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L-Phenylalanine Mustard (Melphalan) Uptake and Cross-Linking in the RPMI 6410 Human Lymphoblastoid Cell Line¹

McEachern Laboratory and Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

L-Phenylalanine mustard (melphalan) induced a time- and concentration-dependent arrest of cycling RPMI 6410 cells in the G₂ phase of the cell cycle as evidenced by flow cytofluorometry. A melphalan exposure of 1 µg/ml for 1 hr caused a temporary G₂ blockage which was overcome by 48 hr. Higher concentrations or longer exposures lead to irreversible blockages. Melphalan caused DNA cross-linking which was monitored by the alkaline elution method. The cross-linking was shown to be between DNA and protein. The degree of DNA cross-linking increased for approximately 4 hr after a 1-hr drug exposure of 1 µg/ml. At 36 to 48 hr after the drug exposure, the cells overcame the G₂ block and were dividing. The DNA cross-links have apparently been repaired as they are no longer detected by alkaline elution. The extent of melphalan cross-linking was dependent on both drug dosage and exposure time. Using a culture medium lacking amino acids, it was shown that melphalan uptake into RPMI 6410 cells was inhibited by leucine, isoleucine, or glutamine. The increased uptake of melphalan and the increased cross-linking in amino acid-deficient media were reduced by readdition of the aforementioned amino acids.

¹ This work was supported by the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed.

Received 10/29/79. Accepted 1/15/80.

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