Effects of L-phenylalanine mustard and L-buthionine sulfoximine on murine and human hematopoietic progenitor cells in vitro

The effects of L-buthionine sulfoximine (L-BSO) and L-phenylalanine mustard (L-PAM), alone and in combination, on human and murine marrow were explored using in vitro clonogenic assays to establish whether enhanced myelotoxicity might limit the clinical utility of this potent chemotherapeutic combination. One-h exposure to L-PAM produced significant concentration-dependent colony inhibition, with 70% inhibitory concentration (IC70) values ranging from 4.5 to 7.2 microM for all hematopoietic progenitors assayed. The combination of L-PAM plus 4500 microM L-BSO for 1 h did not effectively alter the IC70 values derived for L-PAM alone. In studies where marrow cells were pretreated with L-BSO for 4 h and then L-PAM for 1 additional h, the IC70 values were decreased in both murine and human marrow progenitors compared to the L-PAM control, suggesting modest potentiation of myelotoxicity. The potentiation is not so significant as to preclude human studies with this combination. One- to 5-h exposure of marrow cells from both species to 4500 microM L-BSO was only mildly myelotoxic, producing colony reductions of 22-49%. However, continuous exposure to L-BSO produced concentration-dependent colony inhibition, with IC70 values of 70, 84, and 43 microM for murine colony-forming units-granulocyte/macrophage, blast-forming units-erythroid, and colony-forming unit-erythroid, respectively.