EVALUATION OF CHEMICAL MYELOTOXICITY USING AN IN VIVO LEUKEMIA TRANSPLANT MODEL

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A cell transplant model for F344 rat leukemia was developed to investigate the mechanism of action of carcinogens, and to corroborate data from 2-year studies when necessary. The hypothesis that chemicals containing the dimethyl ester phosphonic acid group were potential leukemogens was tested further with trichlorfon, which was shown to accelerate the process of carcinogenesis: further studies with pesticides containing the diethyl dithiophosphate ester group are underway using the leukemia transplant model to determine the specificity of this tumor induction. The pesticide atrazine is also being investigated in this short-term transplant model since it is suspected to be associated with leukemia and lymphoma in farm workers. Studies of the mechanism of action of glycol alkyl ethers continued, and it was shown in the leukemia transplant model that neither the aldehyde or acid metabolites of ethylene glycol monomethyl ether were responsible for the anti-leukemic activity consistently exhibited by the parent chemical. Further studies with ethylene glycol monomethyl ether acetate showed that this chemical was more effective than the parent compound in extending the tumor latency period in the leukemia transplant model. Mononuclear leukemia cells separated from spleens of leukemic rats at various intervals following leukemia transplantation were used to evaluate the role of selected protooncogenes during the progression of carcinogenesis. The pattern of expression or inactivation of FMS, BCR, ABL, and SRC, protooncogenes involved in differentiation and proliferation of leukocytes, was compared in leukemic cells from spleens of untreated leukemic transplant recipients with those from recipients treated with ethylene glycol monomethyl ether to determine the potential role of these protooncogenes during the progression ofr inhibition of the carcinogenic processes. In vitro tests were also conducted with leukemic cell cultures from F344 rats. L1210 mouse leukemia cells, and HL60 human leukemia cells, which indicated that the parent compound but not the acid metabolite reduced the numbers of growing cells after addition of micromolar concentrations of ethylene glycol monomethyl ether.