The Prostate
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Three regions of chromosome 13 were previously identified for having loss of heterozygosity (LOH) in human prostate cancer. One of them, at 13q33, was defined by LOH at markers D13S158 and D13S280. The XPG/ERCC5 gene, a DNA repair gene that when mutated in the germline leads to xeroderma pigmentosum, has been mapped to 13q33, within one megabase of D13S158 and D13S280. This paper describes LOH and mutational analysis of the XPG gene in human prostate cancers, in order to determine whether the XPG gene is involved in the development of prostate cancer. ⋯ LOH at XPG in prostate cancer supports the conclusion that the 13q33 region contains a gene important in the development of prostate cancer, while lack of mutations of the gene suggests that XPG is not the target gene involved.
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Comparative Study
Expression of transforming growth factor-beta 1 in rat ventral prostate and Dunning R3327 PAP prostate tumor after castration and estrogen treatment.
In normal prostate, TGF-beta 1 is associated to castration induced apoptosis. Combined castration and estrogen treatment, but not castration alone, induces apoptosis in the Dunning R3327 PAP adenocarcinoma. ⋯ The Dunning R3327 PAP tumor contains high levels of TGF-beta 1, which are further increased by combined castration and estrogen treatment. However, since this increase is not apparent until day 3, TGF-beta 1 probably does not contribute to the known induction of apoptosis in the tumor at day 1 after combined castration and estrogen treatment.
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The involution of the prostate gland after castration is an active process which requires the induction of new proteins. The plasminogen activator urokinase has been proposed to be a gene repressed by androgen which is activated upon castration and thus participating in the atrophy of the gland. However, urokinase is secreted by the ventral lobe of the rat prostate and this should be positively affected by androgens. ⋯ Hydrocortisone prevented the increase in PA activity, whereas treatment with actinomycin D, an inhibitor of RNA synthesis, not only did not prevent an increase in PA activity, but actually produced a superinduction in PA activity at 4 days orchiectomy. These data may be interpreted to mean that hydrocortisone stimulated PAI activity and that actinomycin D treatment blocked its induction. However, the actinomycin D data may also indicate that an increase in urokinase protein and mRNA after castration may result from some mechanism to conserve these molecules suggesting that this inhibitor of RNA synthesis prevented the transcription of messages for proteins involved in the degradation of urokinase message.
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Hyperthermia alone or with radiation is used therapeutically for localized solid tumors. Clinical experience shows that sustained tumor temperature exceeding 45 degrees C damages normal tissue. Any agent that enhances the effects of hyperthermia at or below this temperature may have clinical relevance. ⋯ Measurement of cell-cycle progression following a single dose of hyperthermia revealed a reduction of S-phase cells, and subsequent accumulation in G1 over 24 hours. Combination treatment of tumor-bearing rats significantly reduced tumor growth rate when compared with individual agents. These results suggest a potential use of lonidamine in hyperthermic therapy of prostate tumors.
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Tamoxifen (TAM) has previously been shown to inhibit growth of the Dunning R3327 rat prostate adenocarcinoma and to elevate serum prolactin levels. The purpose of this study was to determine the role of prolactin in modulating the effects of tamoxifen on growth of the R3327 prostatic adenocarcinoma. Intact and castrated Copenhagen-Fischer male rats bearing the Dunning R3327 rat prostatic tumor were divided into groups and injected sc five times per week for 16 weeks as follows: vehicle; TAM (0.5 mg/kg); haloperidol (HALO; 0.5 mg/kg); bromocriptine (CB-154; 5 mg/kg); TAM plus HALO; or TAM plus CB-154. ⋯ The inhibitory effect of TAM on R3327 prostatic tumor growth in intact rats appears to be an indirect effect resulting from its ability to reduce serum testosterone levels. In contrast, the stimulatory effect of TAM in castrate rats appears to result directly from an estrogen-like action, which can directly enhance prostatic tumor growth in the presence of low levels of circulating androgens; this stimulatory effect of TAM is more pronounced when prolactin levels are suppressed by CB-154. Clearly, castration alone is more effective than TAM therapy alone or in combination with castration in the retardation of the growth of the androgen-dependent R3327 prostatic tumor in rats.