A wide range of sensitivities to androgens develops in cloned shionogi mouse mammary tumor cells

Abstract

Clones obtained in soft agar from a Shionogi mouse mammary carcinoma show marked heterogeneity of growth characteristics and sensitivities to androgens. These data pertain to spontaneous growth in the absence of androgens, maximal response to dihydrotestosterone (DHT) and Km values of the stimulatory action of DHT ranging from 0.008 to 10 ng/ml (1,250-fold range). Following 13 months in culture in the presence of 10 nM DHT, recloning of one original cell clone led to an even greater variation of androgen-free growth and of the maximal responses to DHT, while the Km values of DHT action ranged from 0.05 to 10 nM (200-fold range). The present demonstration of a marked heterogeneity of Km values of DHT action in subpopulations of tumors grown in a controlled environment has major implications for the efficient antihormonal treatment of androgen-sensitive diseases such as prostate cancer. Such data indicate that cell clones having a high degree of sensitivity to DHT (androgen-hypersensitive) can continue to grow in the presence of castration levels of androgens, thus suggesting that an antiandrogen is required in order to achieve a more complete androgen blockage and to induce a regression of these androgen-hypersensitive tumors.

History of LHRH agonist and combination therapy in prostate cancer

“…23) (Labrie et al 1985 (Bartsch etal. 1983) as well as our previous observations (Marchetti et al 1988, Labrie et al 1985, 1986 1986), clearly demonstrate that low concentrations of androgens are highly active and that small varia¬ tions of these low concentrations of androgens can cause major changes in the responses observed in various androgen-sensitive systems, namely cancer cell growth (Labrie & Veilleux 1986), growth of the normal rat prostate (Bartsch et al 1983, Marchetti et al 1988) as well as LHRH-induced LH release in normal rat gonadotrophs in culture (Labrie et al 1985 (Moghissi etal. 1984, Bélanger etal.…”

“…1985b Fig. 23, the most significant finding is that the apparently low castration levels of semm testosterone at 0.2 to 0.4 ng/ml stimulate growth of the androgen-sensitive mouse mammary carcinoma cells at 36-62% of the maximal growth rate which can be achieved at testosterone levels corresponding to those found in intact men (4 to 8 ng/ml) (Labrie & Veilleux 1986). …”

“…The same group of patients shown in Fig. 23 (Labrie & Veilleux 1986) (Fig. 23) (Labrie et al 1985 (Bartsch etal.…”

Structural Characterization of the Human Androgen Receptor Ligand-binding Domain Complexed with EM5744, a Rationally Designed Steroidal Ligand Bearing a Bulky Chain Directed toward Helix 12

“…We have thus designed and synthesized a set of androgen nucleus derivatives bearing substituents of different sizes and lengths at their C18 position. All these molecules were first tested for their capacities to bind the androgen receptor and to inhibit the DHTstimulated growth of mouse Shionogi mammary carcinoma cells (29,30). We found that, despite their C18 chain, a large set of them bind the receptor with high affinity, often better than that of DHT, the most potent androgen.…”

“…1), a DHT-based molecule with a strong affinity for the hAR despite its size, more than 150% that of DHT, and its bulky chain directed toward H12. In Vitro Assay of Androgenic/Antiandrogenic Activity in Shionogi Cells-Shionogi mouse mammary carcinoma cells (clone 107) were routinely grown as previously described (29,30). Cells between passages 37 and 50 were plated in 24-well plates at a density of 18,000 cells/well and allowed to adhere to the surface of the plates for 24 h. Cell proliferation was measured as follows.…”