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Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361

Lookup NU author(s): Dr Christopher Calabrese, Michael Batey, Professor Alan Calvert, Emeritus Professor Barbara Durkacz, Suzanne Kyle, Professor Herbie Newell, Dr Elena Notarianni, Huw Thomas, Lan Wang, Professor Nicola Curtin

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Abstract

Background: Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts. Methods: The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or γ-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1-/- and PARP-1+/+ cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided. Results: AG14361 at 0.4 μM did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] = 4.9-fold to 5.9-fold; P =.004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI = 1.3-fold to 1.9-fold; P =.002) and inhibited recovery from potentially lethal γ-radiation damage in LoVo cells by 73% (95% CI = 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two- to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours. Conclusion: AG14361 i s, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.


Publication metadata

Author(s): Calabrese C, Almassy R, Barton S, Batey M, Calvert AH, Canan-Koch S, Durkacz B, Hostomsky Z, Kumpf R, Kyle S, Li J, Maegley K, Newell DR, Notarianni E, Stratford I, Skalitzky D, Thomas HD, Wang L, Webber S, William K, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Journal of the National Cancer Institute

Year: 2004

Volume: 96

Issue: 1

Pages: 56-67

Print publication date: 07/01/2004

ISSN (print): 0027-8874

ISSN (electronic): 1460-2105

URL: http://dx.doi.org/10.1093/jnci/djh005

DOI: 10.1093/jnci/djh005

PubMed id: 14709739


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