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 Slocum, H. K. Articles by Hakala, M. T. Search for Related Content PubMed PubMed Citation Articles by Slocum, H. K. Articles by Hakala, M. T.

Mechanism of Natural Resistance to N⁶-(²-Isopentenyl)adenosine in Cultured Cells¹

Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14203

Twenty-one cell lines (six human lines, nine mouse lines) were compared with respect to inhibition of growth by N⁶-(²-isopentenyl)adenosine (IPAR). Six of these, mouse Sarcoma 180, Ehrlich ascites carcinoma, mammary adenocarcinoma (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 ± 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, N⁶-(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 µM) IPAR was converted to IPA.

¹ Supported in part by Grant Ca-04175 of the USPHS.

² Part of this material is derived from the thesis for the degree of Doctor of Philosophy in the Department of Biochemistry, State University of New York at Buffalo. Recipient of Training Grant GM-196001 in Clinical Biochemistry.

Received 7/26/74. Accepted 10/28/74.