PubMed · 11022717
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T Kotake. 2000. [Bicalutamide].. https://pubmed.ncbi.nlm.nih.gov/11022717/
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Hormonal treatment is a androgenoprive therapy. Adjuvant treatment after radical prostatectomy or radiotherapy seems to have no survival benefit. Neoadjuvant hormonal treatment before local therapy has no proven survival benefit. Hormonal treatment in metastatic disease can be initiated immediately, deferred or intermittent. Androgen-deprivation is performed by castration or LHRH-analoga and/or anti-androgens. Maximal androgen-deprivation has significant more side effect and is of only limited survival bebefit for a subgroup of patients. The onset of hormonal treatment is under discussion. An increase of PSA (> 25 ng/ml) and/or occurrence of symptoms is an indication for hormonal treatment. Intermittent androgen-deprivation is under investigation as a new concept.
BACKGROUND: The effect of an EGF-R selective tyrosine kinase (EGF-RTK) quinazoline inhibitor ZM252868 was determined on the androgen-sensitive human prostatic tumour cell line LNCaP, which can also respond via the EGF-R-regulated growth pathway for cell proliferation. Potential interaction or 'cross-talk' between steroid and the growth factor mitogen-activated protein kinase (MAPK) signalling pathway was also investigated. METHODS: The responses of LNCaP cells to various growth factors in the absence and presence of the EGF-RTK inhibitor and/or steroid and anti-androgen Casodex, was determined using cell population analysis. The effect of the inhibitor on the expression of androgen receptor, EGF-R and activated MAPK was assessed immunocytochemically and changes in the MAPK signalling cascade were also determined using Western blotting techniques. RESULTS: The ZM252868 inhibitor had no effect on LNCaP basal growth. At 100 nM and 1 microM concentrations, the inhibitor reduced the marked EGF- and TGF-alpha-stimulated LNCaP cell growth by 60% and to basal levels, respectively. Both bFGF- and 5alpha-DHT-stimulated growth were unaffected in this concentration range. The inhibitor (1 microM) decreased the expression of immunoreactive EGF-R but had no effect on androgen receptor levels. Activation of MAPK by EGF was noted, being down-regulated by the inhibitor at a concentration of 1 microM. MAPK was not activated by 5alpha-DHT. The anti-androgen Casodex reduced 5alpha-DHT-stimulated cell growth but had no effect on EGF-R mediated LNCaP growth or EGF-stimulated activated MAPK activity. Treatment with EGF and 5alpha-DHT in combination produced an additive effect on cell proliferation, with the anti-androgen and the EGF-RTK inhibitor only reducing the 5alpha-DHT- or EGF-stimulated portion of growth, respectively. CONCLUSIONS: The study demonstrated the efficacy and selectivity of the ZM252868 inhibitor in inhibiting EGF-R mediated LNCaP cell growth. Additionally, no interaction between androgen and EGF-R mediated growth pathways was determined.
Several reports indicate that some steroids, in particular sex steroid hormones, can modify cadmium toxicity. We recently reported that cyproterone acetate (CA), a synthetic steroidal antiandrogen that is closely related in structure to progesterone, affects cadmium toxicity in mice. In the present study, we investigated the effect of CA on cadmium toxicity in a rat liver epithelial cell line (TRL 1215) in vitro. Cells were exposed to various concentrations of CA (0,1,10, or 50 microM) for 24 h and subsequently exposed to cadmium (0,50, or 100 microM; as CdCl2) for an additional 24 h. CA pretreatment resulted in a clear decrease in the sensitivity to cadmium. Additional time course study showed CA pretreatment provided protection against cadmium toxicity but only when given for 6 or more hours prior to cadmium exposure. Cellular cadmium accumulation was markedly reduced (60% decrease) in cells pretreated for 6 or more hours with CA. In the presence of protein synthesis inhibitors the protective effect of CA toward cadmium toxicity was abolished. However, in the presence of the GSH synthesis inhibitor, L-buthionine (S,R)-sulfoximide (BSO), the protective effect of CA toward cadmium toxicity remained. CA alone increased metallothionein (MT) levels 2.4-fold, while cadmium (50 microM) alone resulted in a 8.9-fold increase over control. However, cadmium-induced MT synthesis was markedly decreased by CA pretreatment probably because of reduced cadmium accumulation. Analysis of various metal transporters by bDNA signal amplification assay revealed that the ZnT-1 transporter gene, which encodes for a membrane protein associated with zinc efflux, was expressed three-fold more in CA treated cells than control. These data show that CA pretreatment provides protection against cadmium toxicity in vitro and indicate that this protection is due to a decreased accumulation of cadmium rather than through activation of MT synthesis. This decrease of cellular cadmium accumulation appears to be related to events that require protein synthesis and may be due to activation of the genes associated with zinc efflux.