The chemokine CCL21 protects normal marrow progenitors from Ara-C cytotoxicity.
OBJECTIVE
Chemokines are a family of small proteins that regulate leukocyte infiltration into inflamed tissue and play key roles in the pathogenesis of many diseases. Some chemokines can also reversibly inhibit the proliferation of hematopoietic progenitors. We have previously found that the chemokine CCL21 (Exodus-2/SLC/6Ckine/TCA4) is a potent inhibitor of the proliferation of normal hematopoietic progenitors. In this study we sought to determine whether this inhibition of proliferation could be therapeutically exploited by protecting normal marrow progenitors from the cytotoxicity of the S phase-active chemotherapeutic agent Ara-C.


METHODS
Untreated and CCL21-pretreated mice were given doses of Ara-C that are toxic to marrow myeloid progenitors. The recovery of these myeloid progenitors was analyzed by colony formation assays.


RESULTS
It was found that pretreatment with small doses of CCL21 prevented the death of normal murine marrow progenitors from the toxic effects of Ara-C.


CONCLUSIONS
The chemokine CCL21 may be able to prevent Ara-C myelosuppression during acute leukemia induction chemotherapy, and thereby decrease morbidity and mortality of such therapy, and shorten hospital stays.
Hromas
Robert
R
Hematology/Oncology, Biochemistry/Molecular Biology, and the Walther Oncology Center, Indiana University Medical Center, R4-202, 1044 W. Walnut St., Indianapolis, IN 46202, USA. rhromas@iupui.edu
Cooper
Scott
S
Broxmeyer
Hal E
HE
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000627:therapeutic use*; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D051379:Mice; D016196:S Phase / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D003561:Cytarabine