Refractoriness in the therapy of transplanted mouse leukemia.

For specific transfer lines of mouse leukemia, survival time is increased if certain chemical agents are administered. Compounds exerting this effect are ethyl carbamate (14, 18, 20, 28), the nitrogen mustards (5), folie acid antagonists (2, 3, 4, 17, 24, 29), benzene (11,18), potassium arsenite (11, 14, 18), competitive metabolic analogs (1, 15, 18, 19), and specific hormones (7, 37). Radiation therapy may effect similar results (10,11,18). The response to these agents is usually followed by a refractoriness to continued treatment with the same agent. Resistance of specific cells to drug therapy was first observed in trypanasome infections treated with arsenicals (8). It is well known that micro organisms may become insensitive to the effects of sulfonamides and antibiotics. Similarly, the development of resistance to the folie acid antagonist, A-methopterin, was de scribed in AK4 mouse leukemia (6, 9), originally responsive to this agent (2). The new A-methopterin-resistant subline did not respond to other folie acid antagonists possessing a substituent 4-amino group within its molecule (8). Three sublines of lymphatic leukemia, L1210, of strain DBA, were developed (21-23). These exhibited refractoriness to A-methopterin, A-ninopterin, and A-denopterin, all closely related folie acid analogs. Resistance to one of these agents imparted resistance to the other two. The above studies suggested that re sistance to treatment resided in the leukemic cell. The problem of drug fastness may not, however, be confined to the parasitic organism or neoplastic cell. A host factor in drug resistance has been sug gested (12, 13, 25). The purpose of this investigation was to de-