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Selective Reduction of Intracellular Guanosine 5'-Triphosphate Pool by 4-Carbamoylimidazolium 5-Olate in Murine Tumor Cells¹

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-Ikebukuro, Toshima-ku, Tokyo 170, Japan

Ehrlich carcinoma and P388 leukemia cells were rendered resistant to 4-carbamoylimidazolium 5-olate (SM-108), and assessments were made of biochemical and pharmacological determinants for the sensitivity to SM-108 using both sensitive and resistant sublines.

We observed that the treatment of cells with SM-108 in vitro caused a remarkable decrease in the intracellular guanosine 5'-triphosphate pool level in sensitive but not in resistant sublines.

There was no difference in the ability to take up SM-108 between sensitive and resistant sublines, but the cellular conversion of SM-108 to its nucleotide, which is the putative active anabolite of SM-108, proceeded only in sensitive sublines.

Enzymological studies revealed that the activity of adenine phosphoribosyltransferase (EC 2.4.2.7), which is believed to conjugate SM-108 with 5-phospho--D-ribose 1-diphosphate, was very low in the resistant sublines.

These results strongly support our previous hypothesis that SM-108 is activated by adenine phosphoribosyltransferase to SM-108-nucleotide which then inhibits hypoxanthine-5'-monophosphate dehydrogenase (EC 1.2.1.14), a key enzyme for the de novo synthesis of guanosine 5'-monophosphate.

¹ This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture, Japan.

² Present address: Sumitomo Pharmaceuticals Co., Ltd., 2-1, Takatsukasa 4-chome, Takarazuka, Hyogo 665, Japan.

³ To whom requests for reprints should be addressed.

Received 6/11/85. Revised 9/ 3/85. Accepted 9/12/85.