Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361.
Abstract | BACKGROUND: 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 gamma-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 micro M 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 gamma-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:
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Authors | Christopher R Calabrese, Robert Almassy, Stephanie Barton, Michael A Batey, A Hilary Calvert, Stacie Canan-Koch, Barbara W Durkacz, Zdenek Hostomsky, Robert A Kumpf, Suzanne Kyle, Jianke Li, Karen Maegley, David R Newell, Elena Notarianni, Ian J Stratford, Donald Skalitzky, Huw D Thomas, Lan-Zhen Wang, Stephen E Webber, Kaye J Williams, Nicola J Curtin |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 96
Issue 1
Pg. 56-67
(Jan 07 2004)
ISSN: 1460-2105 [Electronic] United States |
PMID | 14709739
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one
- Antineoplastic Agents
- Azulenes
- Enzyme Inhibitors
- Poly(ADP-ribose) Polymerase Inhibitors
- Radiation-Sensitizing Agents
- Benzodiazepines
- Dacarbazine
- Poly(ADP-ribose) Polymerases
- Temozolomide
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Azulenes
- Benzodiazepines
(pharmacology)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, radiotherapy)
- Cell Line, Tumor
- Colorectal Neoplasms
(drug therapy, radiotherapy)
- Dacarbazine
(analogs & derivatives, pharmacology)
- Drug Resistance, Neoplasm
(drug effects)
- Enzyme Inhibitors
(pharmacology)
- Gamma Rays
(therapeutic use)
- Gene Expression Regulation, Enzymologic
(drug effects)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Lung Neoplasms
(drug therapy, radiotherapy)
- Mice
- Poly(ADP-ribose) Polymerase Inhibitors
- Poly(ADP-ribose) Polymerases
(metabolism)
- Radiation-Sensitizing Agents
(pharmacology)
- Temozolomide
- Transplantation, Heterologous
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