ABSTRACT
PURPOSE: The antitumor activities and pharmacokinetics of the hypoxia-activated cytotoxin AQ4N and its metabolites were assessed in several preclinical models of pancreatic cancers. 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: 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.
Subject(s)
Anthraquinones/pharmacology , Antineoplastic Agents/pharmacology , Cell Hypoxia/physiology , Pancreatic Neoplasms/drug therapy , Animals , Anthraquinones/metabolism , Antineoplastic Agents/metabolism , Cell Proliferation/drug effects , Disease Models, Animal , Drug Delivery Systems , Female , Humans , Mice , Mice, Nude , Neoplasm Metastasis/drug therapy , Prodrugs/metabolism , Prodrugs/pharmacologyABSTRACT
BACKGROUND: Glutathione S-transferase T1 detoxifies some environmental carcinogens while activating others and is deleted in 15% to 38% of humans. We sought to determine whether GSTT1 genotype and genotypes of several related genes are associated with risk of squamous cell carcinoma of the head and neck (HNSCC). METHODS: Somatic genotypes for GSTT1, GSTM1, GSTP1, and CYP1A1 were determined in 283 individuals with HNSCC and 208 population-based controls. RESULTS: The OR for presence of GSTT1 was 1.6 (CI, 1.1-2.5, p = 0.03). HNSCC risk was not associated with GSTM1 null genotype, the presence of the GSTP1 Val/Val genotype, or the Val/Val homozygous genotype for CYP1A1. Stratified analysis revealed disparate ORs for women (OR, 3.0; CI, 1.5-6.3) and men (OR, 1.2; CI, 0.7-2.1) for the presence of GSTT1. CONCLUSIONS: In this population, the presence of GSTT1 gene was associated with a significant increase in the risk of HNSCC. This association was particularly robust in women.
Subject(s)
Carcinoma, Squamous Cell/genetics , Genetic Predisposition to Disease , Glutathione Transferase/genetics , Head and Neck Neoplasms/genetics , Polymorphism, Genetic , Aged , Carcinoma, Squamous Cell/epidemiology , Case-Control Studies , Female , Genotype , Head and Neck Neoplasms/epidemiology , Humans , Male , Middle Aged , Risk Factors , Sex Factors , Smoking/epidemiology , White People/geneticsABSTRACT
Although the antineoplastic activity of calcitriol in prostate cancer has been known for many years, the agent's use in oncology has been prevented because of the occurrence of hypercalcemia with daily administration. High-dose pulse administration of calcitriol has the potential to improve the therapeutic index of calcitriol. Results of a phase II study of calcitriol and docetaxel (Taxotere(R)) suggest that this combination may have utility in androgen-independent prostate cancer (AIPC). DN-101, a high-dose (15 mug) formulation of calcitriol suitable for use in oncology, is now being tested in a randomized trial (AIPC Study of Calcitriol Enhancing Taxotere). This formulation of calcitriol could become an important new tool for improving the efficacy of docetaxel in the treatment of AIPC and would join the ranks of other nuclear receptor ligands in cancer treatment. Investigations of DN-101 in the treatment of a broad range of tumor types and in combination with a variety of agents are an exciting new area of research.
