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Biological and Biochemical Differences between Tubercidin (7-Deazaadenosine) and Its 5'-Phosphate Methyl Ester¹

Research Laboratories, The Upjohn Company, Kalamazoo, Michigan 49001

On a molar basis, tubercidin (Tu) was about 20 times more cytotoxic than the methyl ester of tubercidin 5'-phosphate (MepTu) when KB cells were exposed to the drugs for 1 hr. In contrast, the drugs were about equitoxic when they were in contact with cells for 72 hr. The same relationship was seen when the inhibition of DNA synthesis by the drugs was compared after short- and long-term contact of the cells with the drugs.

The delayed cytotoxicity of MepTu toward mammalian cells was mostly due to the slow rate of hydrolysis of MepTu to Tu. The serum in the medium was responsible for most of the hydrolysis while intact KB cells and L1210 cells themselves had less hydrolytic activity.

The rates of hydrolysis of MepTu by serum of different animal species are described. Human serum had low hydrolytic capacity while mouse serum was highly active. The amount of MepTu taken up by blood cells was proportional to the percentage of hydrolysis of MepTu to Tu.

Both Tu and MepTu (after hydrolysis to Tu) were present in the acid-soluble pool as Tu phosphates and were incorporated into RNA and to a much lesser extent into DNA.

¹ This study was supported in part by Contract PH43-68-1023 with Chemotherapy, National Cancer Institute, NIH, Bethesda, Md. 20014.

² Present address: The Squibb Institute for Medical Research, New Brunswick, N. J. 08903.

Received 11/ 2/70. Accepted 7/13/71.