Combined use of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) in normal and leukemia-bearing mice.

Mice were treated with daily injections of methylglyoxal bis(guanyl-hydrazone) (MGBG) without or with concurrent administration of 2-difluoromethylornithine (DFMO) in drinking water for 15 days. Analysis of 10 different tissues for their MGBG content during the treatment revealed little evidence for a tissue specific cumulative accumulation of the drug given either alone or in combination with DFMO. On the contrary, tissue MGBG levels tended to increase until the 4th to 7th day of the treatment, whereafter a gradual decline or a plateau was obvious in most tissues. The concomitant DFMO treatment produced a consistent elevation of tissue MGBG concentrations in bone marrow cells and possibly also in intestinal tissue. In L1210 leukemia-bearing DBA mice, MGBG was most actively taken up by the ascitic leukemia cells. A priming of the tumor-bearing mice with DFMO for a few days before the start of MGBG injections resulted in a strikingly enhanced accumulation of the latter drug in the leukemia cells and also in the spleen, which was apparently heavily infiltrated by tumor cells. In liver, small intestine and in bone marrow cells of tumor-bearing animals the concentration of MGBG was not influenced by the DFMO treatment. In DBA mice without the L1210 tumor, DFMO only insignificantly increased the level of MGBG in bone marrow cells whereas no increase was seen in the spleen, in contrast to the same organ obtained from tumor-bearing mice. This combined treatment, in comparison with DFMO or MGBG alone, also produced the best therapeutic response as revealed by marked reduction of the tumor mass.