Fine structural effects of a DDT derivative on a rat adrenocortical carcinoma
R. KRÜGER1, U. J. UHL1 and K. H. VOIGT1
1Department of Pathology, University of the Saarland, 6650 Homburg/Saar
2Department of Physiology I, University of Ulm, 7900 Ulm, Federal Republic of Germany
The adrenostatic effect of o,p’-DDD (1,1-dichloro-2-0-chlorophenyl-2-p-chloro- phenyl-ethane), a derivative of the insecticide DDT, was detected incidentally in the course of a toxicity examination (Nelson & Woodard, 1949). The effect is based on the blocking of steroid biosynthesis when cholesterol is converted to pregnenolone. Since clinical observations have shown o,p’-DDD is capable of producing a regression of adrenocortical carcinoma and its metastases, this drug is used for the treatment of these tumours (Bergenstal et al., 1959; Gallagher et al., 1962). Recently, Moore et al. (1980) have published an examination of the morphological changes in adrenocortical carcinomas during o,p’-DDD treatment. They reported ultrastructural findings, mostly the severe destruction of mitochondria. They did not see any nuclear alterations as were found by Hart et al. (1973) in the adrenocortical cells of dogs following application of o,p’-DDD. In our study, we set out to confirm a possible cytostatic effect of o,p’-DDD.
Twenty male Sprague-Dawley rats (weight 70 ± 5 g) were implanted intramuscularly with a suspension of SNELL carcinomatous tissue and physiological salt solution (1:10). When the tumours became palpable, 14 days after transplantation, 900 mg o,p’-DDD/kg body weight was administered to 10 animals for 14 days up to the 28th day following transplantation. The drug was dissolved in corn oil and injected orally. A control group of 10 animals was treated with corn oil only. The animals were sacrificed on the 29th day. The tumours were dissected, weighed and prepared for light and electron microscopical examination in the usual way.
After 14 days o,p’-DDD treatment, the mean tumour weight decreases significantly (P = 0.001) from 12.0 g in the controls to 9.1 g in the treated animals. Spontaneous necroses increase from 34% of the tumour area to 53% in the o,p’-DDD-treated group.
Ultrastructurally, tumour cells with increased osmiophilia and decreased smooth endoplasmic reticulum can be seen. Compared to cells of untreated tumours, the cells of treated tumours display greatly deformed mitochondria with few irregular cristae (Fig. 1). Parallel with the decreased number of cristae, myelin-like concentric membranes increase. Electron-dense linear material in the cytoplasm is evident and identical to membrane remnants of destroyed mitochondria. Crystalline inclusions are
1
comparable with cholesterol esters, which have not been utilized because of disturbed steroid biosynthesis. The nucleus remains intact.
In addition to the mitochondrial alteration of adrenocortical cells in dogs treated with o,p’-DDD, Kaminsky et al. (1962) also reported nuclear alterations with chromatin clumpings. It is possible that o,p’-DDD has a cytostatic effect in addition to its ability to reduce the size of adrenocortical carcinoma in man, a property that is useful clinically (Hutter et al., 1966; Lubitz et al., 1973). The reduction by o,p’-DDD treatment of tumour weight with an increase in the number of necroses supports this assumption. Electron microscopic examination, however, does not show any change of cellular nuclei. On the contrary, pronounced alterations in mitochondria, the most important cellular organelles for steroid biosynthesis, are present, as has also been reported by Moore et al. (1980). These alterations mainly consist of a reduction in the number of mitochondria
and a deformation of the mitochondria present accompanied by the destruction of cristae and mitochondrial membranes. When nuclear alterations are absent and tumour necroses after o,p’-DDD increase, severe mitochondrial changes are not only responsible for the inhibition of steroid biosynthesis, but also for cell death.
Thus, o,p’-DDD does not possess a cytostatic, but a cytotoxic effect by destroying the mitochondria of adrenocortical tumour cells specifically.
References
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