Protective effects of BB-10010 treatment on chemotherapy-induced neutropenia in mice

Chemotherapy-induced neutropenia is a major dose-limiting factor in the man agement of cancer patients. Most chemotherapeutic agents are active against proliferating cells, interfering with DNA replication and/or mitosis. A nu mber of chemokines, notably macrophage inflammatory protein-1 alpha [MIP-1 alpha], have been reported to induce cell-cycle arrest in immature hematopo ietic progenitors, raising the possibility that chemokines, such as MIP-1 a lpha, could be used to reduce or even eliminate the hematologic toxicity of cycle-active chemotherapy, We tested the effectiveness of BB-10010 [a gene tically engineered analog of human MIP-1 alpha] in vivo against three diffe rent cytotoxic drugs [cyclophosphamide (Cy), 5-fluorouracil (5-FU) and cyto sine arabinoside (Ara-C)] commonly used in cancer therapy. BB-10010 treatme nt reduced the toxicity of all three agents, though the precise mode of pro tection varied with the cytotoxic drug used. BB-10010 reduced the neutropen ic interval in Cy-treated mice without affecting the neutropenic nadir, whe reas the absolute neutrophil counts [ANC] of both 5-FU and Ara-C treated mi ce were significantly higher throughout the neutropenic interval for mice r eceiving BB-10010 prior to chemotherapy. These findings indicate that the a bility to manipulate the cell cycle of hematopoietic progenitors with chemo kines, such as BB-10010/MIP-1 alpha and other negative regulators, may be e xploited to reduce chemotherapy-induced neutropenia; furthermore, the fact that BB-10010 is effective against several different cytotoxic agents is ca use for guarded optimism that this approach may be generally applicable, an d, once optimized for patient use, may prove to be of significant clinical benefit. (C) 1999 International Society for Experimental Hematology. Publis hed by Elsevier Science Inc.