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Biomedical subjects

W H Miller

Publications and source records attributed to W H Miller.

At least 37 records · Page 2Linked to original sources
PubMed2000

A phase I-II study of 9-cis retinoic acid and interferon-alpha2b in patients with advanced renal-cell carcinoma: an NCIC Clinical Trials Group study.

Although advanced renal-cell carcinoma (RCC) responds poorly to standard therapies, phase I-II trials have shown activity for combinations of interferon-alpha2b (IFN) with a retinoid. Alitretinoin (9-cis RA) is an endogenous retinoid with high binding affinity for both RAR and RXR receptor families. This phase I-II study enrolled 38 patients with RCC in a dose-escalation study of tolerability, pharmacokinetics (PK), and efficacy of twice daily oral 9-cis RA with subcutaneous IFN. In contrast to studies with similar doses of daily 9-cis RA, PK studies found a consistent reduction in 9-cis RA concentrations of about 50% after multiple b.i.d. doses of 30 or 50 mg/m2, independent of cotreatment with IFN. In the phase I portion, toxicities included systemic symptoms typical of IFN and biochemical abnormalities previously associated with retinoids. Two patients experienced dose-limiting toxicity at 50 mg/m2 b.i.d. of 9-cis RA, thus the recommended phase II dose was 30 mg/m2 b.i.d. One of twenty-six evaluable patients achieved a durable objective partial remission, and repeated dosing with this regimen was poorly tolerated. This combination of retinoid and interferon is not recommended for further study in RCC.

Adult↗
PubMed2000

Feline papillomas and papillomaviruses.

Papillomaviruses (PVs) are highly species- and site-specific pathogens of stratified squamous epithelium. Although PV infections in the various Felidae are rarely reported, we identified productive infections in six cat species. PV-induced proliferative skin or mucous membrane lesions were confirmed by immunohistochemical screening for papillomavirus-specific capsid antigens. Seven monoclonal antibodies, each of which reacts with an immunodominant antigenic determinant of the bovine papillomavirus L1 gene product, revealed that feline PV capsid epitopes were conserved to various degrees. This battery of monoclonal antibodies established differential expression patterns among cutaneous and oral PVs of snow leopards and domestic cats, suggesting that they represent distinct viruses. Clinically, the lesions in all species and anatomic sites were locally extensive and frequently multiple. Histologically, the areas of epidermal hyperplasia were flat with a similarity to benign tumors induced by cutaneotropic, carcinogenic PVs in immunosuppressed human patients. Limited restriction endonuclease analyses of viral genomic DNA confirmed the variability among three viral genomes recovered from available frozen tissue. Because most previous PV isolates have been species specific, these studies suggest that at least eight different cat papillomaviruses infect the oral cavity (tentative designations: Asian lion, Panthera leo, P1PV; snow leopard, Panthera uncia, PuPV-1; bobcat, Felis rufus, FrPV; Florida panther, Felis concolor, FcPV; clouded leopard, Neofelis nebulosa, NnPV; and domestic cat, Felis domesticus, FdPV-2) or skin (domestic cat, F. domesticus, FdPV-1; and snow leopard, P. uncia, PuPV-2).

Animals↗
PubMed1999

Orally bioavailable nonpeptide vitronectin receptor antagonists containing 2-aminopyridine arginine mimetics.

A peptide RGD analog containing a novel 2-aminopyridine arginine mimetic was discovered to have good affinity and selectivity for the vitronectin receptor. Incorporation of the 2-aminopyridine arginine mimetic into the 3-oxo-1,4-benzodiazepine-2-acetic acid integrin antagonist series led to novel and potent nonpeptide vitronectin receptor antagonists with promising levels of oral bioavailability.

Administration, Oral↗
PubMed1999

CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment.

The CCAAT/enhancer binding protein epsilon (C/EBPepsilon) is a nuclear transcription factor expressed predominantly in myeloid cells and implicated as a potential regulator of myeloid differentiation. We show that it was rapidly induced in the acute promyelocytic leukemia (APL) cell line NB4 during granulocytic differentiation after exposure to retinoic acid (RA). Our data suggest that induction of C/EBPepsilon expression was through the retinoic acid receptor alpha (RARalpha) pathway. Reporter gene studies showed that C/EBPepsilon promoter/enhancer activity increased in a retinoid-dependent fashion via the retinoic acid response element (RARE) present in the promoter region of C/EBPepsilon. The RA-induced expression of C/EBPepsilon markedly increased in U937 myelomonoblasts that were induced to express promyelocytic leukemia/RARalpha (PML/RARalpha), but not in those induced to express promyelocytic leukemia zinc finger/RARalpha (PLZF/RARalpha). In retinoid-resistant APL cell lines, C/EBPepsilon either is not induced or is induced only at very high concentrations of RA (>/=10(-6) M). In addition, forced expression of C/EBPepsilon in the U937 myelomonoblastic leukemia cells mimicked terminal granulocytic differentiation, including morphologic changes, increased CD11b/CD66b expression, and induction of secondary granule protein expression. Our data strongly suggest that C/EBPepsilon is a downstream target gene responsible for RA-induced granulocytic differentiation of APL cells.

CCAAT-Enhancer-Binding Proteins↗
PubMed1999

Conformational preferences in a benzodiazepine series of potent nonpeptide fibrinogen receptor antagonists.

Previously, we reported the direct design of highly potent nonpeptide 3-oxo-1,4-benzodiazepine fibrinogen receptor antagonists from a constrained, RGD-containing cyclic semipeptide. The critical features incorporated into the design of these nonpeptides were the exocyclic amide at the 8-position which overlaid the Arg carbonyl, the phenyl ring which maintained an extended Gly conformation, and the diazepine ring which mimicked the gamma-turn at Asp. In this paper, we investigate conformational preferences of the 8-substituted benzodiazepine analogues by examining structural modifications to both the exocyclic amide and the seven-membered diazepine ring and by studying the conformation of the benzodiazepine ring using molecular modeling, X-ray crystallography, and NMR. We found that the directionality of the amide at the 8-position had little effect on activity and the (E)-olefin analogue retained significant potency, indicating that the trans orientation of the amide, and not the carbonyl or NH groups, made the largest contribution to the observed activity. For the diazepine ring, with the exception of the closely analogous 3-oxo-2-benzazepine ring system described previously, all of the modifications led to a significant reduction in activity compared to the potent 3-oxo-1, 4-benzodiazepine parent ring system, implicating this particular type of ring system as a desirable structural feature for high potency. Energy minimizations of a number of the modified analogues revealed that none could adopt the same low-energy conformation as the one shared by the active (S)-isomer of the 3-oxo-1, 4-benzodiazepines and 3-oxo-2-benzazepines. The overall data suggest that the features contributing to the observed high potency in this series are the orientation of the 3-4 amide and the conformational constraint imposed by the seven-membered ring, both of which position the key acidic and basic groups in the proper spatial relationship.

Benzodiazepines↗
PubMed1999

Effective dose equivalent due to gamma-ray emissions from hot particles.

The quantification of dose from hot particles in the nuclear power industry has received a good deal of attention in the past few years. Specifically, calculational models have been developed to determine shallow dose equivalent from both beta and gamma-rays (using VARSKIN) and to estimate deep dose equivalent based upon the gamma dose at a tissue depth of 1 cm. These two values are reported for regulatory purposes. The purpose of this study is to estimate another measure of dose from hot particles (or from skin contamination over a small area), specifically the effective dose equivalent which takes into account all organs of the body receiving appreciable dose from the gamma-ray emissions from the contamination. While it is generally recognized that this dose will be small, this study gives representative doses for a range of hot particle locations and gamma-ray energies. MCNP and the ADAM phantom have been used for the calculational model. The effective dose equivalent is found to range from 0.1 to 12 microSv h(-1) MBq(-1) (0.4 to 43 microrems h(-1) microCi(-1)) of gamma activity, depending upon the location of the hot particle on the body.

Dose-Response Relationship, Radiation↗
PubMed1999

Antihistamines in the management of allergic pruritus in dogs and cats.

Antihistamines clearly have a place in the management of pruritus in the atopic dog and cat and, in this paper, important aspects of pharmacology and pharmacokinetics, adverse effects and precautions, and clinical use of these compounds are reviewed. Successful use of antihistamines is dependent on, among other considerations, the adherence to recommended doses and frequencies of administration, the recognition and control of concurrent and secondary factors, the willingness to try several different compounds, and the realisation that these agents are best employed in a preventive fashion.

Animals↗
PubMed1999

Acyclovir is phosphorylated by the human cytomegalovirus UL97 protein.

Acyclovir (ACV) has shown efficacy in the prophylactic suppression of human cytomegalovirus (HCMV) reactivation in immunocompromised renal transplant patients without the toxicity associated with ganciclovir (GCV). The HCMV UL97 gene product, a protein kinase, is responsible for the phosphorylation of GCV in HCMV-infected cells. This report provides evidence for the phosphorylation of ACV by UL97. Anabolism studies with the HCMV wild-type strain AD169 and with recombinant mutants derived from marker transfer experiments performed by using mutant UL97 DNA from both clinical isolates and a laboratory-derived strain resistant to GCV showed that mutations in the UL97 gene cripple the ability of recombinant virus-infected cells to anabolize both GCV and ACV. These mutant UL97 recombinant viruses were less susceptible to both GCV and ACV than was the wild-type strain. A recombinant herpes simplex virus type 1 strain, in which the thymidine kinase gene is deleted and the UL13 gene is replaced with the HCMV UL97 gene, was able to induce the phosphorylation of ACV in infected cells. Finally, purified UL97 phosphorylated both GCV and ACV to their monophosphates. Our results indicate that UL97 promotes the selective activity of ACV against HCMV.

Acyclovir↗
PubMed1999

Design and characterization of orally active Arg-Gly-Asp peptidomimetic vitronectin receptor antagonist SB 265123 for prevention of bone loss in osteoporosis.

The Arg-Gly-Asp (RGD)-binding integrin alpha(V)beta(3) is highly expressed on osteoclasts and has been proposed to mediate cell-matrix adhesion required for osteoclast-mediated bone resorption. Antagonism of this receptor should prevent stable osteoclast adhesion and thereby inhibit bone resorption. We have generated an orally bioavailable, nonpeptide RGD mimetic alpha(v)beta(3) antagonist, SB 265123, which prevents bone loss in vivo when dosed by oral administration. SB 265123 binds alpha(v)beta(3) and the closely related integrin alpha(v)beta(5) with high affinity (K(i) = 3.5 and 1.3 nM, respectively), but binds only weakly to the related RGD-binding integrins alpha(IIb)beta(3) (K(i) >1 microM) and alpha(5)beta(1) (K(i) >1 microM). The compound inhibits alpha(v)beta(3)-mediated cell adhesion with an IC(50) = 60 nM and more importantly, inhibits human osteoclast-mediated bone resorption in vitro with an IC(50) = 48 nM. In vivo, SB 265123 completely blocks bone resorption in a thyroparathyroidectomized rat model of acute bone resorption when dosed at 2.5 mg/kg/h by continuous i.v. infusion. When dosed orally with 3 to 30 mg/kg b.i.d. , in the ovariectomy-induced rat model of osteoporosis, SB 265123 prevents bone resorption in a dose-dependent fashion. This is the first report of an orally active alpha(v)beta(3) antagonist that is effective at inhibiting bone resorption when dosed in a pharmaceutically acceptable fashion. Such a molecule may provide a novel therapeutic agent for the treatment of postmenopausal osteoporosis.

Acetates↗
PubMed1999

Preclinical pharmacokinetics and interspecies scaling of a novel vitronectin receptor antagonist.

Allometric scaling may be used in drug development to predict the pharmacokinetics of xenobiotics in humans from animal data. Although allometry may be successful for compounds that are excreted unchanged or that are oxidatively metabolized (with corrections for metabolic capacity), it has been more challenging for compounds excreted primarily as conjugates in bile. (S)-10, 11-Dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[ a, d]cycloheptene-10-acetic acid (SB-265123) is a novel alphavbeta3 ("vitronectin receptor") antagonist. In this study, the in vivo pharmacokinetics and in vitro plasma protein binding of SB-265123 were examined in four species: mice, rats, dogs, and monkeys. In monkeys and dogs, SB-265123 exhibited moderate clearance, whereas low clearance (<20% hepatic blood flow) was observed in the rat, and high clearance (>70% hepatic blood flow) was seen in the mouse. The concentration-time profiles indicated the possibility of enterohepatic recirculation; subsequent studies in bile duct-cannulated rats demonstrated extensive biliary excretion of an acyl-glucuronide of SB-265123. In allometric scaling to predict the disposition of SB-265123 in humans, various standard correction factors were applied, including protein binding, maximum lifespan potential, and brain weight; each failed to produce adequate interspecies scaling of clearance (r(2) < 0.72). Consequently, a novel correction factor incorporating bile flow and microsomal UDP-glucuronosyltransferase activity in each species was applied, demonstrating substantial improvement in the correlation of the allometric plot (r(2) = 0.96). This study demonstrates a novel allometric correction that may be applicable to compounds that undergo conjugation and biliary excretion.

Acetates↗
PubMed1998

Trivalent antimonials induce degradation of the PML-RAR oncoprotein and reorganization of the promyelocytic leukemia nuclear bodies in acute promyelocytic leukemia NB4 cells.

Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation that fuses the genes encoding the promyelocytic leukemia protein (PML) and the retinoic acid receptor (RAR). The resulting PML-RAR protein induces a block in the differentiation of the myeloid progenitor cells, which can be released by retinoic acid (RA) in vitro and in vivo. The RA-induced differentiation of APL blasts is paralleled by the degradation of the fusion protein and the relocation of wild-type PML from aberrant nuclear structures to its normal localization in nuclear bodies. Recently, arsenic trioxide (As2O3) treatment was proposed as an alternative therapy in APL, because it can induce complete remission in both RA-sensitive and -resistant APL patients. Intriguingly, As2O3 was also shown to induce degradation of the PML-RAR chimera and to reorganize PML nuclear bodies. Here we show that trivalent antimonials also have striking effects on RA-sensitive and RA-resistant APL cells. Treatment of the APL-derived NB4 cells and the RA-resistant subclone NB4R4 with antimony trioxide or potassium antimonyl tartrat triggers the degradation of the fusion protein and the concomitant reorganization of the PML nuclear bodies. In addition, as reported for As2O3, the antimonials provoke apoptosis of NB4 and NB4R4 cells. The mechanism of antimony action is likely to be similar to that of As2O3, notably both substances induce the attachment of the ubiquitin-like SUMO-1 molecule to the PML moiety of PML-RAR. From these data, we propose that, in analogy to As2O3, antimonials might have a beneficial therapeutic effect on APL patients, perhaps with less toxicity than arsenic.

Antimony↗
PubMed1998

Estrogen receptor expression activates the transcriptional and growth-inhibitory response to retinoids without enhanced retinoic acid receptor alpha expression.

Estrogen receptor (ER)-positive human breast cancer cells are hormonally regulated and are inhibited by retinoids, whereas most ER-negative breast cancer cells are not. Here, we compared retinoid-induced transcriptional activation and growth inhibition in the ER-negative breast cancer cell line MDA-MB-231, stably transfected to express wild-type ER (S30), with that of the ER-positive MCF-7 line and the ER-negative parental line. Retinoids inhibited growth of the ER-expressing S30 clone but not of the parental MDA-MB-231 cells. Unlike a previously reported MDA-MD-231 subclone that was transfected to express a mutated ER (G400V), S30 did not express increased levels of retinoid receptor RNA or protein, nor was there increased binding activity to retinoid-responsive DNA elements. However, stable expression of ER increased retinoid activation of transcription of a retinoic acid (RA) response elements from the low level in MDA-MB-231 to approach the level of MCF-7. The restored growth inhibition and transcriptional regulation by RA were unaffected by treatment with ER agonists or antagonists. Transient expression of ER but not of other nuclear receptors in MDA-MB-231 cells also activated retinoid-induced transcription, showing that this response is specific to ER. Furthermore, the effect of exogenously expressed ER on retinoid response was much greater than that obtained by overexpression of RA receptor alpha and/or retinoid X receptor alpha. Finally, a panel of ER mutants showed that enhancement of retinoid-induced transcriptional activity was dependent on the integrity of the DNA binding domain.

Antineoplastic Agents↗
PubMed1998

The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer.

BACKGROUND: Although significant advances have been made in the treatment of some malignancies, the prognosis of patients with metastatic tumors remains poor. Differentiating agents redirect cells toward their normal phenotype and therefore may reverse or suppress evolving malignant lesions or prevent cancer invasion. In addition, they offer a potential alternative to the classic cytostatic drugs. METHODS: The purpose of this review was to examine the current and potential future roles of differentiating agents in the treatment of cancer. RESULTS: Initial studies with differentiating agents focused on retinoid therapy. Although retinoids have shown some clinical success, their widespread use has been limited by resistance and, in the chemopreventive setting, toxicity. This has led to the synthesis of a number of new retinoids that currently are undergoing clinical investigation. A further approach to overcoming the drawbacks associated with exogenous retinoids has been to increase the levels of endogenous retinoic acid (RA) by inhibiting the cytochrome P450-mediated catabolism of RA using a novel class of agents known as retinoic acid metabolism blocking agents (RAMBAs). Liarozole, the first RAMBA to undergo clinical investigation, preferentially increases intratumor levels of endogenous RA resulting in antitumor activity. CONCLUSIONS: Although studies using exogenous retinoids in this setting have not yet fulfilled their initial promise, studies with a growing set of synthetic retinoids are ongoing. Furthermore, modulation of endogenous retinoids may offer a significant new potential treatment for cancer.

Antineoplastic Agents↗
PubMed1998

Role of the histone deacetylase complex in acute promyelocytic leukaemia.

Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.

Antineoplastic Agents↗