title: Predictive value of colony-forming unit assays for engraftment and leukemia-free survival after transplantation of chemopurged syngeneic bone marrow in rats.
abstract: We evaluated the efficacy of in vitro clonogenic assays for acute myeloid leukemia (AML) (CFU-Leuk) and granulocyte-macrophage progenitor cells derived from normal bone marrow (BM) (CFU-GM) to predict hematopoietic engraftment, median survival time (MST) and leukemia-free survival (LFS) in LBN rats that received injections of untreated or drug-treated AML and/or normal BM cells. Injection of untreated AML cells resulted in a log-linear relationship between AML cell dose and time of death from leukemia; LBN rats given 10(6) cells died with AML (MST, 24 days; range, 19-28) after injection. A minimum of 0.5-1.0 X 10(6) untreated normal BM cells was needed to insure satisfactory hematopoietic reconstitution in at least 50% of lethally irradiated LBN rats. After ex vivo incubation with graded concentrations of 4-hydroperoxycyclophosphamide (4HC) or bleomycin (BLEO), LBN AML or normal BM cells were cultured for CFU-Leuk or CFU-GM and injected into untreated or lethally irradiated syngeneic recipients. Over a variety of drug concentrations (4HC, 3-30 micrograms/ml; BLEO, 100-10,000 mU/ml) and cell doses (10(6)-10(7)/animal) examined, the log-kill estimates derived from in vitro CFU-Leuk assays correlated with the observed MST or LFS. Recovery of greater than 1% CFU-GM from 4HC- or BLEO-treated suspensions of normal BM was associated with satisfactory engraftment in lethally irradiated LBN rats. Clonogenic assays also predicted for engraftment and LFS in animals that received mixtures of AML and normal BM cells (1:10) treated with 4HC and/or BLEO. We conclude that CFU-Leuk and CFU-GM assays are useful screening techniques to develop and evaluate strategies for ex vivo purging with chemotherapeutic agents in this preclinical model of autologous marrow transplantation for AML.
authors.affiliation: Division of Pediatric Oncology, Johns Hopkins Oncology Center, Baltimore, MD 21205.
authors.forename: J M
authors.initials: JM
authors.lastname: Wiley
authors.forename: A M
authors.initials: AM
authors.lastname: Yeager
mesh_terms: D000208:Acute Disease; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000401:mortality / Q000473:pathology*; D003114:Colony-Forming Units Assay / Q000592:standards*; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D007951:Leukemia, Myeloid / Q000453:epidemiology / Q000473:pathology / Q000601:surgery*; D011237:Predictive Value of Tests; D051381:Rats; D013234:Stem Cells / Q000187:drug effects; D014185:Transplantation, Isogeneic / Q000401:mortality / Q000473:pathology*
chemical_list: D001761:Bleomycin; D003520:Cyclophosphamide; C011272:perfosfamide