Selective tumor targeting by the hypoxia-activated prodrug AQ4N blocks tumor growth and metastasis in preclinical models of pancreatic cancer.
OBJECTIVE
The antitumor activities and pharmacokinetics of the hypoxia-activated cytotoxin AQ4N and its metabolites were assessed in several preclinical models of pancreatic cancers.


METHODS
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.


CONCLUSIONS
AQ4N undergoes rapid and selective conversion into the potent antineoplastic metabolite AQ4 in tumors in vivo and provides proof of principle for the use of hypoxia-activated prodrugs in the treatment against pancreatic cancers.
Lalani
Alshad S
AS
Novacea, Inc., South San Francisco, California and KuDOS Pharmaceuticals Ltd., Cambridge, United Kingdom. lalani@novacea.com
Alters
Susan E
SE
Wong
Alvin
A
Albertella
Mark R
MR
Cleland
Jeffrey L
JL
Henner
William David
WD
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011355:Prodrugs; C094428:AQ4N