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Effect of Insulin on DNA Synthesis and DNA Polymerase Activity in Organ Culture of Rat Mammary Carcinoma, and the Influence of Insulin Pretreatment and of Alloxan Diabetes¹

Department of Internal Medicine and Laboratory of Clinical Investigation, Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, ² Brussels, Belgium

As previously reported, 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas of the rat are usually insulin dependent for cell proliferation in organ culture, although a few proliferate readily in the complete absence of insulin. This problem was further investigated by studying the effect of insulin on DNA polymerase in the cultured explants.

It was found for most tumors that DNA synthesis and DNA polymerase activity ran a closely parallel time course. Stimulation of DNA synthesis was delayed in onset and was accompanied by a concomitant rise in DNA polymerase activity. In tumors with insulin-independent DNA synthesis, DNA polymerase was also insulin independent. These observations support our earlier interpretation that the stimulating property of insulin is not merely a permissive effect, mediated through energy-yielding reactions, but rather involves activation or induction of enzyme systems responsible for DNA synthesis.

The level of the DNA-synthesizing process at onset of culture varied markedly from tumor to tumor, even in the same rat. It ranged from low to highly activated. The activated state, which was most frequently encountered, would seem to result from an "overresponsiveness" of the process to stimulating factors in vivo. The fact that inactivation invariably occurred after induction of alloxan diabetes, together with other lines of evidence, suggest that insulin may be one of these factors.

Hypersensitivity to stimulating factors and insulin independence possibly represent successive steps toward escape from the normal growth-regulating mechanisms. Loss of insulin dependence, as revealed in culture, appears to accompany the specific ability of the tumor to grow in diabetic rats.

¹ This work was supported in part by Contract EURATOM-ULB-PISE 026-63-4-BIAC and by a grant of Fédération Belgo-Luxembourg eoise des Industries du Tabac to the European Organization for Research on Treatment of Cancer.

² This department is affiliated with the European Organization for Research on Treatment of Cancer.

Received 5/11/70. Accepted 9/23/70.