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Cancer Chemotherapy and Pharmacology

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01-02-2018 | Original Article

Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

Authors: Xiaojun Liu, Yingjun Jiang, Billie Nowak, Bethany Qiang, Nancy Cheng, Yuling Chen, William Plunkett

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2018

Abstract

Purpose

The mechanism of action of CNDAC (2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosyl-cytosine) is unique among deoxycytidine analogs because upon incorporation into DNA it causes a single strand break which is converted to a double strand break after DNA replication. This lesion requires homologous recombination (HR) for repair. CNDAC, as the parent nucleoside, DFP10917, and as an oral prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors. The purpose of this study is to investigate the potential of CNDAC for the therapy of ovarian cancer (OC).

Methods

Drug sensitivity was evaluated using a clonogenic survival assay. Drug combination effects were quantified by median effect analysis.

Results

OC cells lacking function of the key HR genes, BRCA1 or BRCA2, were more sensitive to CNDAC than corresponding HR proficient cells. The sensitization was associated with greater levels of DNA damage in response to CNDAC at clinically achievable concentrations, manifested as chromosomal aberrations. Three classes of CNDAC-based drug combinations were investigated. First, the PARP1 inhibitors, rucaparib and talazoparib, were selectively synergistic with CNDAC in BRCA1/2 deficient OC cells (combination index < 1) at a relatively low concentration range. Second, cisplatin and oxaliplatin had additive combination effects with CNDAC (combination index ~ 1). Finally, paclitaxel and docetaxel achieved additive cell-killing effects with CNDAC at concentration ranges of the taxanes similar for both BRCA1/2 deficient and proficient OC cells.

Conclusions

This study provides mechanistic rationales for combining CNDAC with PARP inhibitors, platinum compounds and taxanes in ovarian cancer lacking BRCA1/2 function.

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Title: Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations
Authors: Xiaojun Liu
Yingjun Jiang
Billie Nowak
Bethany Qiang
Nancy Cheng
Yuling Chen
William Plunkett
Publication date: 01-02-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-017-3483-6

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Abstract

Purpose

Methods

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Conclusions

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