Differential sensitivity of murine myeloid FDC-P1 cells and apoptosis resistant mutant(s) to anticancer drugs

There is growing evidence which suggests that dysregulation of apoptosis ma y lead to several disease states including cancer. To investigate the mecha nism controlling the induction of cell death, apoptosis defective/resistant (Apt-) mutants were isolated and characterized in this study. FDC-P1, a mo use myeloid cell line that depends upon IL-3 for survival and growth but un dergoes apoptosis when deprived of growth factor, was mutagenized by treatm ent with ethyl methane sulfonate. We selected cells that survived the growt h factor deprivation but did not grow without the factor. Surviving cells w ere cloned by limiting dilution and four clones that showed the least morph ological characteristics and biochemical changes of apoptosis were chosen. Unlike the parent FDC-P1, these mutants were cross resistant to apoptosis i nduced by a variety of antitumor drugs such as Adriamycin, Dexamethasone, V P-16. as well as reactive oxygen species (ROS) generated by xanthine/xanthi ne oxidase (X/XO). We used one of these Apt- mutant to test candidate death genes. Our findings suggest that the preferential increase in Bax/Bcl-2 ra tio. p53. c-Myc, Caspase-3 and decrease in AP-1 on treatment with various a nticancer drugs may contribute to the preferential apoptotic response in FD C-P1 cells but to varying degrees. Whereas, the higher constitutive level o f antioxidant enzymes superoxide dismutase and catalase in the Apt- mutant may contribute at least in part to its resistance. (C) 2001 Elsevier Scienc e B.V. All rights reserved.