Abstract | PURPOSE: EXPERIMENTAL DESIGN: The cytotoxic effects of AQ4N prodrug and its bioreduced form, AQ4, were tested against multiple human tumor cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Nude mice bearing s.c. or orthotopically implanted human BxPC-3 or Panc-1 tumor cells were treated with AQ4N. Tumor growth inhibition, time to progression/end point, and liver metastasis were evaluated in treatment versus control groups. Plasma and tumor levels of AQ4N and its metabolites were quantitated by liquid chromatography-tandem mass spectrometry. RESULTS: In contrast to AQ4N, the bioreduced AQ4 metabolite displayed potent cytotoxicity in many human tumor lines, including those derived from human pancreatic adenocarcinomas. Single-agent administration of AQ4N significantly delayed tumor growth, progression, and survival in a manner comparable with gemcitabine in multiple pancreatic tumor models in vivo. Survival increases were accompanied by a reduction in incidence and spread of liver metastasis. Quantitation of AQ4N and its metabolites in tumor-bearing mice showed that the prodrug is rapidly cleared from the circulation by 24 h and neither of the bioreduced metabolites was detected in plasma. In contrast, AQ4N readily penetrated BxPC-3 tumors and the cytotoxic AQ4 metabolite rapidly accumulated in tumor tissues at high levels in a dose-dependent fashion. CONCLUSION:
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Authors | Alshad S Lalani, Susan E Alters, Alvin Wong, Mark R Albertella, Jeffrey L Cleland, William David Henner |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 13
Issue 7
Pg. 2216-25
(Apr 01 2007)
ISSN: 1078-0432 [Print] United States |
PMID | 17404106
(Publication Type: Journal Article)
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Chemical References |
- Anthraquinones
- Antineoplastic Agents
- Prodrugs
- AQ4N
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Topics |
- Animals
- Anthraquinones
(metabolism, pharmacology)
- Antineoplastic Agents
(metabolism, pharmacology)
- Cell Hypoxia
(physiology)
- Cell Proliferation
(drug effects)
- Disease Models, Animal
- Drug Delivery Systems
- Female
- Humans
- Mice
- Mice, Nude
- Neoplasm Metastasis
(drug therapy)
- Pancreatic Neoplasms
(drug therapy)
- Prodrugs
(metabolism, pharmacology)
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