Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding of [3H] [D-Ala2, MePhe4, Gly-ol5]enkephalin ([3H]DAGO), [3H]D-Ala2,D-Leu5]enkephalin ([3H]DADLE) and (+/-)-[3H]ethylketocyclazocine ([3H]EKC) to neurotumor tissues derived from S20Y neuroblastoma cells transplanted into A/Jax mice was examined. Specific and saturable binding to [3H]DADLE and [3H]EKC was detected, and the data fit a single homogeneous binding site for each ligand. Scatchard analysis for [3H]DADLE and [3H]EKC yielded Kd values of 0.65 and 0.45 nM, respectively, and Bmax values of 9.2 and 116 fmol/mg protein. Binding was dependent on time, temperature, and pH, and was sensitive to Na+ and guanine nucleotides. Pretreatment of the tumor homogenates with trypsin markedly reduced binding to both ligands, suggesting that the binding sites were proteinaceous in character. Displacement experiments indicated that delta (delta) receptor related compounds (e.g. DPDPE, ICI 174,864) avidly displaced [3H]DADLE, whereas kappa (kappa) related compounds (e.g. U50,488, dynorphin) markedly competed with [3H]EKC. Mu (mu) receptor drugs (e.g. DAGO, beta-FNA, morphine) were not potent in displacing either [3H]DADLE or [3H]EKC. These results are the first to characterize opioid binding sites in tumor tissue. The function of these sites is unclear, but previous evidence as to the growth regulatory properties of endogenous opioid systems may suggest that either one, or both, binding sites may be involved in carcinogenic events.
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PMID:Characterization of opioid binding sites in murine neuroblastoma. 289 49

The gross and histopathologic findings seen in the stomachs of rats and mice treated with 2 different H2 receptor antagonists are presented. Studies with the first drug, ICI 125,211, elicited dysplasia/carcinoma lesions in 17 of 828 treated rats with 12 of the 17 lesions occurring in the pyloric region of the stomach. No tumors occurred in mice on study for 18 months. Studies conducted with another drug candidate, ICI 162,846, produced neuroendocrine carcinomas in the stomach of rats and mice. Twenty-five rats out of 312 treated male and female rats had neuroendocrine carcinomas in the gastric fundus with a higher tumor incidence in females. In a 24-month mouse study with ICI 162,846, 45 of 300 treated mice developed neuroendocrine carcinomas in the gastric fundus with a higher incidence in males.
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PMID:Morphologic stomach findings in rats and mice treated with the H2 receptor antagonists, ICI 125,211 and ICI 162,846. 290 45

Twenty-seven patients with metastatic adenocarcinoma of the prostate were treated with the new luteinizing hormone-releasing hormone analog, Zoladex (ICI 118,630) for up to ninety-eight weeks. Initially, treatment was randomized between Zoladex 250 micrograms and 500 micrograms self-injected subcutaneously every day for a minimum period of twelve weeks following which a sustained-release, once-monthly depot formulation of Zoladex 3.6 mg s.c. was used. Acute rises in serum gonadotropins and testosterone during the first two days were followed by declines in hormone levels over the following three weeks. Median time to castration with 500 micrograms/day was twenty-two days compared with forty-three days with 250 micrograms/day (p = 0.06). No significant endocrinologic changes occurred during the transfer to the depot, and serum testosterone remained 95 per cent suppressed throughout the duration of the study. After three months the median daily serum Zoladex concentrations ranged between 0.47 and 0.53 ng/ml and were not significantly different among the three dosage forms. No specific correlation among serum Zoladex concentrations, endocrinologic parameters, and tumor response rates were found. Hot flashes initially, and decreased libido were the only common complaints. Zoladex was well tolerated, and no side effects required dose-modification or removal from the study. Tumor response rates up to one year appeared to be comparable to the conventional endocrine therapies. This analog in monthly depot formulation is recommended for further clinical evaluation.
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PMID:Zoladex (ICI 118,630): clinical trial of new luteinizing hormone-releasing hormone analog in metastatic prostatic carcinoma. 294 17

A long-acting LRH agonist (ICI 118630, Zoladex) was given by monthly subcutaneous injection to 25 patients with previously untreated symptomatic advanced prostatic carcinoma. The medication was well tolerated with the only side effect being hot flushes in 15 patients. Subjective improvement occurred in 22 patients, and disease remission or stabilization judged by objective criteria was seen in 21 and 18 patients from the total group at 3 and 6 months of treatment, respectively. Twelve of 18 patients followed for 1 year were still in objective remission/stabilization. Prostate volume measured by ultrasound decreased by a mean value of 75% and urine flow increased significantly. There were significant falls in serum testosterone and gonadotrophin levels and significant although lesser reductions in serum androstenedione and dehydroepiandrosterone. These changes were accompanied by significant reductions in serum acid and alkaline phosphatase and a rise in serum osteocalcin. Four patients (16%) experienced an initial tumor flare. Although only a small number of patients were studied, Zoladex appeared to be a well-tolerated agent for treatment of prostatic carcinoma, with an initial clinical response similar to that seen with standard endocrine therapy.
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PMID:Treatment of metastatic prostate carcinoma with the depot LRH analog Zoladex. 296 31

To investigate the clinical efficacy, safety and endocrinology of ICI 118630 (Zoladex) depot formulation at 3 different dose levels (0.9, 1.8 and 3.6 mg), 90 patients were randomized to receive either one of the 3 doses from April, 1985 to March, 1986 in 28 centers. The depot preparation was injected subcutaneously every 4 weeks 3 times (for up to 12 weeks). Clinical efficacy was evaluated in terms of tumor response and overall subjective response. In 70 patients eligible for tumor response evaluation, 14 out of 22 (63.6%) in the 0.9 mg group, 11 out of 23 (47.8%) in the 1.8 mg group, and 17 out of 25 (68.0%) in the 3.6 mg group showed clinical improvement, that is, either complete response or partial response. In 72 eligible patients for overall subjective response evaluation, clinical subjective improvement was observed in 75.0, 81.8 and 88.0% of the patients in the 3 groups, respectively. There was no significant difference between the groups. As for endocrinology, there were 75 eligible patients. Endocrinological effect was observed in 23 out of 25 (92.0%) in the 0.9 mg group, 100% in both 1.8 mg and 3.6 mg groups. There was no significant difference between the groups. Castration was achieved by week 3.5 +/- 1.7 of therapy on average and by week 2 in the earliest case. There was no significant difference in incidence of side effects between the 3 groups: 5 out of 26 (19.2%) in the 0.9 mg group, 8 out of 29 (27.6%) in the 1.8 mg group, and 2 out of 30 (6.7%) in the 3.6 mg group. Flares presented as an increase in bone pain in 2 and as ureteric obstruction in 2 all in the 1.8 mg group but none in the other 2 dose groups. These flares disappeared on further treatment with Zoladex. These patients showed a clinical-response. The blood level of Zoladex was dose dependent, reaching its peak at week 2 of therapy in all 3 dose groups. There was no evidence of accumulation. Since these results demonstrate that 3.6 mg produces medical castration earlier, it may well be considered as an optimal dose in men.
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PMID:[Endocrine therapy of prostatic carcinoma with slow release (depot) formulation of the LH-RH analog ICI 118630 (Zoladex)]. 296 22

The trial drug was ICI 118.630 (Zoladex). Inclusion criteria were histologically confirmed advanced prostate cancer (T greater than 2 or N+ or M+), life expectancy greater than 3 months, and no previous radiotherapy, orchiectomy, or chemotherapy. Treatment started in November 1984; 30 patients were recruited. The period of treatment ranged from 6 to 144 weeks (median of 59.5 weeks). One patient died after 6 weeks of rapidly progressive renal failure. Data were updated to the end of August 1987. The mean age was 67.9 years (53-83 years). Subjective response was evaluated by a mean symptoms score (using daytime micturition, nocturia, dysuria, hesitancy, and flow) and a score of three different items: patients' activity, bone pain, and use of analgesics. Only 7.1% of the patients showed a permanent positive response. Four different objective responses (complete, partial, stable disease, and progression) were possible after evaluating the T category, tumor dimensions, metastases, and prostatic acid phosphatase. Testosterone (T) and plasmatic LH levels rose after administration: T dropped below the castration level (1 ng/ml) within a few days and remained constantly low. The rate of progressive disease was 27.6%; disease control was possible in 72.4% of the patients (PR or SD).
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PMID:LH-RH analogue treatment for advanced prostate cancer. 297 66

Ethylnitrosourea-induced pulmonary adenomas of the mouse have been reported as being predominantly Clara cell in origin. The response of these tumor cells in vivo to the secretory agonist, isoproterenol (10 mg/kg) and the antagonist, propranolol (2.0 mg/kg) 1 hour after intraperitoneal injection into 120-day-old tumor-bearing mice was examined. Ultrastructural morphometry was used to quantitate the secretory response of tumor cells by measuring the volume density of the secretory granules. In the intact animal, isoproterenol stimulated secretion in the Clara cell adenomas (40% decrease in volume density with no change in surface to volume ratio of granules), while propranolol prevented this effect. In addition, beta-adrenergic receptors on isolated tumor cells were demonstrated by radioligand-binding assay by using [125I]iodocyanopindolol (ICYP). Scatchard analysis of data derived from whole cells indicates a maximum receptor-binding capacity of 27 fmoles/mg of protein and a KD of 0.029 nM. Isoproterenol displacement of ICYP binding yields an IC50 of 8 X 10(-7) M and a calculated KD of 3.36 X 10(-7) M. The beta 2 identity of these receptors was determined by utilizing the relatively specific beta 1 and beta 2 antagonists practolol and ICI-118,551, respectively. Practolol failed to displace more than 30% of ICYP binding even at 100 microM, while ICI-118,551 displacement of ICYP yielded a linear Hofstee plot (r = 0.93) and a KD of 5.04 X 10(-9) M. These findings suggest that the secretory activity of Clara cell-like pulmonary adenomas is under beta-adrenergic control similar to that of normal bronchiolar Clara cells.
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PMID:Beta-adrenergic regulation of secretion from Clara cell adenomas of the mouse lung. 302 4

Tamoxifen (ICI 46474) is the trans-isomer of 1(p-beta-dimethylaminoethoxy-phenyl)-1, 2-diphenylbut-1-ene. In several but not all mammal species it is a potent anti-estrogen. It is thought to act by blocking estrogen receptors. Patients were 68 women with advanced primary carcinoma of the breast, recurrences in the chest wall or soft tissue metastases. The oral dose of tamoxifen was either 10 mg or 20 mg twice daily. Patients were seen and laboratory tests done monthly for 6 months. Side effects were usually trivial and their incidence was the same at both dose levels. Of 26 patients who showed a reduction in tumor size to half or less, 5 had been in remission for over a year and another 10 for over 6 months. Some tumor responses were spectacular. The drug was less effective for bone deposits. In this study 12 of 33 patients (36%) receiving 10 mg of tamoxifen twice daily showed a definite response while a futher 8 (24%) showed a partial response. A definite response was seen in 14 out of 35 (40%) receiving 20 mg twice daily and a partial response in a further 13 (37%). The total response for low dosage was 60% and for high dosage 77%.
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PMID:Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. 456 4

Clinical results of tamoxifen ('Nolvadex'-ICI) monotherapy in 44 premenopausal women with advanced breast cancer have been reviewed. Objective tumor regression was achieved in 12 (27%) patients and a further 10 (22%) were classified as 'stabilized'. Median duration of response was 12.7 months at the time of analysis. Greatest benefits occurred in soft tissue dominant and receptor-positive tumors, but there was no correlation between tumor response and other clinical manifestations of estrogen deprivation (e.g. menstrual disturbance, hot flushes). The benefits of conventional doses of tamoxifen do not therefore appear to be influenced by menopausal status and compare favorably to achievements reported after surgical oophorectomy.
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PMID:Tamoxifen (Nolvadex) for premenopausal patients with advanced breast cancer. 636 11

We previously identified a codon 351 (Asp-->Tyr) mutant estrogen receptor (ER) in a tamoxifen-stimulated human breast tumor line. To examine its biological activity, we have constructed cell lines from the ER-negative human breast cancer cell line MDA-MB-231 that stably express either the wild type (S30) or mutant ER (BC-2). ER expression was confirmed by Western blot, ligand-binding studies, and ER-enzyme immunoassay. The growth characteristics of the S30 and BC-2 cell lines were compared when treated with estradiol, fixed-ring 4-hydroxytamoxifen [(fr) 4-OH TAM], or ICI 182,780. (fr) 4-OH TAM is a stable, high affinity tamoxifen analog. Many investigators have recognized that growth of ER-negative cell lines stably transfected with ER is inhibited by estradiol. Similarly, both S30 and BC-2 cell lines are inhibited by estradiol in a concentration-dependent manner. (fr) 4-OH TAM has no effect on S30 proliferation but inhibits the growth of BC-2 cells. The pure antiestrogen ICI 182,780 can block the growth-inhibitory effect of estradiol in both cell lines and the growth-inhibitory effect of (fr) 4-OH TAM in the BC-2 cells. In transient transfection analyses using a luciferase reporter plasmid containing two copies of the Xenopus vitellogenin A2 estrogen response element, estradiol stimulated luciferase transcription through both the wild type and mutant estrogen receptors, while (fr) 4-OH TAM stimulated transcription to a greater extent through the mutant receptor. These results demonstrate that the estrogenicity of (fr) 4-OH TAM is increased by binding to the codon 351 mutant ER, and that ER activation and growth inhibition are associated.
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PMID:A naturally occurring estrogen receptor mutation results in increased estrogenicity of a tamoxifen analog. 747 79


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