BB-10010 MIP-1-ALPHA IN-VIVO MAINTAINS HEMATOPOIETIC RECOVERY FOLLOWING REPEATED CYCLES OF SUBLETHAL IRRADIATION/

Macrophage inflammatory protein-alpha (MIP-1 alpha) is an inhibitor of stem cell proliferation affording protection against damage from agen ts that express their cytotoxicity specifically in the DNA synthesis p hase of the cell cycle. Its ability also to modify the self-renewal ca pacity 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 cycl e. Such non-cell cycle-active cytotoxic agents are used clinically in repeated treatment regimens, which are often limited or terminated bec ause of accumulating haemopoietic damage. BB-10010, a non-aggregating variant of MIP-1 alpha, was administered as a continuous dose (1600 mu g 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 afte r 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 tw o cycles the marrow-repopulating ability (MRA) was also measured. In t he control bone marrow (no BB-10010) CFU-S fell to <1% of normal withi n 1 day of irradiation and recovered to 40% at 14 days. Repeated treat ments increased the level of damage, and after four cycles CFU-S recov ered to only 10% of normal. BB-10010 afforded little benefit in the fi rst treatment cycle, but by the end of the fourth cycle CFU-S still re covered to 35% of normal. MRA was reduced to 7% of normal by the irrad iation protocol - about half that maintained by BB-10010 protection. W e conclude that BB-10010 (MIP-alpha) reduces the degree of accumulated haemopoietic stem cell damage following repeated non-cell cycle-speci fic cytotoxic insults - a principle which should be valuable in repeat ed clinical cytotoxic therapy regimens.