Mechanism of natural resistance to N6-(delta2-isopentenyl)adenosine in cultured cells.
Twenty-one cell lines (six human lines, and nine mouse lines) were compared with respect to inhibition of growth by N-6-(delta-2-isopentenyl)adenosine (IPAR). Six of these, mouse Sarcoma 180, Ehrilich ascites carcinoma, mammary adenocarconoma (TA3), leukemia L1210, mouse kidney, and canine kidney cells, differed by up to 16-fold with respect to their sensitivity and were chosen for further study. One factor contributing to the resistance was a slower formation of intracellular 5-monophosphate of IPAR (IPAMP) due to reduced adenosine kinase activity. Because of this slower formation of IPAMP in the resistant cells, a higher extracellular IPAR was required for the maintenance of equal intracellular IPAMP levels. Regardless of the degree of resistance, the rate of decay of intracellular IPAMP was similar and very rapid, with a half-life of 37 plus or minus 5 min. In the sensitive cells IPAMP was cleaved back to IPAR, while in the resistant cells IPAR was cleaved further to the free base, N-6-(delta-2-isopentenyl)adenine (IPA), which accumulated in the medium. The rate of formation of IPA constitutes an irreversible inactivation of IPAR, because IPA is not converted back to IPAMP and is not growth inhibitory. In one of the resistant cells (mouse kidney) the inactivation was so rapid that in 1 hr 25% of the extracellular (30 muM) IPAR was converted to IPA.
D000230:Adenocarcinoma; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor; D002460:Cell Line; D002478:Cells, Cultured; D002854:Chromatography, Paper; D004351:Drug Resistance; D006801:Humans; D007668:Kidney; D007939:Leukemia L1210; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D010430:Pentosyltransferases / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D012510:Sarcoma 180; D014316:Tritium
D000475:Alkenes; D010710:Phosphates; D014316:Tritium; D010430:Pentosyltransferases; D010770:Phosphotransferases; D000241:Adenosine