Cellular pharmacodynamics of several anthracycline antibiotics

Authors:
  • NBNicholas R. Bachur
    Nicholas R. Bachur
  • MSMalcolm Steele
    Malcolm Steele
  • WMW. Delano Meriwether
    W. Delano Meriwether
  • RHRobert C. Hildebrand
    Robert C. Hildebrand
Publisher website
Google Scholar
Abstract
Alterations in the C-9 side chain of the anthracycline antibiotics, adriamycin and daunorubicin, have a profound effect on antibiotic uptake and accumulation by cultured L1210 cells. The degree of inhibition of DNA and RNA biosynthesis in the L1210 cells is directly related to the cellular uptake and accumulation of the drug analogues. Polar drug metabolites, daunorubicinol and adriamycinol, retain inhibitory activity against nucleic acid metabolism but have a decreased membrane binding and permeability. Cellular uptake and accumulation of the C-9 analogues are inversely related to drug polarity. We propose that the polarity of the anthracycline analogues contributes heavily to the differences in therapeutic index and in vivo activity through fundamental effects on membrane permeability, metabolism, and macromolecular binding.