Biochemical mode of cytotoxic action of neplanocin A in L1210 leukemic cells.
Neplanocin A, a novel antitumor antibiotic, was investigated to determine the biochemical mode(s) of its cytotoxic action. The molecule is an adenosine analogue with a unique cyclopentane structure in its ribose moiety. Both sublines of L1210 and P388 leukemia resistant to neplanocin A were cross-resistant in vitro to bredinin and 9-beta-D-arabinofuranosyladenine, which have been reported to be activated by adenosine kinase. The adenosine kinase activity was markedly reduced in the resistant sublines as compared with that of the respective sensitive lines. Furthermore, neplanocin A competitively inhibited the phosphorylation reaction of adenosine in a cell-free system. The results indicate that neplanocin A is activated by adenosine kinase. Regarding the target site for neplanocin A, the antibiotic suppressed RNA synthesis to a significantly greater extent than DNA synthesis. This RNA-preferential effect is unique among common antimetabolic antitumor agents.
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000248:Adenosine Kinase / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004351:Drug Resistance; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology; D007941:Leukemia P388 / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D012334:RNA, Neoplasm / Q000096:biosynthesis
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; C031096:neplanocin A; D000248:Adenosine Kinase; D000241:Adenosine