Metabolism and action of neplanocin A in Chinese hamster ovary cells.
Neplanocin A is a naturally occurring carbocyclic analog of adenosine which contains a cyclopentene moiety in place of ribose and has demonstrated antitumor and antimicrobial activity. This compound was highly toxic to Chinese hamster ovary (CHO) cells; the approximate minimum inhibitory concentration of neplanocin A for inhibition of clone formation was 0.1 microM. The toxicity of the agent was greatly reduced by prior treatment with adenosine deaminase. [3H]Uridine incorporation into perchloric acid insoluble material in growing cells was inhibited by neplanocin A more dramatically than that of [3H]thymidine or [3H]leucine. Treatment with the drug resulted in a marked depression of ATP pool levels. High pressure liquid chromatographic analysis of cellular nucleotide pools from cells treated with neplanocin A revealed the formation of an apparent drug metabolite (NpcTP) that eluted in the triphosphate region of the chromatographic profile. Treatment of NpcTP with alkaline phosphatase produced a nucleoside with properties similar to neplanocin A. An adenosine-kinase-deficient cell line formed little, if any, NpcTP but demonstrated only slight resistance to the agent. These observations suggest that neplanocin A was efficiently metabolized to the triphosphate level but that this metabolite was responsible for only a fraction of the observed toxicity.
P P
PP
Saunders
M T
MT
Tan
R K
RK
Robins
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000248:Adenosine Kinase / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D009711:Nucleotides / Q000378:metabolism; D010053:Ovary; D012313:RNA / Q000096:biosynthesis
D000903:Antibiotics, Antineoplastic; D009711:Nucleotides; D012313:RNA; C031096:neplanocin A; D000248:Adenosine Kinase; D000241:Adenosine