Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007112 (prostatic adenocarcinoma)
 2,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain-enhanced delivery and sustained release of estradiol (E2) may be potentially useful in the treatments of vasomotor hot flushes and prostatic adenocarcinoma and for fertility regulation. Therefore, we have evaluated a redox-based estradiol-chemical delivery system (E2-CDS) for the brain. The mechanism of this drug delivery is based on an interconvertible dihydropyridine in equilibrium pyridinium salt redox reaction. In this study, we investigated the dose- and time-dependent effects of E2-CDS on the tissue distribution of E2-Q+ and E2, the inactive (intermediate) and active metabolites, respectively, of the E2-CDS. Ovariectomized rats received a single iv injection of E2-CDS at 0.01, 0.1, or 1.0 mg/kg or an E2 dose of 0.7 mg/kg or the drug's vehicle, 2-hydroxypropyl-beta-cyclodextrin (HPCD), on day 0. Tissue samples including brain and peripheral tissues were then analyzed for both E2-Q+ and E2 at 1, 7, 14, 21, or 28 days following the E2-CDS administration. Initially, both E2-Q+ and E2 were detected in all tissues analyzed. The dose-distribution and time-course study demonstrates that (1) at 24 hr (1 day) after administration of E2-CDS, all tissues showed a dose-proportional increase in concentrations of E2-Q+ and E2; (2) the enzymatic oxidation of E2-CDS to E2-Q+ was dose dependent over the 100-fold dose range examined; and (3) the disappearance of E2-Q+ as well as E2 was slow in whole brain and hypothalamus, with an apparent t1/2 = 8-9 days, while both of these metabolites were rapidly cleared from plasma, liver, fat, anterior pituitary, kidney, lung, heart, and uterus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dose and time-course evaluation of a redox-based estradiol-chemical delivery system for the brain. I. Tissue distribution. 228 Oct 37

The response of androgen-sensitive Noble (Nb) rat prostatic adenocarcinoma [2Pr-121D (1)] to varying doses (50 approximately 1,000 micrograms/kg body weight) of diethylstilbestrol (DES) was investigated and characterized with respect to cytosol and nuclear androgen binding profiles, histology and pattern of relapse. Inhibition of tumor growth was closely related to the dose of DES. Treatment at all but the lowest dose (50 micrograms/kg) initially caused tumor regression, whereas serum testosterone concentrations in all groups, including that receiving the lowest dose, were decreased to castrate levels. Histologically, while extensive cellular destruction was clearly evident at higher doses of DES, some active tumor cells appeared to survive. Tumors eventually relapsed when higher doses of DES were stopped or with the continued administration of low doses. The cytosol dihydrotestosterone (DHT) receptor in this tumor line, as determined by sucrose density gradient, dextran charcoal and Sephadex column methods, was negative. Nuclear binding, however, was positive. Salt-extractable and salt-resistant fractions of nuclei derived from the untreated primary tumor and relapsed tumor following DES treatment contained high affinity androgen receptor. Comparison of binding constants revealed no significant differences. Our findings, based on the Nb rat prostatic tumor model, indicate that DES acts not only by eliminating circulating testosterone, but also by a direct cytotoxic effect on malignant cells. The results also suggest the lack of an apparent relationship between the loss of hormone responsiveness associated with recurrence of prostatic tumor growth and nuclear androgen binding parameters.
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PMID:Growth inhibition by diethylstilbestrol and relapse of the Noble rat prostatic tumor. 337 90

The objective of this study was to determine whether androgen receptor levels in a transplantable animal model of prostatic adenocarcinoma correlated with androgen responsiveness of the tumor. This is the first comparative study of androgen receptor levels in 3 subcellular compartments (cytosol, nuclear salt-extractable and nuclear salt-resistant fractions) of 4 Dunning R3327 rat prostatic adenocarcinoma sublines that vary in their response to androgen ablation. Tumors were harvested from intact adult male rats in order to best approximate the human clinical setting in which receptor levels are quantitated prior to androgen ablative therapy. Only the nuclear salt-resistant (nuclear matrix) and total nuclear androgen receptor contents were significantly different among all tumor sublines. The properties of the tumors studied and their nuclear salt-resistant androgen receptor levels were as follows: H tumor--well-differentiated, slow growing, androgen-dependent, 63 +/- 11 fmol./mg. DNA; HI tumor--well-differentiated, slow growing, androgen-insensitive, 19 +/- 8 fmol./mg. DNA; G tumor--poorly-differentiated, fast growing, androgen-sensitive, 195 +/- 42 fmol./mg. DNA; and AT-2 tumor--anaplastic, fast growing, androgen-insensitive, no detectable receptors. There was no apparent quantitative relationship between androgen receptor content and tumor growth rates, which varied considerably irrespective of the androgen responsiveness of the tumor. However, there was a qualitative relationship between nuclear salt-resistant or total nuclear receptor content and androgen responsiveness. Higher levels of receptor (H and G tumor sublines) were associated with responsiveness to androgen ablation (cessation or slowing of growth, respectively), whereas lower levels of receptor (HI and AT-2 sublines) were associated with androgen insensitivity. These observations, based on relatively homogeneous tumors, may have important implications for human prostatic cancers which appear to be composed of heterogeneous cell populations.
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PMID:The relationship of androgen receptor levels to androgen responsiveness in the Dunning R3327 rat prostate tumor sublines. 647 Dec 35

The growth of the R3327-G rat prostatic adenocarcinoma was significantly reduced when implanted in orchiectomized male rats (ORCH tumors). Tumors grown in intact animals (control tumors) had a doubling time of 7.4 days as compared to 9.2 days in ORCH tumors. A computer-based analysis of flow cytometric DNA histograms also detected significant differences between control and ORCH tumors. ORCH tumors were found to have 25% fewer cells with hyperdiploid DNA than control tumors (p less than 0.01). This androgen sensitivity in growth rate and the proportion of hyperdiploid cells were further reflected in the binding of [3H]methyltrienolone ([3H]-R1881) to cytoplasmic (cytosol) and nuclear tumor extracts. ORCH tumor cytosols had a [3H]R1881 binding capacity which was 70% lower than controls (6071 fmol/g tumor tissue). Nuclear [3H]R1881 binding in ORCH tumors was undetectable in seven of eight samples while in control tumors, binding was detectable in five of six preparations. Sucrose density gradient analysis showed that cytosolic [3H]R1881 receptors sedimented at 8.1 S in low salt and 4.6 to 3.3S in high salt. Nuclear [3H]R1881 receptors in high salt sedimented at 4.1 to 3.3S. Competition experiments using [3H]R1881 showed that [3H]-R1881 receptors were primarily androgenic, although some displacement by estradiol did occur. In contrast, [3H]estradiol binding was found to be highly specific. The binding capacity of [3H]estradiol in ORCH tumor cytosols was 30% higher than controls (962 fmol/g tumor issue), while binding to ORCH and control nuclear extracts was similar. These data suggest that the inhibition of androgen-sensitive R3327-G tumor cells was related to the concentration of androgen receptors and that this in turn was expressed as a reduction in the proportion of hyperdiploid cells.
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PMID:Hormone sensitivity of the R3327-G rat prostate adenocarcinoma: growth rate, DNA content, and hormone receptors. 707 99