Cellular pharmacology and antitumor activity of N-(p-azidobenzoyl)-daunorubicin,a photoactive anthracycline analogue |
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| Authors: | Steven D. Averbuch Ronald E. Clawson Nicholas R. Bachur Ronald L. Felsted |
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| Affiliation: | (1) Laboratory of Biological Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Building 37, Room 5D02, 20205 Bethesda, MD, USA;(2) Present address: Medical Chemical Defense R and D Program, U. S. Army Medical R and D Command, Att. 5GRDPLE, 21701 Fort Detrick, Frederick, MD, USA;(3) Clinical Pharmacology Branch, DCT, NCI, National Institutes of Health, Building 10, Room 6N119, 20205 Bethesda, MD, USA |
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| Abstract: | Summary We have previously utilized N-(p-azidobenzoyl)daunorubicin (NABD), a photoactive analogue of daunorubicin (DNR), to identify unique anthracycline-binding polypeptides in rodent tissues and in tumor cells. Using cultured P388 tumor cells, we have now compared the cellular pharmacology and antitumor activity of NABD with that of DNR. Although rapidly accumulated by cells, the intracellular concentration of NABD was less than 20% that of DNR at steady-state levels. The cellular uptake of both drugs by P388 cells was dependent on extracellular drug concentration in the medium and on temperature. The rapid efflux of NABD and DNR from P388 cells in drug-free medium was reduced at lowered temperature (0 °C). Cytofluorescence microscopy demonstrated that NABD was predominantly localized in the cytoplasm, in contrast to the nuclear localization of DNR. NABD produced dose-dependent inhibition of [3H]thymidine (IC50=10.0  M) and [3H]uridine (IC50=1.60 M) incorporation in P388 cells to a lesser degree than DNR ([3H]thymidine, IC50=0.15 M and [3H]uridine, IC50=0.70 M). Continuous exposure to NABD inhibited P388 cell proliferation with an IC50 of 0.27 M, compared with an IC50 of 0.017 M for DNR. NABD is a pharmacologically active, photoactive analogue of DNR, which possesses properties different from those of the parent drug but similar to those of other anthracycline analogues. Photoaffinity labeling studies with NABD may identify important cytoplasmic constitutents which interact with this type of anthracycline and perhaps with the anthracycline antibiotics in general.Abbreviations used NABD N-(p-azidobenzoyl)daunorubicin - DNR daunorubicin - D2 daunorubicinol - NABD2 N-(p-azidobenzoyl)daunorubicinol - dDa 7-deoxydaunorubicin aglycone - dD2a 7-deoxydaunorubicinol aglycone - TLC thin-layer chromatography - HPLC high-pressure liquid chromatography - THF tetrahydrofuran - PBS phosphate-buffered saline - DMSO dimethylsulfoxide |
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