Protective effects of BB-10010 treatment on chemotherapy-induced neutropenia in mice.
Chemotherapy-induced neutropenia is a major dose-limiting factor in the management of cancer patients. Most chemotherapeutic agents are active against proliferating cells, interfering with DNA replication and/or mitosis. A number of chemokines, notably macrophage inflammatory protein-1 alpha [MIP-1alpha], have been reported to induce cell-cycle arrest in immature hematopoietic progenitors, raising the possibility that chemokines, such as MIP-1alpha, could be used to reduce or even eliminate the hematologic toxicity of cycle-active chemotherapy. We tested the effectiveness of BB-10010 [a genetically engineered analog of human MIP-1alpha] in vivo against three different cytotoxic drugs [cyclophosphamide (Cy), 5-fluorouracil (5-FU) and cytosine arabinoside (Ara-C)] commonly used in cancer therapy. BB-10010 treatment reduced the toxicity of all three agents, though the precise mode of protection varied with the cytotoxic drug used. BB-10010 reduced the neutropenic interval in Cy-treated mice without affecting the neutropenic nadir, whereas the absolute neutrophil counts [ANC] of both 5-FU and Ara-C treated mice were significantly higher throughout the neutropenic interval for mice receiving BB-10010 prior to chemotherapy. These findings indicate that the ability to manipulate the cell cycle of hematopoietic progenitors with chemokines, such as BB-10010/MIP-1alpha and other negative regulators, may be exploited to reduce chemotherapy-induced neutropenia; furthermore, the fact that BB-10010 is effective against several different cytotoxic agents is cause for guarded optimism that this approach may be generally applicable, and, once optimized for patient use, may prove to be of significant clinical benefit.
Western Pennsylvania Cancer Institute, Pittsburgh 15224-2207, USA.
G L
GL
Gilmore
D K
DK
DePasquale
R K
RK
Shadduck
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000276:immunology; D004336:Drug Antagonism; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins