Development Of A 2', 2-Difluorodeoxycytide(Gemcitabine)-resistant Variant Of The Human Lung Adenocarcinoma Cell Line A549 And Study On The Mechanism Of Drug Resistance

2',2-Difluorodeoxycytide(Gemcitabine) is a relatively new deoxycydine analogue which has shown good antitumor activity both in experimental and clinical administration for treatment of solid tumors. Resistance to gemcitabine can be a problem in the treatment of several kinds of solid tumors, such as non-small cell lung cancer, breast cancer and ovarian cancer. A number of resistance mechanisms of gemcitabine have been recognized in the past. Since gemcitabine has a complex mechanism of action with multiple cellular targets, resistance can be multifactorial. The advent of DNA microarray technology and its capacity for simultaneous probing of the genome on high-density microarray has enabled the analysis of the expression profiles of thousands of genes. In views of the complex array of genetic factors contributing to drug resistance, DNA microarray should be useful for examining the development of drug resistance in cancer. This is the first report about the expression profiles of gemcitabine resistant lung cancer cells by cDNA microarray.We induced resistance to gemcitabine in human lung adenocarcinoma cell line A549 by exposure to increasing concentration of gemcitabine, named A549-Gem. The IC50, defined as the concentration of gemcitabine causing 50% of growth inhibition, at 72hr exposure increased form 6.56±1. 19u μ mol/l in A549 to 921.09 ± 225. 27 μ mol/1 in A549-Gem tested by MTT assay. The A549-Gem is 140.52-fold resistant to gemcitabine than it's parent cell line A549 (p=0. 0195) . Although the resistant cell line is routinely cultured in 1 umol/l gemcitabine, the resistant phenotype can be maintained for at least 8 weeks without gemcitabine.