Genetic variability in the response of normal murine hematopoietic progenitor cells to photochemical purging

Abstract

Abstract The photosensitizer, Merocyanine 540 (MC540) is currently undergoing phase I/II clinical evaluation as a purging agent for autologous stem cell grafts from patients with AML, ALL, CML, HD, and NHL. The preclinical data that provide the basis for these trials were mostly conducted in or with cells from B6D2F1 and B6AF1 mice. These experiments indicated that combinations of MC540 and light that deplete leukemia cells by 5–8 log deplete granulocyte/macrophage progenitors (CFU-GM) and the radio-protective capacity of bone marrow cells by about 1 log. We have recently shown that hematopoietic cells from 129 mice are substantially less sensitive to MC540-purging than cells from B6D2F1, B6AF1, and C57BL/6 mice. For instance, a combination of MC540 and light that depletes CFU-GM from C57BL/6mice 7.9 fold, depletes CFU-GM from 129 and B6129F1 mice merely 1.4-fold and 2-fold, respectively. This marked difference in photosensitivity cannot be explained by strain-specific differences in the ratio of photosensitive granulocye (CFU-G to photoresistant macrophage (CFU-M) progenitors, as the same rank order of sensitivity is also observed among unipotent CFU-G and CFU-GM as well as among erythroid progenitors from 129, B6129F1, and C57BL/6 mice.Flow cytometric binding studies show increased binding of MC540 to bone marrow cells from C57BL/6 mice, suggesting that the greater photosensitivity of C57BL/6 cells is at least in part attributable to a greater expression of MC540 binding sites in C57BL/6 marrow cells. These findings have obvious implications for the preclinical and clinical evaluation of merocyanines and related purging agents. They also suggest new experimental approches for investigations into the genetic control of photosensitivity.