Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma
التفاصيل البيبلوغرافية
العنوان:
Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma
β-l-Dioxolane-cytidine (l-OddC; BCH-4556; troxacitabine), a novel l-configuration deoxycytidine analogue, was under clinical trials for treating cancer. The cytotoxicity of l-OddC is dependent on its phosphorylation to l-OddCTP by phosphoglycerate kinase (PGK) and its subsequent addition into nuclear DNA. Because PGK is induced with hypoxia, the expression of hypoxia-inducible factor-1α and PGK of H460 cells (human non-small cell lung carcinoma) in vitro and in vivo was studied. In culture, hypoxic treatment induced the protein expression of PGK by 3-fold but had no effect on the protein expression of other l-OddC metabolism-associated enzymes such as apurinic/apyrimidinic endonuclease-1, deoxycytidine kinase, CMP kinase, and nM23 H1. Using a clonogenic assay, hypoxic treatment of H460 cells rendered cells 4-fold more susceptible to l-OddC but not to gemcitabine (dFdC) following exposure to drugs for one generation. Using hypoxia response element-luciferase reporter system, Western blotting, and immunohistochemistry, it was found that hypoxia-inducible factor-1α and PGK expression increased and could be correlated to tumor size. Despite dFdC being more toxic than l-OddC in cell culture, l-OddC (300 mg/kg i.p.) had a stronger antitumor activity than dFdC in H460 xenograft-bearing nude mice. Furthermore, l-OddC retained ∼50% of its antitumor activity with oral gavage compared with i.p. delivery. Oral administration of l-OddC (600 mg/kg p.o.) had a similar area under the curve value compared with i.p. injection of dFdC (300 mg/kg i.p.). In conclusion, the hypoxia, which commonly exists in non-small cell lung carcinoma or other solid tumors resistant to radiotherapy or chemotherapy, is a favorable determinant to enhance the antitumor activity of l-OddC in vivo. [Mol Cancer Ther 2009;8(2):415–23]
