Abstract
Methylglyoxal bis(guanylhydrazone), a cytostatic compound which apparently interferes with the metabolism and/or functions of the natural polyamines (spermidine and spermine), was effectively taken up by cultured human lymphocytic leukemia cells, rapidly resulting in the formation of a concentration gradient of up to 1,000‐fold across the cell membrane in cells grown in the presence of micromolar concentrations of the drug. For an anti‐proliferative effect on the leukemia cells, an intracellular concentration of more than 0.5 mm was required. The uptake of methylglyoxal bis‐(guanylhydrazone) was critically dependent on the growth rate of the leukemia cells. Low intracellular concentrations of the drug were present in cells growing slowly, whereas in rapidly dividing cells the intracellular concentration of the drug approached 5 mm. When given as repeated intravenous infusions to two leukemic children, methylglyoxal bis(guanylhydrazone) exhibited sharp and transient peaks of plasma concentration, the drug having an apparent half‐life in plasma of only 1‐2 h. However, as in cultured cells, the drug was rapidly concentrated in the leukemia cells, reaching concentrations that were distinctly anti‐proliferative. In contrast to the rapid disappearance of methylglyoxal bis(guanylhydrazone) from plasma, the circulation leukemia cells retained the drug for a period of several days with only minimal decrease in the initial concentrations. Methylglyoxal bis(guanylhydrazone) was given to the patients for 1 to 2 months as intravenous infusions, the timing of which was determined by regular assays of the drug concentrations in the leukemia cells. In agreement with the results obtained with the cultured cells, an intracellular concentration of about 0.5 to I mm was apparently required for growth‐inhibitory action to occur. Regular determination of the cellular drug concentrations indicated that methylglyoxal bis(guanylhydrazone) could be given as weekly infusions. This treatment schedule represents much lower dosing of the drug than the earlier daily regimens which were commonly associated with unacceptable toxicity.