BB-10010/MIP-1 alpha in vivo maintains haemopoietic recovery following repeated cycles of sublethal irradiation.

Abstract

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) is an inhibitor of stem cell proliferation affording protection against damage from agents that express their cytotoxicity specifically in the DNA synthesis phase of the cell cycle. Its ability also to modify the self-renewal capacity of the regenerating cells is now shown to improve and maintain haemopoietic recovery following therapy (sublethal irradiation) whose cytotoxic damage is not limited solely to the DNA-S phase of this cycle. Such non-cell cycle-active cytotoxic agents are used clinically in repeated treatment regimens, which are often limited or terminated because of accumulating haemopoietic damage. BB-10010, a non-aggregating variant of MIP-1 alpha, was administered as a continuous dose (1600 micrograms kg-1 24 h-1) via a subcutaneously implanted pump over a period of 7 days. A dose of 4.5 Gy total-body gamma-rays was given 3-4 h after implantation. Day 8 and 12 spleen colony-forming units (CFU-S) were assayed on days 1, 7 and 14 after irradiation. This cycle of treatment was repeated four times (total 56 days), and on day 14 of the last two cycles the marrow-repopulating ability (MRA) was also measured. In the control bone marrow (no BB-10010) CFU-S fell to < 1% of normal within 1 day of irradiation and recovered to 40% at 14 days. Repeated treatments increased the level of damage, and after four cycles CFU-S recovered to only 10% of normal. BB-10010 afforded little benefit in the first treatment cycle, but by the end of the fourth cycle CFU-S still recovered to 35% of normal. MRA was reduced to 7% of normal by the irradiation protocol-about half that maintained by BB-10010 protection. We conclude that BB-10010 (MIP-1 alpha) reduces the degree of accumulated haemopoietic stem cell damage following repeated non-cell cycle-specific cytotoxic insults-a principle which should be valuable in repeated clinical cytotoxic therapy regimens.