[Pneumoconiosis and exposure to wood].
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Humans↗
Biomedical subjects
M Vincent
Publications and source records attributed to M Vincent.
Direct interaction of the KRAB/Cys2-His2 zinc finger protein ZNF74 with a hyperphosphorylated form of the RNA polymerase II largest subunit.
We previously identified ZNF74 as a developmentally expressed gene commonly deleted in DiGeorge syndrome. ZNF74 encodes an RNA-binding protein tightly associated with the nuclear matrix and belongs to a large subfamily of Cys2-His2 zinc finger proteins containing a KRAB (Kruppel-associated box) repressor motif. We now report on the multifunctionality of the zinc finger domain of ZNF74. This nucleic acid binding domain is shown here to function as a nuclear matrix targeting sequence and to be involved in protein-protein interaction. By far-Western analysis and coimmunoprecipitation studies, we demonstrate that ZNF74 interacts, via its zinc finger domain, with the hyperphosphorylated largest subunit of RNA polymerase II (pol IIo) but not with the hypophosphorylated form. The importance of the phosphorylation in this interaction is supported by the observation that phosphatase treatment inhibits ZNF74 binding. Double immunofluorescence experiments indicate that ZNF74 colocalizes with the pol IIo and the SC35 splicing factor in irregularly shaped subnuclear domains. Thus, ZNF74 sublocalization in nuclear domains enriched in pre-mRNA maturating factors, its RNA binding activity, and its direct phosphodependent interaction with the pol IIo, a form of the RNA polymerase functionally associated with pre- mRNA processing, suggest a role for this member of the KRAB multifinger protein family in RNA processing.
Animals↗
Nuclear translocation and carboxyl-terminal domain phosphorylation of RNA polymerase II delineate the two phases of zygotic gene activation in mammalian embryos.
In mammalian embryos, zygotic gene transcription initiates after a limited number of cell divisions through a two-step process termed the zygotic gene activation (ZGA). Here we report that RNA polymerase II undergoes major changes in mouse and rabbit preimplantation embryos during the ZGA. In transcriptionally inactive unfertilized oocytes, the RNA polymerase II largest subunit is predominantly hyperphosphorylated on its carboxy-terminal domain (CTD). The CTD is markedly dephosphorylated several hours after fertilization, before the onset of a period characterized by a weak transcriptional activity. The largest subunit of RNA polymerase II then lacks immunological and drug-sensitivity characteristics related to its phosphorylation by the TFIIH-associated kinase and gradually translocates into the nuclei independently of DNA replication and mitosis. A phosphorylation pattern of the largest subunit, close to that observed in somatic cells, is established in both mouse and rabbit embryos at the stage when transcription becomes a requirement for further development (respectively at the 2- and 8/16-cell stage). As these events occurred in the presence of actinomycin D, the nuclear translocation of RNA polymerase II and the phosphorylation of the CTD might be major determinants of ZGA.
Animals↗
A pharmacogenetic approach to blood pressure in Lyon hypertensive rats. A chromosome 2 locus influences the response to a calcium antagonist.
In a backcross population (n = 281) derived from a cross of the Lyon hypertensive rat with Lyon normotensive rat, we investigated whether genetic factors influence the acute cardiovascular responses to pharmacological modulation of the renin-angiotensin system, the sympathetic nervous system, and the voltage-sensitive L-type calcium channels. Using microsatellite markers, a quantitative trait locus was identified and mapped on rat chromosome 2 that specifically influences the systolic (peak LOD score 4.4) and diastolic (peak LOD score 4.1) blood pressure responses to administration of a dihydropyridine calcium antagonist, PY108-068. The locus accounted for 10.3 and 10.4% of the total variances in the systolic and diastolic responses to PY108-068, respectively. In marked contrast, the locus had no effect on either basal blood pressure or on the responses to acute administration of a ganglionic blocking agent, trimetaphan, or of an angiotensin II subtype 1 receptor antagonist, losartan. These findings provide strong direct support for the paradigm that genetic factors may influence the response to antihypertensive drugs and suggest that the heterogeneity seen in the responses to different antihypertensive agents in human essential hypertension may have a significant genetic determination.
Animals↗
Immunosuppressor binding to the immunophilin FKBP59 affects the local structural dynamics of a surface beta-strand: time-resolved fluorescence study.
The interaction of the immunophilin domain of FKBP59 (FKBP59-I) with immunosuppressant drugs was investigated by steady-state and time-resolved fluorescence of tryptophan. One of the two Trp residues present in this protein (W89), conserved in almost all immunophilins, is buried in the hydrophobic core and participates in the immunosuppressant binding. By comparison with the highly homologous protein FKBP12, containing only the buried Trp, it has been concluded that its weak fluorescence is due to an atypical H-bond interaction involving the indole nitrogen and the Phe129 benzene ring. The second Trp residue (W59) in FKBP59-I is located on the external hydrophilic side of the 50-60 beta-sheet [Craescu, C. T., Rouvière, N., Popescu, A., Cerpolini, E., Lebeau, M.-C., Baulieu, E.-E., & Mispelter, J. (1996) Biochemistry 35, 11045-11052] and is responsible for >95% of the fluorescence emission. The long lifetime of the major excited state, the large activation energy of thermal quenching, and the rotational correlation time distribution pattern suggest that its environment is not highly mobile. Binding of the immunosuppressant drugs FK506 and rapamycin leads to a approximately 60% decrease of the fluorescence intensity without any change in the fluorescence emission maximum. Time-resolved measurements show that this "quenching" is due to a conformational change which depletes the long excited-state lifetime population to the profit of a more quenched minor excited state, which becomes prominent in the complexes. This is accompanied by a strong slowing of the indole ring dynamics in the case of FK506 and by a complete immobilization in the case of rapamycin, as shown by two-dimensional (tau, theta) maximum entropy analysis of the polarized fluorescence decays. Binding of the immunosuppressant drugs therefore modifies the structure and the dynamics of the external side of the 50-60 beta-sheet in FKBP59-I, which could be relevant for the formation of ternary complexes with other protein targets.
Acrylamide↗
Cloning and expression of a complementary DNA encoding a molluscan octopamine receptor that couples to chloride channels in HEK293 cells.
A cDNA encoding a G-protein-coupled receptor was cloned from the central nervous system of the pond snail Lymnaea stagnalis. The predicted amino acid sequence of this cDNA most closely resembles the Drosophila tyramine/octopamine receptor, the Locusta tyramine receptor, and an octopamine receptor (Lym oa1) that we recently cloned from Lymnaea. After stable expression of the cDNA in HEK293 cells, we found that [3H]rauwolscine binds with high affinity to the receptor (KD = 6.2.10(-9) M). Octopamine appears to be the most potent naturally occurring agonist to displace the [3H]rauwolscine binding (Ki = 3.0.10(-7) M). Therefore, the receptor is considered to be an octopamine receptor and is consequently designated Lym oa2. The novel receptor shares little pharmacological resemblance with Lym oa1, indicating that the two receptors represent different octopamine receptor subfamilies. Octopaminergic stimulation of Lym oa2 does not induce changes in intracellular concentrations of cAMP or inositol phosphates. However, electrophysiological experiments indicate that octopamine is able to activate a voltage-independent Cl- current in HEK293 cells stably expressing Lym oa2. Although opening of this chloride channel most probably does not require the activation of either protein kinase A or C, it can be blocked by inhibition of protein phosphorylation.
Amino Acid Sequence↗
Heat-shock inactivation of the TFIIH-associated kinase and change in the phosphorylation sites on the C-terminal domain of RNA polymerase II.
The C-terminal domain (CTD) of the RNA polymerase II largest subunit (RPB1) plays a central role in transcription. The CTD is unphosphorylated when the polymerase assembles into a preinitiation complex of transcription and becomes heavily phosphorylated during promoter clearance and entry into elongation of transcription. A kinase associated to the general transcription factor TFIIH, in the preinitiation complex, phosphorylates the CTD. The TFIIH-associated CTD kinase activity was found to decrease in extracts from heat-shocked HeLa cells compared to unstressed cells. This loss of activity correlated with a decreased solubility of the TFIIH factor. The TFIIH-kinase impairment during heat-shock was accompanied by the disappearance of a particular phosphoepitope (CC-3) on the RPB1 subunit. The CC-3 epitope was localized on the C-terminal end of the CTD and generated in vitro when the RPB1 subunit was phosphorylated by the TFIIH-associated kinase but not by another CTD kinase such as MAP kinase. In apparent discrepancy, the overall RPB1 subunit phosphorylation increased during heat-shock. The decreased activity in vivo of the TFIIH kinase might be compensated by a stress-activated CTD kinase such as MAP kinase. These results also suggest that heat-shock gene transcription may have a weak requirement for TFIIH kinase activity.
Binding Sites, Antibody↗
A phase I pilot study of pelvic radiation and alpha-2A interferon in patients with locally advanced or recurrent rectal cancer.
PURPOSE: The purpose of this pilot study was to determine the maximum tolerated dose of alpha-2a interferon given by subcutaneous injection and combined with high dose pelvic radiation for locally advanced or recurrent rectal cancer. METHODS AND MATERIALS: In this Phase I pilot study, patients with locally advanced, unresectable, or recurrent rectal cancer with or without distant metastases received external beam pelvic radiotherapy over 5 to 6 weeks combined with escalating doses of alpha-2a interferon. Interferon was escalated in increments of 3 million units for each patient cohort, starting at 3 million units subcutaneously 3 days weekly during pelvic radiation. Radiotherapy consisted of 44 Gy (2 Gy fractions) to the pelvis followed by a boost of 6 Gy or 16 Gy to gross pelvic tumor, depending on the presence or absence of small bowel in the boost field, respectively. Between 1991 and 1993, 10 patients were treated on this study, five with locally advanced and five with locally recurrent rectal cancer. RESULTS: At 6 million units of interferon, Grade 3 (WHO criteria) toxicities were as follows: diarrhea (one), leukopenia (one), and neutropenia (one). One patient died of a massive GI bleed at this dose level. Death was not felt to be treatment related. The maximum tolerated dose of interferon was 3 million units three times weekly with radiation. Three patients had unusual complications at 4, 6, and 6 months possibly related to treatment. The first had a right distal ureteric stricture with a right urinoma. The second had a sudden left foot drop that has remained stable. The third had sudden onset of bilateral lower extremity paraplegia with spontaneous resolution. CONCLUSIONS: The maximally tolerated dose of interferon alpha-2a given three times weekly during pelvic radiation was 3 million units based on acute side effects. Nevertheless, even at this dose level there were three unusual subacute complications possibly related to treatment. Caution is advised when combining interferon alpha-2a with high dose pelvic radiation, especially in patients with predisposing conditions (such as diabetes) for radiotherapy complications.
Aged↗
Laurdan solvatochromism: solvent dielectric relaxation and intramolecular excited-state reaction.
Absorption, steady-state, and time-resolved fluorescence measurements have been performed on laurdan dissolved either in white viscous apolar solvents or in ethanol as a function of temperature. The heterogeneity of the absorption spectra in white oils or in ethanol is consistent with semiempirical calculations performed previously on Prodan. From steady-state and time-resolved fluorescence measurements in apolar media, an excited state reaction is evidenced. The bimodal lifetime distribution determined from the maximum entropy method (MEM) analysis is attributed to the radiative deexcitation of a "locally excited" (LE) state and of a "charge transfer" (CT) state, whereas a very short component (20 ps), the sign and the amplitude of which depend on the emission wavelength, is attributed to the kinetics of the interconvertion reaction. The observation of an isoemissive point in the temperature range from -50 degrees C to -110 degrees C in ethanol suggests an interconvertion between two average excited-state populations: unrelaxed and solvent-relaxed CT states. A further decrease in temperature (-190 degrees C), leading to frozen ethanol, induces an additional and important blue shift. This low temperature spectrum is partly attributed to the radiative deexcitation of the LE state. Time-resolved emission spectra (TRES) measurements at -80 degrees C in the ethanol liquid phase show a large spectral shift of approximately 2500 cm(-1) (stabilization energy of the excited state: 7.1 kcal x M(-1)). The time-dependent fluorescence shift (TDFS) is described for its major part by a nanosecond time constant. The initial part of the spectral shift reveals, however, a subnanosecond process that can be due to fast internal solvent reorientation and/or to intramolecular excited-state reactions. These two relaxation times are also detected in the analysis of the fluorescence decays in the middle range of emission energy. The activation energy of the longest process is approximately 3 kcal x M(-1). At -190 degrees C, one subnanosecond and one nanosecond excited-state reactions are also evidenced. They are likely due to intramolecular rearrangements after the excitation, leading to the CT state and not to solvent relaxation, which is severely hindered in these temperature conditions. Therefore, both intramolecular and solvent relaxations are responsible for the large Stokes shift displayed by this probe as a function of solvent polarity. A possible scheme is proposed for the deexcitation pathway, taking into account the kinetics observed in these different solvents.
2-Naphthylamine↗
Analysis of phenotypic consequences of renin gene polymorphism in Lyon rats.
OBJECTIVE: To investigate phenotypic consequences of renin gene polymorphism between Lyon hypertensive (LH) and normotensive (LN) rats because previously we demonstrated cosegregation of the LH allele with increased blood pressure in a cross of LH with LN rats. DESIGN: Two studies were conducted. Study 1 used a cohort of male F2 rats from a LH x LN cross. Eighty-two rats homozygous for the hypertensive (HH) renin gene allele were compared with 82 rats homozygous for the normotensive (NN) allele. Urinary steroid excretion was measured in 24 h urine samples collected from rats aged 6 weeks. The direct aortic blood pressure was recorded in 30-week-old rats and, after they had been killed, their kidney renin concentration (KRC) was measured. In study 2, renin, angiotensinogen and angiotensin converting enzyme plasma concentrations and renin messenger RNA (mRNA) levels were measured in renal and extra-renal tissues from 6- and 25-week-old LH and LN parental and HH and NN F2 male rats. METHODS: Urinary steroids and plasma components of the renin-angiotensin system (RAS) were measured using specific radioimmunoassays. mRNA levels were quantified by northern blotting. RESULTS: In study 1, HH F2 rats had a higher blood pressure (151.5 +/- 8.2 versus 146.0 +/- 7.4 mmHg, P < 0.001) and a lower KRC (514 +/- 203 versus 666 +/- 304 micrograms A1/h per g cortex, P < 0.01) than did NN rats aged 30 weeks. In covariate analysis the decrease in KRC in HH rats was attributable to their increased blood pressure rather than to the renin genotype. The renin genotype of rats aged 6 weeks was not associated with a change in the urinary excretion of aldosterone, desoxycorticosterone, corticosterone or 18-hydroxy desoxycorticosterone. In study 2, we found no difference either in plasma levels of RAS components or in renal or extrarenal renin mRNA levels either between parental LH and LN rats or between HH and NN F2 rats apart from a higher plasma renin concentration in LH rats aged 6 weeks. Renal, but not extra-renal, renin mRNA levels declined with age. CONCLUSIONS: We found no evidence of a renin genotype-dependent phenotypic difference in the RAS that could account for the effect of the renin locus on blood pressure in Lyon rats. Our findings suggest that the effect of the locus on blood pressure might be due to an as yet unidentified gene linked to renin.
Animals↗
Cervicogenic headache. Josey's cases revisited.
Before Sjaastad coined the term cervicogenic headache (CR) 15 years ago, neck-related headaches have been considered by different authors for many years. Even after the publication of diagnostic criteria, dispute on the clinical picture, differential diagnosis, pathophysiology and treatment of CR still persists. A paper published in 1949 by Josey reports on 6 "illustrative" cases of cervical-related headaches. Indeed, looked from a more recent perspective, those cases could eventually correspond to CH. Important topics such as the relatively high frequency, fixed unilaterality of the pain, relation to previous trauma, irradiation from the back to the forehead, normal or slightly abnormal roentgenograms, and the mechanical precipitation of attacks are some of the topics considered by Josey. The female gender was not prevalent in Josey's series. Traction and analgesics were basically the recommended treatment. CR is probably a common disorder, an idea already considered by a clinician in 1949. This syndrome was not adequately described before Sjaastad's group papers in the 80's.
Female↗
Discrimination of run-on transcription from constitutive genes and antisense expression vectors in the same cells.
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Base Sequence↗
Relationship of red blood cell ion transport alterations and serum lipid abnormalities in Lyon genetically hypertensive rats.
Alterations of Na+ and K+ transport in erythrocytes of hypertensive humans or animals are often associated with abnormal lipid metabolism. The aim of the present study was to investigate red blood cell ion transport in Lyon inbred strains selected from Sprague-Dawley rats for different blood pressure levels. Lyon strains are characterized by important metabolic changes, including plasma lipid abnormalities. Serum triglycerides, cholesterol, and uric acid as well as red blood cell Na+ and K+ (Rb+) transport mediated by Na(+)-K+ pump or Na(+)-K+ cotransport and cation leaks were studied in hypertensive (LH), normotensive (LN), and low blood pressure (LL) Lyon rats aged 12 weeks. Increased erythrocyte Na+ content (Nai+) and higher levels of serum triglycerides, cholesterol, and uric acid were demonstrated in LH rats compared with LN animals. Nevertheless, at this age serum triglycerides and erythrocyte Nai+ of LL rats were even higher than those of LH animals. There were no significant differences between Lyon strains in either Na(+)-K+ pump activity or bumetanide-resistant (BR) cation leaks. The activity of bumetanide-sensitive (BS) Na(+)-K+ cotransport mediating inward Na+ movement was highest in LL rats and lowest in LH animals. In Lyon rats, Nai+ was positively related to serum triglycerides, whereas blood pressure correlated positively with BR Na+ leak and negatively with BS net Na+ uptake. A similar association of erythrocyte Nai+ with serum triglycerides was also observed in Prague hereditary hypertriglyceridemic rats (HTG) that were selected from Wistar rats for high plasma triglycerides. The major difference of the two forms of genetic hypertension associated with abnormal lipid metabolism was in BS net Na+ uptake, which was enhanced in HTG but reduced in LH rats. This was probably due to differences in plasma cholesterol, which was elevated in LH but not in HTG animals. Our study in Lyon rats confirmed the positive association of blood pressure with Na+ leak as a characteristic feature of genetic hypertension.
Animals↗
The nuclear matrix protein p255 is a highly phosphorylated form of RNA polymerase II largest subunit which associates with spliceosomes.
The monoclonal antibody CC-3 recognizes a phosphodependent epitope on a 255 kDa nuclear matrix protein (p255) recently shown to associate with splicing complexes as part of the [U4/U6.U5] tri-snRNP particle [Chabot et al. (1995) Nucleic Acids Res. 23, 3206-3213]. In mouse and Drosophila cultured cells the electrophoretic mobility of p255, faster in the latter species, was identical to that of the hyperphosphorylated form of RNA polymerase II largest subunit (IIo). The CC-3 immunoreactivity of p255 was abolished by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole, which is known to cause the dephosphorylation of the C-terminal domain of subunit IIo by inhibiting the TFIIH-associated kinase. The identity of p255 was confirmed by showing that CC-3-immunoprecipitated p255 was recognized by POL3/3 and 8WG16, two antibodies specific to RNA polymerase II largest subunit. Lastly, the recovery of RNA polymerase II largest subunit from HeLa splicing mixtures was compromised by EDTA, which prevents the interaction of p255 with splicing complexes and inhibits splicing. Our results indicate that p255 represents a highly phosphorylated form of RNA polymerase II largest subunit physically associated with spliceosomes and possibly involved in coupling transcription to RNA processing.
3T3 Cells↗
New prolyl endopeptidase inhibitors: in vitro and in vivo activities of azabicyclo[2.2.2]octane, azabicyclo[2.2.1]heptane, and perhydroindole derivatives.
A series of potent and selective prolylendopeptidase (PEP) inhibitors of the alpha-keto heterocyclic type has been obtained by replacing the classical central proline of 1-[1-(4-phenylbutanoyl)-L-prolyl]pyrrolidine (SUAM 1221,3) by non-natural amino acids PHI, ABO, and ABH. These 4-phenylbutanoyl side-chain-containing inhibitors exhibited potent in vitro inhibitory potencies with IC50 around 30 nM (compounds 24 and 25). Modulation of the side chain by replacement of the terminal phenyl ring by the dicyclopropyl moiety afforded derivatives 30 and 32 with improved potencies (IC50 between 10 and 20 nM). Furthermore, replacing the linear 4-phenylbutanoyl side chain by the (2-phenylcyclopropyl)carbonyl entity provided potent inhibitors with IC50 culminating at 0.9 nM on a rat cortex enzymatic preparation (compound 70). The configuration of the cyclopropyl ring had to be R,R in order to obtain not only a strong PEP inhibition in vitro but also a good activity in vivo, exemplified by inhibitor 68, which gave ID50 ip and po of 0.3 and 1 mg/kg, respectively. Finally, demonstration of the cognition-enhancing properties of compound 54 was given in the passive avoidance test using scopolamine-induced amnesia in the rat, where it dose dependently inhibited the scopolamine-induced decrease in avoidance response.
Alzheimer Disease↗
Conformational transitions within the calmodulin-binding site of Bordetella pertussis adenylate cyclase studied by time-resolved fluorescence of Trp242 and circular dichroism.
The sequence situated around Trp242 in Bordetella pertussis adenylate cyclase, a bifunctional protein of 1706 amino acid residues, forms the core of the calmodulin-binding site. Peptides varying in size and in affinity for calmodulin, and preserving the same sequence around Trp242 were analyzed by time-resolved fluorescence spectroscopy. Their dynamic properties were compared to those of the catalytic domain of B. pertussis adenylate cyclase corresponding to the first 400 amino acid residues of the protein and in which the Trp69 residue was replaced by Phe. The heterogeneity of the fluorescence intensity decays of Trp242 is likely due to the existence of conformers in equilibrium as is suggested by the effect of trifluoroethanol both on the secondary structure content and the lifetime distributions. Binding to calmodulin leads to striking effects on the lifetime distribution profiles by selecting a major excited state population and therefore one major conformer. Trp242 still presents some degree of rotational freedom in the complexes. The reduction of rotational freedom is more important for the shorter peptides than for the longest one. A similar selection of one major conformer with the same lifetime was also observed for the Trp242 in the mutant protein when bound to calmodulin, as in the complexes with the peptides. We conclude that the site of interaction of B. pertussis adenylate cyclase with calmodulin has similar conformational flexibility as that evidenced in the isolated peptides. This property of the molecule allows a better adjustment of the enzyme upon interaction with calmodulin.
Adenylyl Cyclases↗
Remodeling of the cytoskeletal lattice in denervated skeletal muscle.
The effect of denervation-induced atrophy on the cytoskeletal lattice in rat fast- and slow-twitch skeletal muscle has been investigated. Immunochemical analyses and immunofluorescence microscopy experiments employing monospecific antibodies to dystrophin, desmin, and alpha-tubulin were carried out on intact and denervated muscles. The relative cellular content of dystrophin and desmin were reduced in the soleus muscle (slow-twitch), while significant increases were shown in the gastrocnemius muscle (fast-twitch). In both muscles, alpha-tubulin levels increased up to 12-fold as a function of time compared to control values. Immunofluorescence microscopy revealed a distinct rearrangement of the microtubule network toward a predominantly longitudinal alignment, which was accompanied by an increase in the density of the fluorescence. It is concluded that the relative increase of the three structural proteins in the fast-twitch gastrocnemius muscle may be related to the apparent resistance of this muscle type to denervation-induced atrophy. The increased alpha-tubulin content in denervated slow- and fast-twitch muscles could be indicative of an adaptive mechanism designed to maintain the integrity of the muscle fiber in view of eventual regenerative activities.
Animals↗
Phase II trial of ZD1694 (Tomudex) in patients with advanced pancreatic cancer.
BACKGROUND: Currently available therapies for advanced pancreatic cancer offer only palliative benefits, and patients with this disease have a poor prognosis. We undertook a phase II trial of ZD1694 (Tomudex), a quinazoline folate analogue that is a potent and selective thymidylate synthase inhibitor, to determine this analogue's efficacy and safety in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: ZD1694, 3.0 mg/m2, was administered to 42 adult patients with pancreatic adenocarcinoma as a 15-minute intravenous infusion every 3 weeks for up to 6 doses. Objective tumor response was assessed every 6 weeks; clinical examinations, adverse event assessments, and clinical laboratory tests were performed every 3 weeks. RESULTS: ZD1694 produced an overall response rate of 5% (95% confidence limits [CI], 1% to 16%) in the study group. Of 42 patients, 2 (5%) had a partial response, 12 (29%) had stable disease, 21 (50%) had disease progression, and 5 (11%) could not be evaluated for response. Grade 3 vomiting, grades 3 and 4 fever, grade 3 leukopenia, grade 4 thrombocytopenia, and grades 3 and 4 liver function elevations were reported. Toxic effects with ZD1694 were reversible and manageable. CONCLUSIONS: ZD1694 has an acceptable safety profile but limited activity in patients with advanced pancreatic cancer.
Adult↗