Cytokinetic and biochemical effects of 5-iminodaunorubicin in human colon carcinoma in culture.

The semisynthetic anthracycline, 5-iminodaunorubicin (IM), was investigated to see whether modification of the benzoquinone moiety to produce a drug with low free radical potential would alter the cytotoxic and biochemical characteristics of this drug in comparison to Adriamycin (ADR), an agent with high free radical potential. Cell viability was measured in human colon carcinoma (HT-29) cells by soft-agar cloning. Upon exposure to either log-phase or early plateau-phase cells for 2 hr to IM or ADR, a threshold exponential cell lethality curve was obtained. Prolonging during exposure to 24 hr produced an exponential decline in cell survival and a marked reduction in viability of both log-phase and early plateau-phase cells. Inhibition of DNA synthesis in log-phase cells after 2 and 24 hr of exposure to IM and ADR paralleled the increased cell lethality produced by the drugs. In contrast, total RNA synthesis was not inhibited by IM, whereas ADR impaired both RNA and DNA synthesis. Nuclear rRNA, synthesis was not significantly inhibited following 24 hr of exposure to 10(-7) M ADR or IM but was inhibited by 85 and 35% at 10(-6) M ADR or IM, respectively. The affinity of IM and ADR for HT-29 DNA was measured in vitro by displacement of acridine orange binding and was found to be similar for both analogs. These studies suggest that the cytotoxicity of IM and ADR results from the interactions of these drugs with DNA.