Preclinical assessment of purging with VP-16-213: key role for long- term
marrow cultures
BH Kushner, JH Kwon, SC Gulati and H Castro-Malaspina
An evaluation of the effects of VP-16 on normal human marrow cells and
representative lymphoma-leukemia cell lines was performed to assess this
agent's applicability to ex vivo marrow purging. Tumoricidal dose curves
were defined using malignant lymphoid (SK-DHL2 and Reh) and myeloid (HL-60)
cells admixed with a 20-fold excess of irradiated marrow cells to simulate
a borderline remission marrow. One-hour treatments yielded ID50 of less
than 5 mumol/L of VP-16 for clonogenic units from each cell line;
rare-to-zero clonogenic units survived exposure to 50 to 100 mumol/L.
CFU-Mix, BFU-E, and CFU-GM were equal in their sensitivity to VP-16
(ID50s25 to 30 mumol/L). Marrows treated with 75 mumol/L were completely
depleted of these colony-forming cells but produced CFU-GM in one-stage
long-term marrow cultures (LTMCs). This dose had little adverse effect on
the proliferative capacity of marrow stromal progenitors, as measured by
CFU-F (ID50 271 mumol/L) and by the unperturbed development of adherent
layers in LTMCs. Furthermore, these stromal layers were able to support
hematopoiesis as well as controls in co-culture experiments with autologous
marrow cells (two-stage LTMCs). In conclusion, doses of VP-16 that cleanse
marrow of lymphoma-leukemia cells spare hematopoietic and stromal
progenitors as demonstrated by LTMCs. These data favor the use of VP-16 in
the clinical autotransplant setting.
Volume 69,
Issue 1,
pp. 65-71,
01/01/1987
Copyright © 1987 by The American Society of Hematology
