This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Egorin, M. J. Articles by Bachur, N. R. Search for Related Content PubMed PubMed Citation Articles by Egorin, M. J. Articles by Bachur, N. R.

Cellular Pharmacology of N,N-Dimethyl Daunorubicin and N,N-Dimethyl Adriamycin

Laboratory of Clinical Biochemistry, Baltimore Cancer Research Program, Division of Cancer Treatment, National Cancer Institute, NIH, Baltimore, Maryland 21201

The cellular accumulation and disposition of the anthracycline antibiotics daunorubicin (DNR) and Adriamycin (ADR) were compared to those of their N,N-dimethyl derivatives. The cellular accumulation of N,N-dimethyl daunorubicin (DMD) was greater than that of N,N-dimethyl adriamycin (DMA) which was greater than the accumulation of DNR or ADR. DNR- and ADR-resistant P388 murine leukemia cells accumulated less of each drug than did DNR- and ADR-sensitive P388 murine leukemia cells. The presence of 15% fetal bovine serum in the incubation medium did not affect the accumulation of DNR, increased the accumulation of DMD by 20 to 25%, and reduced that of ADR and DMA by 20 to 25%. Lowered temperature (0°) reduced the intracellular accumulation of all four drugs. Sodium azide (10 mM) did not alter the cellular accumulation of DNR or ADR but reduced the intracellular content of DMD and to a lesser extent that of DMA. The loss of all four drugs from cells placed in drug-free medium was greatly reduced at 0° compared to 37°. Sodium azide (10 mM) increased the efflux of DMD but did not affect that of DNR, ADR, or DMA. Unlike intact L1210 cells, isolated nuclei accumulated more ADR than DNR and more DMA than DMD. The nuclear accumulation of DMA >ADR >DMD >DNR. Nuclear accumulation of all four drugs reached equilibrium by 10 to 30 min and was the same at 0° and 37°. All four drugs were lost from nuclei placed into drug-free buffer, and this loss was reduced at 0°. DMD and DMA were nuclearly localized as were DNR and ADR. All four drugs produced dose-dependent inhibition of [³H]uridine incorporation, and DMD and DMA inhibited DNR- and ADR-resistant P388 cells to the same degree as they did DNR- and ADR-sensitive P388 cells. DNR and ADR inhibited [³H]thymidine incorporation more than [³H]-uridine incorporation, whereas DMD and DMA inhibited these processes to the same degree.

¹ To whom requests for reprints should be addressed.

Received 7/10/79. Accepted 3/10/80.