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The Antimitochondrial Action of 2-Chloro-4',4''-bis(2-imidazolin-2-yl)terephthalanilide and Methylglyoxal Bis(guanylhydrazone)¹

Departments of Experimental Therapeutics and Experimental Pathology, Roswell Park Memorial Institute, Buffalo, New York

The polycationic drugs 2-chloro-4', 4''-bis(2-imidazolin-2-yl)terephthalanilide (NSC 38280)³ and methylglyoxal bis(guanylhydrazone) (MeGAG) behaveas mitochondrial poisons during therapy of the L1210 tumor. Cellular respiration is partly inhibited and the phosphorylation of isolated mitochondria is uncoupled. In common with 2,4-dinitrophenol, the drugs selectively inhibit acetate incorporation into lipid, and under limited circumstances they can abolish the cellular pools of ATP. The mitochondrial effects are: (a) potentiated during synergistic therapy with MeGAG and stilbamidine or hydroxystilbamidine, (b) abolished when the antitumor effect of MeGAG is antagonized by spermidine, and (c) not present during treatment with the therapeutically ineffective dimethylglyoxal bis(guanylhydrazone) or with therapeutically effective but distant congeners of NSC 38280. The tumor can compensate for the loss of its aerobic energy supply with fermentative sources of energy from the host. Antimitochondrial action thus may underlie many of the physiologic effects of these drugs, and a mitochondrial function other than the supply of ATP may be involved in their antitumor action.

¹ This work was supported in part by USPHS Research Grants CA-07777 and CA-06673 from the National Cancer Institute.

³ The following abbreviations are used: NSC 38280, 2-chloro-4',4''-bis(2-imidazolin-2-yl)terephthalanilide; MeGAG, methylglyoxal bis(guanylhydrazone); ATP, adenosine triphosphate; DNP, 2,4-dinitrophenol; DNase, deoxyribonuclease; Me₂GAG, dimethylglyoxal bis(guanylhydrazone)

² Present addres: Cytogenetics and Cytology Unit, Office of the Associate Director for Field Studies, National Cancer Institute, Bethesda, Maryland.

Received 4/21/65.

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