Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1 alpha in vivo.
The proliferative status of the stem cell compartment is thought to be controlled by both positive and negative regulators of proliferation. These regulators have obvious clinical potential in manipulating the integrity and proliferative status of the stem cell in vivo during patient treatment for neoplastic disease. We have tested the ability of the human recombinant homologue of murine macrophage inflammatory protein-1 alpha (rhMIP1 alpha) to suppress the proliferation of primitive murine progenitors in vitro and in vivo. This recombinant protein (stem cell inhibitor, similar to the human homologue of MIP 1 alpha, LD78) is active in a dose-dependent manner in vitro on CFU-S measured at day 12 and to a slightly lesser extent on the more mature CFU-S that are measured at day 8. SCI/rhMIP1 alpha is also active in vivo in two separate models of bone marrow regeneration in which the high proliferative status of the CFU-S compartment is reduced to the quiescent state with a single inoculation of SCI/rhMIP1 alpha. The inhibitory activity of the recombinant protein was then tested in a relevant therapeutic model in which the observed protection of part of the stem cell compartment is reflected by a significant improvement in the kinetics of neutrophil recovery. These results establish the feasibility of testing SCI/rhMIP1 alpha in a range of chemotherapy regimes as a preliminary to clinical trials to attempt to protect the stem cell compartment during treatment for neoplastic disease.
Dunlop
D J
DJ
CRC Beatson Laboratories, Bearsden, Glasgow.
Wright
E G
EG
Lorimore
S
S
Graham
G J
GJ
Holyoake
T
T
Kerr
D J
DJ
Wolpe
S D
SD
Pragnell
I B
IB
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002999:Clone Cells; D003561:Cytarabine / Q000633:toxicity; D016207:Cytokines / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D019402:Macrophage Inflammatory Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D015846:Monokines / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011994:Recombinant Proteins; D003561:Cytarabine