ADRIAMYCIN STIMULATES PROLIFERATION OF HUMAN LYMPHOBLASTIC LEUKEMIC-CELLS VIA A MECHANISM OF HYDROGEN-PEROXIDE (H2O2) PRODUCTION

It is becoming clear that adriamycin cytotoxicity may be mediated by s emiquinone-free radicals derived from the drug itself and reactive oxy gen species (ROS), Recent evidence supports the concept that low conce ntrations of ROS are able to stimulate cell proliferation, and, based on the observation that subtoxic concentrations of adriamycin can also induce cell proliferation, we hypothesize that low concentrations of adriamycin stimulate cell proliferation by a ROS generation mechanism, We have employed spin-trapping and electron spin resonance (ESR) spec troscopy to investigate the nature of the adriamycin-generated ROS. Th e spin trap 3,5-dibromo-4-nitrosobenzenesulphonate (DBNBS), which is o xidized in the presence of H2O2 and peroxidase enzymes, was used to pr oduce a characteristic three-line spectrum, and it was found that an i dentical spectrum was produced by human lymphoblastic leukaemic cells (CCRF-CEM cells) after exposure to adriamycin, We tested our hypothesi s further by exposing CCRF-CEM cells to subtoxic concentrations of adr iamycin (10(-8) 10(-9) and 10(-10) M) and low concentrations of H2O2 ( 10(-8) 10(-9) and 10(-10) M) and subsequently monitored cell prolifera tion. We found that low concentrations of both adriamycin and H2O2 sig nificantly stimulate CCRF-CEM cell proliferation. We therefore conclud e that subtoxic concentrations of adriamycin are likely to induce cell proliferation via an H2O2 mediated mechanism.