Advanced prostate cancer is treated by androgen ablation and/or androgen receptor (AR) antagonists. In order to investigate the mechanisms relevant to the development of therapy-resistant tumours, we established a new tumour model which closely resembles the situation in patients who receive androgen ablation therapy. Androgen-sensitive LNCaP cells were kept in androgen-depleted medium for 87 passages. The new LNCaP cell subline established in this manner, LNCaP-abl, displayed a hypersensitive biphasic proliferative response to androgen until passage 75. Maximal proliferation of LNCaP-abl cells was achieved at 0.001 n M of the synthetic androgen methyltrienolone (R1881), whereas 0.01 n M of this compound induced the same effect in parental cells. At later passages (> 75), androgen exerted an inhibitory effect on growth of LNCaP-abl cells. The non-steroidal anti-androgen bicalutamide stimulated proliferation of LNCaP-abl cells. AR protein expression in LNCaP-abl cells increased approximately fourfold. The basal AR transcriptional activity was 30-fold higher in LNCaP-abl than in LNCaP cells. R1881 stimulated reporter gene activity in LNCaP-abl cells even at 0.01 n M , whereas 0.1 n M of R1881 was needed for induction of the same level of reporter gene activity in LNCaP cells. Bicalutamide that acts as a pure antagonist in parental LNCaP cells showed agonistic effects on AR transactivation activity in LNCaP-abl cells and was not able to block the effects of androgen in these cells. The non-steroidal AR blocker hydroxyflutamide exerted stimulatory effects on AR activity in both LNCaP and LNCaP-abl cells; however, the induction of reporter gene activity by hydroxyflutamide was 2.4- to 4-fold higher in the LNCaP-abl subline. The changes in AR activity were associated neither with a new alteration in AR cDNA sequence nor with amplification of the AR gene. Growth of LNCaP-abl xenografts in nude mice was stimulated by bicalutamide and repressed by testosterone. In conclusion, our results show for the first time that the non-steroidal anti-androgen bicalutamide acquires agonistic properties during long-term androgen ablation. These findings may have repercussions on the natural course of prostate cancer with androgen deprivation and on strategies of therapeutic intervention. © 1999 Cancer Research Campaign

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LHRH-antagonists might represent a useful new type of androgen deprivation to treat prostatic cancer. In this context adult intact male rats were treated subcutaneously with different concentrations of the new LHRH-antagonist antide either once (1, 3, 6, 10, 15 mg/kg) or on 5 consecutive days (5 x 3 mg/kg). The effect on serum concentration of LH and testosterone and the effect on the weights of testes, prostate, and seminal vesicles was investigated after different periods of time (24 hours, 1, 2, 3, 5, and 8 weeks). Histological evaluation of the testes was also performed. A clear dose-dependent inhibitory effect on the above-mentioned parameters was observed. The most effective treatment schedule was the single application of 15 mg/kg resulting in castration-like inhibition of prostate weights and marked inhibition of spermatogenesis within 2 weeks, which was maintained 8 weeks after the injection. Serum LH and serum testosterone concentrations were below the detection limit of the assay within 2 weeks and showed first signs of recovery after 8 weeks. Histologically, no signs indicative of irreversible effects (testes) were observed. To summarize, the LHRH-antagonist antide was found to have a profound long-lasting inhibitory but reversible effect on the reproductive system of adult intact male rats. These data emphasize the suitability of this type of compound for the treatment of prostatic cancer.

S,gnal transducuon reduced by epidermal growth factor (EGF) vm ,ts receptor revolves two second messengers, chacylglycerol (DG) and momtol msphosphate, both products of phosphandylmo~to|-specdic phosphohpase C wluch seem to pamctpate m the regulauon of cellular prohferauon by EGF We observed that A431 cells and HeL~ cells m response to EGF accumulate substanual amounts of phosphauchc actd (PA), the potenual product of DG kmase However, PA appears earher and stays longer elevated than expected from DG avadabxhty thus rinsing the poss~bd~ty of an EGF-mduced acuvatxon of a phosphohpase D (PLD) In the presence of prm=ry alcohols PLD effects the phosphandyl transfer reacuon producmg PA-alcohol, a reacuon known to be excluszvely ~ by PLD m mtact cells A431 cells and cells prelabeled w~th [14C]-oleate produce m the presence of ethanol (0 5%) or l-butanol (0 2%) substanual amounts of labeled PA-alcohol m response to EGF These results mchcate that acuvauon of PLD had occurred Acuvauon of PLD may x~present a novel mgnal transducing pathway wluch may pamctpate m the regulauon of cell prohferauon by EGF -a hypothes~s presently mvesugated m thts laboratory Supported by the Deutsche Forschungsgememschaft.