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Potentiation of the Antimitochondrial and Antiproliferative Effects of Bis(guanylhydrazones) by Phenethylbiguanide¹

Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263

The ability of methylglyoxal-bis(guanylhydrazone) (MGBG) and 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) to interact with the hypoglycemic agent, phenethylbiguanide (DBI), in affecting the bioenergetic functions of isolated rat liver mitochondria was studied. DBI was found to increase markedly the inhibitory effect of either 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) or MGBG on respiration of isolated rat liver mitochondria. Conversely, these bis(guanylhydrazones) enhanced the inhibitory potency of DBI and increased the apparent affinity of mitochondria for the drug. As with MGBG and 4,4'-diacetyldiphenylurea-bis(guanylhydrazone), the potassium cationophore, valinomycin, increased the sensitivity of mitochondrial respiration to DBI. It is suggested that the enhancement of bis(guanylhydrazone) inhibition of mitochondrial respiration by DBI involves inhibition of proton fluxes across the inner mitochondrial membrane and the subsequent alkalinization of the mitochondrial matrix. This drug interaction was extended to the level of antiproliferative activity in which DBI was found to potentiate the growth-inhibitory effects of MGBG on murine L1210 leukemia in vivo.

¹ This investigation was supported by Research Grants CA-22153 and CA-24538 from the National Cancer Institute, Department of Health, Education, and Welfare.

² Permanent address: Department of Pharmacology, Medical School of Gdansk, 38 Hibnera str., PL. 80227 Gdansk-6, Poland.

³ Permanent address: Department of Toxicology, Medical School in Gdanski, K. Marksa 107, 80-416, Gdansk-6, Poland.

⁴ To whom requests for reprints should be addressed.

Received 10/17/80. Accepted 6/10/82.