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Apparent Autophagocytosis of Mitochondria in L1210 Leukemia Cells Treated in Vitro with 4,4'-Diacetyl-diphenylurea-bis(guanylhydrazone)¹

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

The aromatic bis(guanylhydrazone), 4,4'-diacetyl-diphenylurea-bis(guanylhydrazone) (DDUG), has potent antiproliferative activity in vitro, which has been attributed to its ability to bind linear DNA and inhibit DNA polymerase. The ultrastructural effects of this drug were investigated and compared with those of methylglyoxal-bis(guanylhydrazone), an aliphatic bis(guanylhydrazone) which has recently been found to produce extensive mitochondrial damage in a variety of cultured cell lines.

In cultured L1210 leukemia cells, DDUG inhibited cell growth by 24 hr at concentrations similar to those of methylglyoxal-bis(guanylhydrazone) (1 to 10 µM) and had a unique effect on the ultrastructure of mitochondria. Unlike treatment with methylglyoxal-bis(guanylhydrazone), the mitochondria did not become swollen and distorted as a consequence of DDUG exposure but instead became lamellated with layers of membranes which seemed to derive from endoplasmic reticulum. Frequently, parcels of cytoplasm, including polyribosomes, were also enveloped with the mitochondria. The myelin-like structures eventually lost all evidence of internal structure (i.e., cristae). After 24 hr treatment with 5 µM DDUG, most mitochondria of most cells became involved in this manner, while other cellular organelles remained as in control cells. The membranous enveloping of mitochondria and cytoplasm resembled autophagocytosis and, in fact, was confirmed by cytochemical staining to have some acid phosphatase activity associated with it.

It is proposed that this unique drug effect may contribute to the antiproliferative action of DDUG. The induction of cellular autophagocytosis of mitochondria by DDUG is interesting in its own right and may identify the drug as a useful experimental tool in the study of this cellular phenomenon, or mitochondrial biogenesis.

¹ This investigation was supported in part by research Grants CA-22153 and CA-13038 from the National Cancer Institute, Department of Health, Education, and Welfare.

² A portion of these findings represents research performed in partial fulfillment of the requirements for the Ph.D. degree.

³ Deceased January 10, 1978.

⁴ To whom requests for reprints should be addressed.

Received 11/27/78. Accepted 12/20/79.