Abstract

The cytotoxic and biochemical activity of the pyrrolopyrimidine antibiotic, sangivamycin, was examined in a human colon carcinoma in tissue culture. Logarithmically growing cells were more sensitive than early plateau-phase cells to the lethal effects of the drug as determined by colony formation in soft agar. Cell lethality in both log- and plateau-phase cells became more pronounced when drug exposure time was increased from 2 hr to 24-48 hr. Reduced cell viability correlated with the inhibition of total RNA synthesis after 2 hr of drug exposure, and with reduced DNA synthesis and incorporation of drug into DNA and RNA after 24-48 hr of drug exposure. Fractionation of total RNA into non-poly(A)-containing and poly(A)-containing RNA indicated that inhibition of the synthesis of both RNA species occurred after 24 hr of exposure of log-phase cells to sangivamycin. Neither RNA fraction was affected in plateau-phase cells after 48 hr of drug exposure. In contrast, a close correlation was found between the incorporation of [³H]sangivamycin into poly(A)RNA and cell lethality after 24-48 hr of exposure of both log- and plateau-phase cells to sangivamycin. These results show that a human colon carcinoma is responsive to sangivamycin following prolonged drug-exposure intervals and that the associated cytotoxicity correlates closely with the incorporation of drug into mRNA, as well as inhibition of DNA synthesis.