Experimental evaluation of potential anticancer agents. VI. Anatomical distribution of leukemic cells and failure of chemotherapy.

Abstract

A quantitative bioassay for L1210 leukemic cells in mouse tissues and fluids has been developed. This bioassay is based on the direct relationship between the number of leukemic cells inoculated into appropriate inbred mice and their respective life-spans. When 105 or 106 L1210 ascites cells are inoculated intraperitoneally, small numbers of these leukemic cells can be detected in various tissues and organs at 3 and 24 hours, and detectable numbers appear in the brain between 2 and 4 days. The rate of appearance of such cells in the brain appears to be associated with the size of inoculum employed. If amethopterin therapy is initiated at 24 hours, the appearance in the brain of intraperitoneally inoculated cells is significantly delayed. When amethopterin therapy is delayed until 7 days after intraperitoneal (I.P.) inoculation of L1210 ascites leukemic cells (at which time intracerebral infiltration has occurred), such therapy is of minimal effectiveness. If as few as 100-1,000 L1210 cells were inoculated into the brain and I.P. therapy was initiated 24 hours later with amethopterin, 6-mercaptopurine, cytoxan, azaserine, 5-fluorouracil, or mitomycin C, none of these drugs provided consistent and significant increase in host life-span, whereas marked effects were achieved with these drugs against the disease resulting from I.P. or intravenous (I.V.) inoculation of L1210 cells. Intraperitoneally administered 1-methyl-1-nitrosourea provided slight to moderate increase in the life-span of mice receiving intracerebral L1210 leukemic cells. The results presented would appear to allow for the working hypothesis that failure of a number of the well known antileukemic drugs in this experimental system may in some instances be associated with entry of leukemic cells into the brain and their continued multiplication in this site in spite of I.P. or I.V. administration of certain drugs sufficient to partially or almost completely suppress the advancement of the disease in other tissues.