Effects of structural modifications of anti-tumour antibiotics luzopeptins on cell growth and macromolecule biosynthesis.

Luzopeptin analogues, A, B and C (in decreasing degree of acetylation) were active, less active and inactive, respectively, against several animal tumour models. All bound to isolated DNA avidly. The present studies with cultured Novikoff hepatoma cells showed that luzopeptins A, B and C were inhibitory, less inhibitory and ineffective, respectively, on cell colony formation ability and whole-cell DNA and RNA synthesis. RNA synthesis was more sensitive than DNA synthesis to luzopeptins A and B. All had no direct effect on protein synthesis. All inhibited the DNA and RNA syntheses of isolated nuclei and luzopeptins B and C were slightly more active than luzopeptin A inhibition of RNA synthesis in isolated nuclei. All similarly inhibited DNA polymerase activity in vitro, but luzopeptin C was more active against RNA polymerase activity in vitro. It is concluded that luzopeptin cytotoxicity probably resulted from inhibition of DNA and RNA biosynthesis. Because all analogues bound avidly to isolated DNA and inhibited its functions, the differential anti-tumour activity may be attributed to the differential ability of these luzopeptins to traverse the cell membrane and, to some extent, other intracellular barriers. This probably is a result of difference in acetylation, resulting in differences in hydrophobicity.