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Biomedical subjects

R E Steele

Publications and source records attributed to R E Steele.

At least 55 records · Page 3Linked to original sources
PubMed1991

Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease.

A new class of potent, selective, nonsteroidal inhibitors of aromatase have been discovered. The most potent member of this series is fadrozole hydrochloride, CGS 16949 A, 4-(5,6,7,8-tetrahydroimidazo[1,5-alpha]pyridin-5-yl)benzonitrile monohydrochloride, 26a. In addition, the 6,7-dihydropyrrolo[1,2-c]imidazole (21a) and the 6,7,8,9-tetrahydroimidazo[1,5-alpha]azepine (21b) analogues were synthesized and evaluated. CGS 16949 A's ability to selectively inhibit aromatase (IC50 = 4.5 nM) over other cytochrome P-450 enzymes and suppress estrogen production when administered orally make it a suitable candidate to test the potential of an aromatase inhibitor in estrogen-dependent diseases including breast cancer.

Animals↗
PubMed1990

Novel aromatase inhibitors.

Aminoglutethimide (AG), an inhibitor of the aromatase enzyme, inhibits the biosynthesis of estrogens and displays well-documented anti-tumor efficacy in breast-cancer. However, this efficacy is accompanied by a relative lack of specificity in inhibiting aromatase and moderate tolerability. We report on two new non-steroidal aromatase inhibitors (CGS 16949A and CGS 18320B) which are more potent, selective and efficacious in their inhibition of aromatase than AG. Both compounds inhibit aromatase more potently in vitro and in vivo (over 400 and 1000 times respectively) than AG. They are both more selective in their inhibition of aromatase with CGS 18320B showing an improved selectively over CGS 16949A. When administered to adult female rats, both compounds elicit responses in serum hormones similar to those seen after ovariectomy. The duration of action of CGS 18320B, however, appears to be longer than that of CGS 16949A. CGS 18320B and CGS 16949A cause almost complete regression of DMBA-induced mammary tumors in adult female rats and almost completely suppress the appearance of new tumors. Thus CGS 16949A and CGS 18320B represent significant advances in the search for novel aromatase inhibitors which are more potent, selective and efficacious than aminoglutethimide.

Animals↗
PubMed1990

Structure and expression of fyn genes in Xenopus laevis.

By low stringency screening of a Xenopus laevis oocyte cDNA library with a probe prepared from the yes oncogene of the avian retrovirus Y73, we have isolated clones encoding a 537 amino acid protein with 96% amino acid identity to the protein product of the human fyn proto-oncogene. In addition to the high degree of conservation at the amino acid sequence level, we also find a surprisingly high degree of sequence conservation between portions of the 5' untranslated regions of the frog and human genes. Probing of total DNA from a homozygous diploid frog with a fragment from one of the cDNA clones gave a hybridization pattern which is consistent with the presence of two fyn genes in the haploid Xenopus laevis genome. Hybridization analysis revealed that the ovary contains two different sized fyn RNAs, one 3.8 kb in length and the other 3.1 kb in length. Our finding of fyn transcripts brings to three the number of protein-tyrosine kinases of the src family whose mRNAs are found in X. laevis oocytes. This suggests that multiple protein-tyrosine kinases of the src family are required for processes in oogenesis or early development.

Amino Acid Sequence↗
PubMed1989

The two Xenopus laevis SRC genes are co-expressed and each produces functional pp60src.

The haploid genome of Xenopus laevis contains two src genes, and transcripts from both genes are found in the maternal RNA pool of the oocyte (Steele, R. E. (1985) Nucleic Acids Res. 13, 1747-1761). We have now isolated cDNA clones which contain complete coding sequences from both src mRNAs. In vitro translation of RNAs transcribed in vitro from these clones produces in each case a protein with an apparent molecular mass of 57 kDa. The in vitro-synthesized proteins show identical protease cleavage patterns. Sequence analysis of the coding regions of the two cDNAs revealed that they both produce 532-amino acid polypeptides which differ from each other at only eight sites. Analysis of silent site changes between the two coding sequences suggests that the two genes began diverging about 25 million years ago. Hybridization with probes specific for each of the two src RNAs indicates that the two genes are co-expressed in embryos and in at least some adult tissues as well as during oogenesis. Finally, expression of each of the cDNA clones in yeast causes the appearance of proteins which are recognized by an antibody which binds to phosphotryosine.

Amino Acid Sequence↗
PubMed1989

Structure and expression of STK, a src-related gene in the simple metazoan Hydra attenuata.

Both cDNA clones and a genomic DNA clone encoding a 509-amino-acid protein that is 64% similar to chicken pp60c-src were isolated from the simple metazoan Hydra attenuata. We have designated this gene STK, for src-type kinase. Features of the amino acid sequence of the protein encoded by the STK gene suggest that it is likely to be myristoylated and regulated by phosphorylation in a manner similar to that found for pp60c-src. The genomic sequence encoding the protein was found to be interrupted by at least two introns, one of which was located in a position identical to that of one of the introns in the chicken src gene. The STK gene was expressed during early development of H. attenuata and at high levels in the epithelial cells of adult polyps. Probing of Hydra proteins with an antibody to phosphotyrosine indicated that the major phosphotyrosine-containing protein in H. attenuata may be the STK protein itself. H. attenuata is the simplest organism from which a protein-tyrosine kinase gene has been isolated. The presence of such a gene in the evolutionarily ancient phylum Cnidaria suggests that protein-tyrosine kinase genes arose concomitantly with or shortly after the appearance of multicellular organisms.

Amino Acid Sequence↗
PubMed1989

The yes proto-oncogene is present in amphibians and contributes to the maternal RNA pool in the oocyte.

Low stringency screening of a cDNA library from the frog Xenopus laevis with a viral yes oncogene probe resulted in the isolation of clones with restriction maps which were distinct from previously identified X. laevis src cDNA clones. The polypeptide produced by in vitro translation of RNA synthesized from one of the clones was slightly larger in size than X. laevis pp60src, but gave protease cleavage patterns which were nearly identical to those yielded by pp60src. Determination of the DNA sequence of this clone revealed that it is derived from a X. laevis yes gene homologue. Transcripts from the yes gene were found in the ovary and consisted of a major 3.4 kb species and additional minor species. These findings indicate that the duplication event separating the src and yes genes occurred prior to the appearance of amphibians and that the yes gene product is likely to play an important role in oogenesis or early development.

Amino Acid Sequence↗
PubMed1988

Extracorporeal shock wave lithotripsy-induced perirenal hematomas.

Subcapsular or perirenal bleeding is the most commonly experienced adverse effect directly attributable to externally applied shock waves. The first consecutive 3,620 extracorporeal shock wave lithotripsy treatments with the HM3 Dornier lithotriptor at our institution resulted in 24 hematomas in 21 patients, for an incidence of 0.66 per cent. Various factors associated with treatment were examined. The number of shock waves (up to 2,000) and voltage up to 24 kv. did not correlate with the development of hematoma. Coagulation studies were normal in all patients with hematomas. There was no correlation of patients size and weight, or stone size, number or location with the occurrence rate of perinephric hematoma. Patients with pre-existing hypertension, particularly those with unsatisfactory control of hypertension, had a significantly increased incidence of perinephric hematoma. The incidence of hematoma in hypertensive patients was 2.5 per cent and it increased to 3.8 per cent in patients with unsatisfactory control of hypertension. Therefore, pre-existing hypertension is a significant risk factor in the occurrence of post-extracorporeal shock wave lithotripsy bleeding. The incidence of perinephric hematoma also was increased in patients with pre-treatment urinary tract infection and those who underwent simultaneous bilateral treatment. Management of post-extracorporeal shock wave lithotripsy bleeding generally is conservative although a third of the patients required transfusion.

Female↗
PubMed1988

Aromatase inhibition in the dog. I. Effect on serum LH, serum testosterone concentrations, testicular secretions and spermatogenesis.

Chronic treatment of intact male beagles with an orally active nonsteroidal aromatase inhibitor (4-(5,6,7,8-tetrahydroimidazo [1,5a] pyridin-5-yl) benzonitrile hydrochloride; CGS 16949; CIBA-GEIGY) at a dosage of 2.5 mg./kg. per day for six months resulted in increased (p less than 0.01) serum LH and testosterone concentrations compared to placebo-fed controls. The increases in serum LH and testosterone concentrations occurred by one week of treatment and were maintained over the six month period. Testes of CGS 16949A fed dogs obtained at termination of the experiment when perfused in vitro in the presence of a maximally stimulating concentration of LH secreted nondetectable amounts of estradiol and estrone and higher (p less than 0.01) amounts of testosterone, androstenedione and dihydrotestosterone than testes of control dogs. Despite these changes in androgen secretion there was no evidence on any effect of aromatase inhibition upon spermatogenesis. These data support the hypothesis that in the dog, estrogens play a major role in negative feedback of the hypothalamic-pituitary-testicular axis.

Animals↗
PubMed1988

Aromatase inhibition in the dog. II. Effect on growth, function, and pathology of the prostate.

To evaluate the role of aromatase inhibitors in the treatment of benign prostatic hyperplasia (BPH), the effects of a potent, oral, nonsteroidal aromatase inhibitor [4-(5,6,7,8-tetrahydroimidazo[1,5a]pyridin-5yl)benzonitrile; CGS-16949A, CIBA-GEIGY] on canine BPH have been studied. Twelve mature beagles with enlarged prostates were divided into two groups of similar age, prostatic size, and prostatic histology. Dogs were given either CGS-16949A at a dosage of 2.5 mg./kg./day p.o. (n = 6) or an oral placebo (n = 6) for 25 weeks. Treatment with aromatase inhibitor had no significant effect on prostatic weight nor on total DNA content when compared to controls (p greater than 0.1). Semen volume did not change with treatment, and prostatic tissue concentrations of testosterone, dihydrotestosterone (DHT), and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol) were similar for the treated and control beagles (p greater than 0.1). Protein concentration in the ejaculate, however, was significantly greater for the dogs receiving CGS-16949A (p less than 0.01). Histologically, there was no difference in the incidence or type of BPH between the two treatment groups. Beagles treated with aromatase inhibitor, however, did have a more severe inflammatory infiltrate of the prostatic parenchyma than the control dogs (p less than 0.01). The mean serum testosterone concentration for the beagles treated with aromatase inhibitor was 10 times greater than that for the control animals (p less than 0.01). The endocrine effect of this aromatase inhibitor in the male canine is presented in the preceding paper. Taken together, these results suggest that inhibition of endogenous aromatase activity is not an effective treatment for spontaneous BPH in the intact canine.

Animals↗
PubMed1988

Thermotolerance and synthesis of heat shock proteins: these responses are present in Hydra attenuata but absent in Hydra oligactis.

Organisms respond to environmental stress by synthesizing a small number of highly conserved heat shock proteins. In organisms as diverse as bacteria, plants, invertebrates, and vertebrates, synthesis of these proteins is directly correlated with the acquisition of thermotolerance. While studying the freshwater coelenterate hydra, we observed that Hydra oligactis was extremely sensitive to thermal stress. In contrast, the related species Hydra attenuata survives short-term exposure to high temperatures. Furthermore, after incubation at an elevated but nonlethal temperature, H. oligactis did not become thermotolerant. H. attenuata, however, acquired thermotolerance after such a preincubation. In H. attenuata the major heat shock protein was found to be 60 kDa in size. H. oligactis did not synthesize detectable levels of this protein or any new species of proteins in response to stress. Several other species of hydra were found to behave like H. oligactis in response to stress. Thus, these findings provide direct support for the hypothesis that heat shock proteins are required for stress tolerance and that the major heat shock protein in hydra does not have any effects on normal growth or physiology. The findings also indicate that the presence of a heat shock response might be related to the natural environment in which an organism lives.

Animals↗
PubMed1987

Comparison of results and morbidity of percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy.

Two new therapies, percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy, are revolutionizing the treatment of upper urinary tract calculi. We report the success and morbidity rates in 110 patients undergoing percutaneous nephrostolithotomy and 982 patients treated with extracorporeal shock wave lithotripsy. Staghorn calculi were excluded from this series. The over-all success rate (free of stones plus small asymptomatic residual fragments) was comparable with both modalities (percutaneous nephrostolithotomy 98 per cent and extracorporeal shock wave lithotripsy 95 per cent), although the presence of residual fragments was more common in kidneys treated with extracorporeal shock wave lithotripsy (24 versus 7 per cent). Patient morbidity as measured by temperature elevation, length of postoperative stay, pain and blood loss was significantly less (p less than 0.05) with extracorporeal shock wave lithotripsy than with percutaneous nephrostolithotomy. Re-treatment rates were similar with both procedures, and tended to increase in relation to increasing stone size and stone number. Post-treatment ancillary procedures (cystoscopy and stone manipulation, and percutaneous nephrostomy) were used more frequently with extracorporeal shock wave lithotripsy. Because of its efficacy and low morbidity, we conclude that extracorporeal shock wave lithotripsy is the treatment of choice for upper urinary tract calculi less than 2 cm. in diameter. However, percutaneous nephrostolithotomy will continue to have a primary role in the management of larger stones and cystine stones, and it will be used as a secondary procedure after unsuccessful extracorporeal shock wave lithotripsy treatments. In addition, because of the complimentary nature of these 2 new technologies certain complex stones, such as staghorn calculi, may be handled best by a combination of the 2 techniques.

Fever↗
PubMed1987

Management of upper ureteral calculi with extracorporeal shock wave lithotripsy.

The results of 471 extracorporeal shock wave lithotripsy treatments in 465 patients with solitary ureteral stones managed by several different techniques are reported. In situ treatment was performed in 123 cases without instrumentation and in 47 after placement of a ureteral catheter. Retrograde stone manipulation was performed in 245 cases immediately before extracorporeal shock wave lithotripsy and an additional 56 were manipulated with ureteral stent placement at least 1 week before extracorporeal shock wave lithotripsy. The success rate was significantly greater if the stone was manipulated into the kidney before extracorporeal shock wave lithotripsy. Significantly less energy (p less than 0.0001) was required for complete disintegration if the stone was free floating in the kidney. The need for subsequent procedures was significantly less (p less than 0.0001) for stones manipulated successfully into the kidney. Complications were infrequent, with the most common being ureteral perforation in 5.1 per cent of the cases, all of which were managed conservatively. Extracorporeal shock wave lithotripsy is the treatment of choice for proximal ureteral calculi because it is less morbid than percutaneous approaches and provides significantly better results than ureteroscopy. An attempt at manipulation of proximal ureteral calculi back into the kidney should be made before extracorporeal shock wave lithotripsy.

Adolescent↗
PubMed1987

Extracorporeal shock-wave lithotripsy.

Analysis of our data clearly demonstrates that morbidity, secondary treatment, post-treatment manipulations, and failure of treatment increase as the stone size increases because of the increased stone fragment burden. Patients whose stone burden was less than 2 cm clearly had less morbidity. Composition of the stone may also alter the success of treatment (with cystine, calcium oxalate monohydrate, and brushite stones being resistant to treatment). However, post-treatment morbidity and complications were observed in all categories. Perirenal hematomas are unpredictable by current preoperative testing. Obstruction with pain can occur any time after treatment but usually occurs within the first 48 hours in the majority of patients. Only 1 per cent of our patients required hospitalization in another institution after discharge. Ambulatory ESWL requires that staff at the facility or a urologist be able to observe and appropriately follow the patient for 24 to 48 hours after treatment.

Adult↗
PubMed1986

Extracorporeal shock wave lithotripsy experience in children.

Extracorporeal shock wave lithotripsy treatment for calculi of the upper urinary tract was performed in 15 children between 3 and 17 years old. Success was achieved in 93 per cent of the cases (72 per cent were free of stone and 21 per cent had insignificant fragments). No major complications were encountered in the series.

Adolescent↗