Differential killing efficacy of twenty antitumor drugs on proliferating and nonproliferating human tumor cells

The lethal effects of a 1-hr treatment with 20 antitumor drugs on proliferating and nonproliferating cultured human colon carcinoma cells (line LoVo) were analyzed quantitatively by the colony-forming technique. Proliferating cells were obtained from exponentially growing cultures, while nonproliferating cells were from cultures in a stationary phase of growth. The 1-hrtreatment was intended to approximate serum peak levels after bolus administration. Two agents, cis-platinum and vin-desine, were more effective on nonproliferating than on proliferating cells. Mitomycin C, nitrosoureas, and dihydroxybisal-kylanthracenedione were equally effective on proliferating and nonproliferating cells. The low lethal activity (<1 log) of methylglyoxal bis(guanylhydrazone), hycanthone, and vinblastine was similar in proliferating and nonproliferating cells. For most drugs (Adriamycin, rubidazone, bleomycin, maytansine, vincristine, epipodophyllotoxin, fluorouracil, hydroxyurea, methotrexate, and transplantinum) cytotoxicity was significantly'less pronounced (or even totally absent) in nonproliferating than in proliferating cells. These results demonstrate the significance of cellular proliferation kinetics in determining sensitivity to antitumor therapy. Nonproliferating human cells have decreased sensitivity to most antitumor agents. An occasional agent may present increased activity to nonproliferating cells; but at best, few agents can be expected to be as effective on nonproliferating as on proliferating cells.