhibitors of PARP1 that interfere with homologous recombination (HR) repair or base excision repair (BER) and agents such as temozolomide that cause DNA damage repaired by the BER pathway were also synergistic with CNDAC. The toxicity of the nitrogen mustards bendamustine and cytoxan, or of platinum compounds, which generate DNA adducts repaired by nucleotide excision repair and HR, was additive with CNDAC. An additive cell killing was also achieved by the combination of CNDAC with taxane mitotic inhibitors (paclitaxel and docetaxel). At concentrations that allow survival of the majority of wild-type cells, the synergistic or additive combination effects were selective in HR-deficient cells. This study provides mechanistic rationales for combining CNDAC with other active drugs. Mol Cancer Ther; 15(10); 2302-13. ©2016 AACR.

• Authors: Xiaojun Liu, Yingjun Jiang, Billie Nowak, Sarah Hargis, William Plunkett
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 10 Pg. 2302-2313 (10 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27474148 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Tumor Suppressor Protein p53
• Cytarabine
• 2'-cyano-2'-deoxyarabinofuranosylcytosine
• Platinum
• Dacarbazine
• Poly (ADP-Ribose) Polymerase-1
• Temozolomide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cricetinae
• Cytarabine (analogs & derivatives, pharmacology)
• DNA Breaks (drug effects)
• Dacarbazine (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Drug Interactions
• Drug Synergism
• Homologous Recombination (drug effects, genetics)
• Humans
• Platinum (pharmacology)
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors)
• Temozolomide
• Tumor Suppressor Protein p53 (genetics, metabolism)