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Cellular Pharmacokinetics of Mercaptopurine in Human Neoplastic Cells and Cell Lines

Pediatric Branch [S. Z., G. E. J., D. G. P.], and Division of Cancer Treatment [B. A. C.], National Cancer Institute, NIH, Bethesda, Maryland 20205

The accumulation, metabolism, and retention of mercaptopurine (MP) was studied in four human neoplastic cell lines (three acute leukemia lines Molt-4, CCRF-CEM, and HL-60; and one Burkitt's lymphoma line, Wilson), each of which was sensitive to MP. Two cell lines resistant to MP (Wilson^R and CCRF-CEM^R) were also studied. The cell lines were incubated for 3 h in 10 µM [¹⁴C]MP and then placed in drug-free media for an additional 3 h. Cell samples were obtained at regular intervals, and the intracellular MP metabolites were measured in the acid-soluble fractions by anion-exchange high-pressure liquid chromatography. MP accumulated progressively within cells during the 3-h drug exposure period and declined rapidly when the cells were placed in drug-free media. Over 80% of the intracellular MP was present in the form of three nucleotide metabolites, MP ribose monophosphate, thioxanthosine monophosphate, and thioguanosine monophosphate. MP ribose monophosphate was found in greatest amount, accounting for 59–85% of the intracellular metabolite pool. Thioxanthosine monophosphate thioguanosine monophosphate were detected in lesser amounts. Study of leukemic cells obtained from patients demonstrated a similar pattern of MP accumulation, metabolism, and retention, although the overall amounts of the various metabolites formed were less. In contrast, there was essentially no MP nucleotide metabolite formation in the two MP-resistant cell lines. A more complete understanding of the cellular pharmacokinetics of MP in human neoplastic cells is likely to lead to a more rational use of the drug in the clinical setting.

¹ To whom requests for reprints should be addressed, at Room 13C-118, Building 10, Pediatric Branch, National Cancer Institute, NIH, Bethesda, MD 20205.

Received 1/ 9/85. Revised 4/ 9/85. Accepted 5/21/85.

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