Structure-activity studies with nine glycol alkyl
ethers were conducted with a cellular
leukemia transplant model in male Fischer rats. This in vivo assay measures the effects of chemical treatment on neoplastic progression in transplant recipients. Chemicals were given ad libitum in the
drinking water simultaneously with the transplants and continued throughout the study. In all, 20 million leukemic cells were injected s.c. into syngeneic rats, which after 60 days resulted in a 10-fold increase in relative spleen weights, a 100-fold increase in white blood cell counts, and a 50% reduction in red blood cell (RBC) indices and platelet counts. At this interval,
ethylene glycol monomethyl ether (2-ME) given at a dose of 2.5 mg/ml in the
drinking water completely eliminated all clinical, morphological, and histopathological evidence of
leukemia, whereas the same dose of
ethylene glycol monoethyl ether (2-EE) reduced these responses by about 50%. Seven of the glycol
ethers were ineffective as anti-leukemic agents, including
ethylene glycol, the monopropyl, monobutyl, and monophenyl
ethylene glycol ethers,
diethylene glycol, and the monomethyl and monoethyl
diethylene glycol ethers.
2-ME more than doubled the latency period of
leukemia expression and extended survival for at least 210 days. A minimal effective dose for a 50% reduction in the leukemic responses was 0.25 mg/ml
2-ME in the
drinking water (15 mg/kg
body weight), whereas a 10-fold higher dose of 2-EE was required for equivalent antileukemic activity. In addition, the in vitro exposure of a leukemic spleen mononuclear cell culture to
2-ME caused a dose- and time-dependent reduction in the number of
leukemia cells after a single exposure to 1-100 microM concentrations, whereas the
2-ME metabolite,
2-methoxyacetic acid, was only half as effective. The two glycol alkyl
ethers with demonstrable anti-leukemic activity,
2-ME and 2-EE, also exhibited a favorable efficacy-to-toxicity ratio and should be considered for further development as chemotherapeutic agents.