Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma

Abstract

B-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-1A 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 hypoxiainducible factor-1A 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

Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia

“…These results are in agreement with several studies showing that hypoxia compromised the cytotoxic effect of gemcitabine in PDAC cells (Yokoi and Fidler, 2004; Zhang et al , 2005), but other studies reported no significant effects of gemcitabine cytotoxicity in lung cancer cells (Lam et al , 2009; Wouters et al , 2011), suggesting a cell-dependency of this phenomenon.…”

Perfusion CT in Squamous Cell Carcinoma of the Upper Aerodigestive Tract: Long-Term Predictive Value of Baseline Perfusion CT Measurements

“…Reinforcing this evidence, the weak predictive value (P Ͻ .05) of the T stage for local tumor control in the oropharynx for patients treated with curative surgery or radiation therapy 24,25 and the weak or nonsignificant correlation between the T stage and perfusion-associated parameters 4,11,13 make it hard to predict only on the basis of T. This difficulty highlights the role of perfusion measurements in patients with neoadjuvant chemoradiation. [26][27][28] Finally, the perfusion estimations in our study did not have any predictive value for OS. This is in essential agreement with the results of Hermans et al 11 regarding regional control and cause-specific survival.…”

Impact of Tumor Blood Flow Modulation on Tumor Sensitivity to the Bioreductive Drug Banoxantrone

“…3B). H460 tumors are highly vascularized (Mukhopadhyay et al, 2002;Navab et al, 2009) but have heterogeneous regions of hypoxia (Lam et al, 2009), in agreement with our findings. AQ4N Is More Toxic to scid Mice Than Nude Mice.…”