Macrophage Inflammatory Protein 1 a Attenuates the Toxic Effects of Temozolomide in Human Bone Marrow Granulocyte-Macrophage Colony-forming Cells 1

Macrophage inflammatory protein 1a (MIP-1a) is a chemokine that may act principally by preventing hemopoietic cells from entering G1, thereby attenuating the cytotoxic effects of cell cycle-specific chemotherapeutic agents. Here we examine the effect of MIP-1aon the sensitivity of human granulocyte-macrophage hemopoietic progenitor cells (granulocyte-macrophage colony-forming cells; GM-CFCs) with the cytotoxic effects of antitumor agents that act mainly via alkylation at the O position of guanine in DNA. Mononuclear cell preparations from human bone marrow were used in an in vitro GM-CFC colony-forming assay. The GM-CFC survival from individual patients displayed a range of sensitivities to the methylating agent temozolomide [(Tz) 20–55% survival at 10 mg/ml Tz]. However, in all 16 cases, MIP-1a(50 ng/ml) protected against GM-CFC killing: survival in the presence of MIP-1a ranged from 65– 97% at 10 mg/ml Tz, with GM-CFCs being 1.5–4.5-fold more resistant than control cells from the same patient. The highest levels of protection were seen in the GM-CFCs with the highest sensitivity in the absence of MIP-1a. Similar degrees of protection were seen for the methylating agent streptozotocin, but no protection was detected for the chloroethylating agents carmustine or mitozolomide in the samples for which there was protection against the toxic effects of Tz. Whereas the mechanism of this effect remains to be established, the results may have potential immediate clinical application in the attenuation of hematological toxicity after administration of methylating antitumor agents.