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Cellular Accumulation of Methylglyoxal-bis-guanylhydrazone in Vitro

I. General Characteristics of Cellular Uptake^*

Michael Field, Jerome B. Block, Vincent T. Oliverio and David P. Rall

( Laboratory of Chemical Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland)

Methylglyoxal-bis-guanylhydrazone (MeGAG) has been shown to accumulate against a concentration gradient in normal and leukemic human leukocytes, L1210 mouse ascites tumor cells, and HeLa cells, rabbit reticulocytes, frog and skate erythrocytes, but not mammalian erythrocytes. The accumulation occurs in the absence of detectable cellular metabolism of the drug. The marked effect of temperature changes and metabolic poisons on MeGAG uptake indicates that the accumulation process is coupled to energy metabolism.

Uptake kinetics satisfy a simple Michaelis-Menten model for a saturable carrier transport system at lower concentrations of MeGAG. Studies of competitive inhibition by structural analogs indicate specificity of the postulated transport carrier for diamines (or polyamines) with at least four atoms separating reactive amine groups. The possible relationship of the postulated transport system to the anti-tumor action of MeGAG is discussed.

^* Presented in part before the 54th annual meeting of the American Association for Cancer Research, May, 1963, Toronto, Canada, and published in abstract form in Proc. Am. Assoc. Cancer Res., 4:6, 1963.

Present address: Biophysical Laboratory, Harvard Medical School, Boston, Massachusetts.

Received 6/15/64.