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Enhanced Levels and Enhanced Clonogenic Capacity of Blood Progenitor Cells Following Administration of Stem Cell Factor Plus Granulocyte Colony-Stimulating Factor to Humans
C.G. Begley,
R. Basser,
R. Mansfield,
B. Thomson,
W.R.L. Parker,
J. Layton,
B. To,
J. Cebon,
W.P. Sheridan,
R.M. Fox, and
M.D. Green
From the Centre for Developmental Cancer Therapeutics, affiliates: The Walter and Eliza Hall Institute of Medical Research; Rotary Bone Marrow Research Laboratories; The Royal Melbourne Hospital; Austin and Repatriation Medical Centre; Western Hospital; Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria; Hanson Centre IMVS, Adelaide; Amgen, Kew, Australia; and Amgen Thousand Oaks, CA.
Administration of hematopoietic growth factors is being used increasingly to obtain populations of blood progenitor/stem cells (PBPC) for clinical transplantation. Here we examined the effect of combining stem cell factor (SCF ) and granulocyte colony-stimulating factor (G-CSF ) versus G-CSF alone in a randomized clinical study involving 62 women with early-stage breast cancer. In the first patient cohorts, escalating doses of SCF were administered for 7 days with concurrent G-CSF administration. At baseline, levels of progenitor cells in the bone marrow or blood were comparable in the different patient groups. As with administration of G-CSF alone, the combination of SCF plus G-CSF did not alter the wide variation in levels of PBPC observed between individuals and did not alter the selective nature of PBPC release, with preferential release of day-14 granulocyte-macrophage colony-stimulating factor (GM-CFC) versus day-7 GM-CFC. However, SCF acted to sustain the levels of PBPC after cessation of growth factor treatment; levels of PBPC were elevated 100-fold at later timepoints compared with G-CSF alone. In addition, the maximum levels of PBPC observed were increased approximately fivefold at day 5 of growth-factor administration. The increased levels of PBPC resulted in significantly increased levels of PBPC obtained by leukapheresis. In a subsequent patient cohort, 3-days pretreatment with SCF was introduced and followed by 7 days concurrent SCF plus G-CSF. The 3-days pretreatment with SCF resulted in an earlier wave of PBPC release in response to commencement of G-CSF. In addition, maximum PBPC levels in blood and PBPC yield in leukapheresis products were further increased. Unexpectedly however, SCF pretreatment resulted in progenitor cells with enhanced self-generation potential. Recloning assays documented the ability of approximately 30% of primary granulocyte-macrophage (GM) colonies from control cell populations to generate secondary GM colonies (n = 1,106 primary colonies examined). In contrast approximately 90% of GM colonies from PBPC after SCF pretreatment generated secondary clones and 65% generated secondary colonies. The action of SCF was not explicable in terms of altered SCF, GM-CSF, or G-CSF responsiveness, but SCF pretreatment was associated with maximum serum SCF levels at the time G-CSF was commenced. These results show that PBPC populations mobilized by different growth factor regimens can differ in their functional properties and caution against solely considering number of harvested progenitor cells without regard to their function.
Blood, Vol. 90 No. 9 (November 1), 1997:
pp. 3378-3389
© 1997 by The American Society of Hematology.
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