PMID- 10089064 OWN - NLM STAT- MEDLINE DCOM- 19990527 LR - 20131121 IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 17 IP - 4 DP - 1998 Dec TI - Aclarubicin inhibits etoposide induced apoptosis through inhibition of RNA synthesis in P388 murine leukemic cells. PG - 435-42 AB - It has been reported that aclarubicin inhibits etoposide (VP-16) induced cytotoxicity in human lung cancer cell lines (1, 2). However, it still remains unclear how aclarubicin (ACR) inhibits etoposide-induced cytotoxicity. We report here that the combination of ACR and VP-16 showed antagonistic cytotoxic effect in P388 murine leukemic cells. DNA unwinding assay showed that 1000 ng/ml ACR significantly reduced VP-16 induced early DNA double strand(ds) breaks compared to that of VP-16 alone at a concentration of 10 microM. However, ACR did not inhibit VP-16 induced early DNA double strand breaks at a concentration of 100 ng/ml, a clinically achievable concentration. Furthermore, DNA repair occurred within two hours after removing VP-16 even if ACR was co-cultured at concentrations of 100 and 1000 ng/ml. DNA agarose gel electrophoresis and detection of sub-G1 fraction by flowcytometer showed that 100 ng/ml of ACR inhibited VP-16 induced DNA ladder formation and formation of sub-G1 fraction. Radioactive precursor incorporation studies showed that VP-16 inhibited DNA synthesis rather than RNA synthesis. On the other hand, ACR selectively inhibited RNA synthesis at a concentration of 100 ng/ml. The VP-16 induced increment of [3H]-L-leucine uptake was canceled by addition of 100 ng/ml of ACR. These data suggest that ACR inhibited VP-16 induced apoptosis by the inhibition of RNA synthesis along with protein synthesis, but not early DNA double strand breaks and DNA repair at a concentration of 100 ng/ml in P388 murine leukemic cells. FAU - Nagata, T AU - Nagata T AD - Dept. of Pediatrics, Mie University School of Medicine, Tsu-city, Japan. FAU - Higashigawa, M AU - Higashigawa M FAU - Shimono, Y AU - Shimono Y FAU - Cao, D C AU - Cao DC FAU - Yan Mao, X AU - Yan Mao X FAU - M'soka, T AU - M'soka T FAU - Inamochi, H AU - Inamochi H FAU - Hori, H AU - Hori H FAU - Kawasaki, H AU - Kawasaki H FAU - Sakurai, M AU - Sakurai M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (DNA, Neoplasm) RN - 0 (Neoplasm Proteins) RN - 0 (Nucleic Acid Synthesis Inhibitors) RN - 0 (RNA, Neoplasm) RN - 6PLQ3CP4P3 (Etoposide) RN - 74KXF8I502 (Aclarubicin) SB - IM MH - Aclarubicin/*pharmacology MH - Animals MH - Antibiotics, Antineoplastic/*pharmacology MH - *Apoptosis MH - DNA Damage/drug effects MH - DNA, Neoplasm/biosynthesis/drug effects MH - Drug Interactions MH - Etoposide/*pharmacology MH - Flow Cytometry MH - G1 Phase/drug effects MH - Leukemia P388/genetics/*pathology MH - Mice MH - Neoplasm Proteins/biosynthesis/drug effects MH - Nucleic Acid Synthesis Inhibitors/*pharmacology MH - RNA, Neoplasm/*biosynthesis/drug effects MH - Tumor Cells, Cultured EDAT- 1999/03/24 00:00 MHDA- 1999/03/24 00:01 CRDT- 1999/03/24 00:00 PHST- 1999/03/24 00:00 [pubmed] PHST- 1999/03/24 00:01 [medline] PHST- 1999/03/24 00:00 [entrez] PST - ppublish SO - J Exp Clin Cancer Res. 1998 Dec;17(4):435-42.