Effect of Deoxyribonuclease on Adriamycin-Polynucleotide Complexes1

cemchemotherapy (22, 27, 28), the recent work of Tnouet et a!. (5, 24, 25) using a daunomycmn-DNA compex activated by DNase is an important example. In particular, the novelty of this approach is not in the ar@zymaticrelease mechanism but in the endocytosis mechanism proposed by DeDuve et a!. (6). The high endocytotic activity, characteristic of many tu mom cells, allows the transport of the macmomoleculan com plex into the target cell preferentially (20). Once inside the tumor cell, the complex would most probably be taken up by the lysosomes, the cannier DNA would then be digested by the enzyme DNase, and the drug would be released. The beneficial effect of using such a complex oven using the drug alone depends on the fact that the complex is less toxic than the drug. Indeed, Langslet et a!. (13) recently reported that the camdiotoxicity of daunomycin and adnia mycin was reduced by complexing with DNA. Similar stud ies with ethidium bromide have been reported by Heinen et a!. (10). More recently, Marks and Venditti (18) also studied the effect on admiamycin and actinomycin D in vivo. These last authors pointed out the necessity of considering the effect of DNA as an immunoenhancing agent in this work, based on the fact that DNA could be given either prior to or after the drug was given to achieve similar improvement. Atassi and Tagnon (1) were unable to demonstrate differ ences in activity between adniämycinand its DNA complex in DBF hybrid mice. There was also a difference in opinion on the efficacy of the DNA-adniamycmn complex prepared in different laboratories (11). In addition, controversy exists as to the origin and method of preparation of the DNA complex (24). Therefore, the work carried out in our laboratory nelat ing to the enzymatic basis of this approach should be of interest. Wmoblewski and Bodansky (31) and Kumnick (12) found that the serum enzyme hydrolysis of double-strand DNA yields oligonucleotides with 5'-nucleotide terminals and that this enzyme resembles the DNase I of bovine pancreas (12). Since the stability of the DNA complex before reaching the target tumor where endocytosis occurs merits some attention, a model study with bovine pancreas DNase I may provide this information (7). Subsequent to endocytosis, the lysosomal DNase II activity will dictate the rate of release of admiamycin. Spleen acid DNase II is a well-known example of this lysosomal activity. This work therefore examines the rate of hydrolysis of DNA, adniamycin-DNA complex, and admiamycin-synthetic polynucleotide complexes by these 2 model enzymes. The results of this investigation should serve as a useful basis to a better understanding of the value