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 Wassermann, K. Articles by Rose, K. M. Search for Related Content PubMed PubMed Citation Articles by Wassermann, K. Articles by Rose, K. M.

Selective Inhibition of Human Ribosomal Gene Transcription by the Morpholinyl Anthracyclines Cyanomorpholinyl- and Morpholinyldoxorubicin¹

Department of Medical Oncology [K. W., F. M. D., R. A. N.]; Department of Laboratory of Medicine [T. D. M.], The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Texas 77030; and Department of Pharmacology [K. M. R.], University of Texas Medical School, Houston, Texas 77225

Upon incubation of cultured mammalian cells with the new anthracycline analogues cyanomorpholinyldoxorubicin and morpholinyldoxorubicin, nucleoli irreversibly segregate into their substructures which form individual portions of the nucleolar mass and characteristic electrondense components adjacent to the nucleolonema; these changes in nucleolar ultrastructure are similar to those produced by actinomycin D (AMD). In the present study we have examined the effects of anthracycline analogues on RNA synthesis, localization of RNA polymerase I in situ, and activity of RNA polymerases in vitro, and compared these effects with those of the parent compound doxorubicin (DOX) and AMD. The results show that, following treatment with cyanomorpholinyldoxorubicin, morpholinyldoxorubicin, and AMD, but not DOX, RNA polymerase I-containing transcription complexes were reduced, reflecting the transcriptional activity of the rRNA genes. The residual RNA polymerase-containing entities were redistributed into cap-like aggregates at the nucleolar periphery. Within 30 min of exposure to cyanomorpholinyldoxorubicin, morpholinyldoxorubicin, and AMD, but not DOX, a 75–90% inhibition of RNA polymerase I activity in situ and in vitro was observed. At this early time there was no significant inhibition of nucleoplasmic RNA labeling in situ or RNA polymerases II and III activities in vitro. At later times following reincubation in drug-free medium, inhibition of all three polymerases was observed. Impairment of RNA synthesis appeared to result from drug interaction with the DNA template rather than an interaction with RNA polymerase I itself. We conclude that the morpholinyl derivatives of DOX are preferential inhibitors of ribosomal gene transcription and that they may have a mechanism of action similar to that of AMD on rRNA synthesis.

¹ Supported by the Danish Medical Research Council Grant 12-5217 (to K. W.), in part by a National Cancer Institute Career Development Award, K04 CA 01135 (to R. A. N.), and by USPHS Grant GM 33442 (to K. M. R.).

² Present address: Laboratory of Molecular Pharmacology, National Cancer Institute, Building 37, Room 5A-19, NIH, 9000 Rockville Pike, Bethesda, MD 20892.

³ To whom requests for reprints should be addressed, at Department of Medical Oncology, Box 52, The University of Texas M. D. Anderson Hospital, 1515 Holcombe Blvd., Houston, TX 77030.

⁴ Present address: Biotechnology Division, 219 CPL, Phillips Petroleum Company, Bartlesville, OK 74004.

⁵ Present address: Division of Immunology, Box 3839, Duke University Medical Center, Durham, NC27710.

Received 10/26/87. Revised 3/ 9/88. Accepted 4/15/88.