The
sugar amine modified
anthracyclines,
3'-(4-morpholinyl)-3'-deaminodaunorubicin (MD) and
3'-(4-methoxy-1-piperidinyl)-3'-deaminodaunorubicin (MEO), are 10-fold more potent than
daunorubicin (DAU) as inhibitors of
RNA synthesis in human colon
carcinoma (HT-29) cells in vitro, although they are 10-fold less cytocidal. In this study, HT-29 cells were exposed for 2 h to 5 X 10(-8) M MD or MEO, or 5 X 10(-7) M DAU; under these conditions total
RNA synthesis is decreased by each
drug by 50%, whereas cell viability is reduced more than 99% by DAU, but less than 10% by MD and MEO. Following the 2-h exposure, the cellular content of DAU was 2-4-fold greater than that of MEO and MD, respectively. All three drugs had a similar inhibitory effect on the different
nuclear RNA fractions and preferentially reduced nucleolar
RNA synthesis (44-49% inhibition) compared to heterogeneous
RNA synthesis (5% inhibition). Polysomal
RNA synthesis was inhibited to a greater degree than
nuclear RNA synthesis by all the
anthracyclines, and non-poly
RNA synthesis was decreased by 50-60% and
poly(A) RNA synthesis by 30%. When treated cells were incubated in
drug-free medium for 2 h,
RNA synthesis returned to 80% of the pretreatment level in MD and DAU treated cells, but by less than 10% in cells treated with MEO, and this difference was due to the more rapid cellular efflux of MD and DAU versus MEO. Thus, MD and MEO are inherently more potent inhibitors than DAU of
RNA synthesis in HT-29 cells, but their reduced cytotoxicity cannot be attributed to differing effects on nucleolar or heterogeneous
RNA synthesis, the nucleocytoplasmic transport of
RNA, or the rate of return of
RNA synthesis following
drug treatment.