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PubMed2000

Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI.

Allergen-induced asthma is characterized by chronic pulmonary inflammation, reversible bronchoconstriction, and airway hyperreactivity to provocative stimuli. Multiple CC-chemokines, which are produced by pulmonary tissue in response to local allergen challenge of asthmatic patients or experimentally sensitized rodents, chemoattract leukocytes from the circulation into the lung parenchyma and airway, and may also modify nonchemotactic function. To determine the therapeutic potential of local intrapulmonary CC-chemokine blockade to modify asthma, a recombinant poxvirus-derived viral CC-chemokine inhibitor protein (vCCI), which binds with high affinity to rodent and human CC-chemokines in vitro and neutralizes their biological activity, was administered by the intranasal route. Administration of vCCI to the respiratory tract resulted in dramatically improved pulmonary physiological function and decreased inflammation of the airway and the lung parenchyma. In contrast, vCCI had no significant effect on the circulating levels of total or allergen-specific IgE, allergen-specific cytokine production by peripheral lymph node T cells, or peritoneal inflammation after local allergen challenge, indicating that vCCI did not alter systemic Ag-specific immunity or chemoattraction at extrapulmonary sites. Together, these findings emphasize the importance of intrapulmonary CC-chemokines in the pathogenesis of asthma, and the therapeutic potential of generic and local CC-chemokine blockade for this and other chronic diseases in which CC-chemokines are locally produced.

Administration, Intranasal↗

PubMed1994

Rate of activation and deactivation of K:Cl cotransport by changes in cell volume in hemoglobin SS, CC and AA red cells.

Red blood cells (RBC) of subjects homozygous for hemoglobin A (AA), C (CC) and S (SS) exhibit different cell volumes which might be related to differences in cell volume regulation. We have investigated how rapidly K:Cl cotransport is activated and deactivated to regulate the cell volume in these cells. We measured the time course of net K+ efflux after step changes in cell volume and determined two delay times: one for activation by cell swelling and a second for deactivation by cell shrinkage. Cell swelling induced by 220 mOsm media activated K+ efflux to high values (10-20 mmol/liter cell x hr) in CC and SS; normal AA had a threefold lower activity. The delay time for activation was very short in blood with a high percentage of reticulocytes (retics): (SS, 10% retics, 1.7 +/- 0.3 min delay, n = 8; AA, 10% retics, 4 +/- 1.5 min, n = 3; CC, 11.6% retics, 4 +/- 0.3, n = 3) and long in cells with a smaller percentage of reticulocytes: (AA, 1.5% retics, 10 +/- 1.4 min, n = 8; CC whole blood 6% retics, 10 +/- 2.0 min, n = 10, P < 0.02 vs. SS). The delay times for deactivation by cell shrinking were very short in SS (3.6 +/- 0.4 min, n = 8, P < 0.02) and AA cells with high retics (2.7 +/- 1 min, n = 3) and normal retics (2.8 +/- 1 min, n = 3), but 8-15-fold longer in CC cells (29 +/- 2.8 min, n = 9). Density fractionation of CC cells (n = 3) resulted in coenrichment of the top fraction in reticulocytes and in swelling-activated cotransport (fourfold) with short delay time for activation (4 +/- 0.3 min) and long delay for deactivation (14 +/- 4 min). The delay time for activation, but not for deactivation, increased markedly with increasing cell density. These findings indicate that all CC cells do not promptly shut off cotransport with cell shrinkage and high rates of cellular K+ loss persist after return to isotonic conditions. In summary, (i) K:Cl cotransport is not only very active in young cells but it is also very rapidly activated and deactivated in young AA and SS cells by changes in cell volume. (ii) Delay times for cotransport activation markedly increased with RBC age and in mature cells with low cotransport rates, long delay times for activation were observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Size↗

PubMed2002

The role of Ins(1,4,5)P(3) in signal transduction of the metabolic neuropeptide Mem-CC in the cetoniid beetle, Pachnoda sinuata.

We have investigated the role of inositol triphosphate, Ins(1,4,5)P(3), in the transduction of the hypertrehalosaemic and hyperprolinaemic signal of the endogenous neuropeptide Mem-CC in the cetoniid beetle Pachnoda sinuata. Flight and injection of Mem-CC into the haemocoel of the beetle induce an increase of Ins(1,4,5)P(3) levels in the fat body of the beetle. When Mem-CC is co-injected with U 73122, which is an inhibitor of phospholipase C, this effect is abolished. Mem-CC also elevates Ins(1,4,5)P(3) concentration in fat body pieces in vitro. The increase in Ins(1,4,5)P(3) levels is tissue-specific and does not occur in brain and flight muscles. Elevation of the Ins(1,4,5)P(3) levels upon injection of Mem-CC is time- and dose-dependent: the maximum response is reached after 3 min and a dose of 10 pmol is needed. Compounds that mimic the action of cAMP (cpt-cAMP, forskolin) do not influence the concentration of Ins(1,4,5)P(3), while those that stimulate G-proteins (aluminium fluoride and cholera toxin) cause an increase of Ins(1,4,5)P(3) levels. The application (in vivo and in vitro) of F-Ins(1,4,5)P(3), an Ins(1,4,5)P(3) analogue that penetrates the cell membrane, causes a mobilisation of carbohydrate reserves via the activation of glycogen phosphorylase but does not stimulate proline synthesis. In addition, U 73122 abolishes the hypertrehalosaemic but not the hyperprolinaemic effect of Mem-CC. The results suggest that the hypertrehalosaemic signal of Mem-CC is mediated via an increase of Ins(1,4,5)P(3) levels in the fat body of P. sinuata.

Animals↗

PubMed1991

Induction of heat-labile sites in DNA of mammalian cells by the antitumor alkylating drug CC-1065.

CC-1065 is a very potent antitumor antibiotic capable of covalent and noncovalent binding to the minor groove of naked DNA. Upon thermal treatment, covalent adducts formed between CC-1065 and DNA generate strand breaks [Reynolds, R. L., Molineux, I. J., Kaplan, D.J., Swenson, D.H., & Hurley, L.H. (1985) Biochemistry 24, 6228-6237]. We have shown that this molecular damage can be detected following CC-1065 treatment of mammalian whole cells. Using alkaline sucrose gradient analysis, we observe thermally induced breakage of [14C]thymidine-prelabeled DNA from drug-treated African green monkey kidney BSC-1 cells. Very little damage to cellular DNA by CC-1065 can be detected without first heating the drug-treated samples. CC-1065 can also generate heat-labile sites within DNA during cell lysis and heating, subsequent to the exposure of cells to drug, suggesting that a pool of free and noncovalently bound drug is available for posttreatment adduct formation. This effect was controlled for by mixing [3H]thymidine-labeled untreated cells with the [14C]thymidine-labeled drug-treated samples. The lowest drug dose at which heat-labile sites were detected was 3 nM CC-1065 (3 single-stranded breaks/10(6) base pairs). This concentration reduced survival of BSC-1 cells to 0.1% in cytotoxicity assays. The generation of CC-1065-induced lesions in cellular DNA is time dependent (the frequency of lesions caused by a 60 nM treatment reaching a plateau at 2 h) and is not readily reversible. The induction of heat-labile sites in cellular DNA was confirmed by gel electrophoretic analyses of the damage to intracellular simian virus 40 (SV40) DNA in SV40-infected BSC-1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗

PubMed1988

Recognition and repair of the CC-1065-(N3-adenine)-DNA adduct by the UVRABC nucleases.

The recognition and repair of the helix-stabilizing and relatively nondistortive CC-1065-(N3-adenine)-DNA adduct by UVRABC nuclease has been investigated both in vivo with phi X174 RFI DNA by a transfection assay and in vitro by a site-directed adduct in a 117 base pair fragment from M13mp1. CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis which binds within the minor groove of DNA through N3 of adenine. In contrast to the helix-destabilizing and distortive modifications of DNA caused by ultraviolet light or N-acetoxy-2-(acetylamino)fluorene, CC-1065 increases the melting point of DNA and decreases the S1 nuclease activity. Using a viral DNA-Escherichia coli transfection system, we have found that the uvrA, uvrB, and uvrC genes, which code for the major excision repair proteins for UV- and NAAAF-induced DNA damage, are also involved in the repair of CC-1065-DNA adducts. In contrast, the uvrD gene product, which has been found to be involved in the repair of UV damage, has no effect in repairing CC-1065-DNA adducts. Purified UVRA, UVRB, and UVRC proteins must work in concert to incise the drug-modified phi X174 RFI DNA. Using a site-directed and multiple CC-1065 modified (MspI-BstNI) 117 base pair fragment from M13mp1, we have found that UVRABC nuclease incises at the eighth phosphodiester bond on the 5' side of the CC-1065-DNA adduct on the drug-modified strand.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗

PubMed1996

Molecular cloning and functional expression of a new human CC-chemokine receptor gene.

The cloning of several receptors activated by either CC or CXC chemokines and belonging to the G protein-coupled family of receptors has been reported recently. In the present work, we describe the cloning of a human gene, named ChemR13, encoding a new CC-chemokine receptor. The gene encodes a protein of 352 amino acids with a calculated molecular mass of 40 600 Da and displaying a single potential site for N-linked glycosylation. Using a set of overlapping lambda clones, the genomic organisation of the locus was investigated, demonstrating that the ChemR13 gene is physically linked, and in the same orientation, as the CC-CKR2 gene that encodes a receptor for the monocyte chemoattractant protein-1 (MCP-1). A distance of 17.5 kb separates the two coding regions, which share 75% identity in nucleic acid and amino acid sequences. Human ChemR13 was functionally expressed in a stably transfected CHO-K1 cell line. Physiological responses to chemokines were monitored using a microphysiometer. Macrophage inflammatory protein 1 alpha (MIP-1 alpha) was the most potent agonist. MIP-1 beta and RANTES were also active at physiological concentrations. The other CC-chemokines, MCP-1, MCP-2 and MCP-3, as well as CXC-chemokines (IL-8, GRO alpha) had no effect. ChemR13 receptor transcripts were detected by Northern blotting in the promyeloblastic cell line KG-1A, suggesting a potential role in the control of granulocytic lineage proliferation or differentiation. ChemR13 is thus a new member of the growing family of chemokine receptors that mediate the recruitment of cells involved in immune and inflammatory processes. Being the fifth functionally identified receptor in his class, this new CC-chemokine receptor (CC-CKR) is tentatively designated CC-CKR5.

Amino Acid Sequence↗

PubMed2000

The thalidomide analogue CC-3052 inhibits HIV-1 and tumour necrosis factor-alpha (TNF-alpha) expression in acutely and chronically infected cells in vitro.

We investigated the in vitro effect of the water-soluble, highly stable thalidomide analogue CC-3052 on HIV-1 expression and TNF-alpha production in latently infected promonocytic U1 cells, acutely infected T cells and monocyte-derived human macrophages (MDM), and in mitogen-stimulated ex vivo cultures from patients with primary acute HIV-1 infection. HIV-1 expression was assessed by Northern blot analysis of RNAs, and ELISA for p24 antigen release and reverse transcriptase (RT) activity. TNF-alpha expression was evaluated by RT-polymerase chain reaction (PCR)-ELISA for mRNA and ELISA for protein secretion. We demonstrated that CC-3052 is able to inhibit HIV-1 expression, as evaluated by mRNA, p24 release and RT activity, in phorbol myristate acetate (PMA)- and cytokine-stimulated U1 cells. Furthermore, CC-3052 inhibited HIV-1 expression, as evaluated by p24 and RT activity, in acutely infected MDM and T cells. As far as TNF-alpha is concerned, CC-3052 significantly reduced TNF-alpha mRNA and protein secretion in PMA-stimulated U937 and U1 cells, and in PMA-stimulated uninfected and acutely infected MDM. Consistently, the addition of CC-3052 reduced TNF-alpha production in phytohaemagglutinin (PHA) and lipopolysaccharide (LPS)-stimulated whole blood cultures from patients during the primary acute phase of HIV-1 infection. Since TNF-alpha is among the most potent enhancers of HIV-1 expression, the effect of CC-3052 on TNF-alpha may account for its inhibitory activity on HIV-1 expression. Given the well documented immunopathological role of TNF-alpha and its correlation with viral load, advanced disease and poor prognosis, CC-3052 could be an interesting drug for the design of therapeutic strategies in association with anti-retroviral agents.

Anti-HIV Agents↗

PubMed1987

Demonstration of the asymmetric effect of CC-1065 on local DNA structure using a site-directed adduct in a 117-base-pair fragment from M13mp1.

Using DNase I and Alu I endonuclease analysis of a site-directed CC-1065-[N3-adenine]DNA adduct in a 117-base-pair fragment from M13mp1 DNA, we have demonstrated that CC-1065 produces an asymmetric effect on DNA conformation that extends more than one helix turn to the 5' side of the covalently modified adenine. CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis, which is believed to mediate its cytotoxic effects through covalent binding to DNA. Previous studies have demonstrated that CC-1065 binds covalently to N3 of adenine and lies within the minor groove of DNA spanning a 4-base-pair sequence to the 5' side of the modified adenine. DNase I footprinting of this site-directed CC-1065-DNA adduct on the noncovalently modified strand shows that inhibition of cleavage occurs over a 12-base region, which is bordered on the 3' side by a site of 2-fold enhancement of cleavage. On the covalently modified strand a much less pronounced inhibition/enhancement pattern of cleavage occurs as far as 11 bases to the 5' side of the covalently modified adenine. While Hae III is able to cleave the DNA on both strands on the 3' side of the covalently modified adenine, Alu I is only able to cleave the covalently modified strand on the 5' side of the adduct. By taking into account the recently published structure of DNase I, we are able to interpret these results and develop a model for the effect of CC-1065 on local DNA structure. In this model, we propose selective drug-induced distortion of the covalently modified strand as a consequence of the alkylation of adenine by CC-1065.

Adenine↗

PubMed1991

Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.

Studies on the structural origin of the DNA alkylation selectivity of the antitumor antibiotic (+)-CC-1065 are detailed. The sites of alkylation of double-stranded DNA were examined for simple derivatives of 7-methyl-1,2,8,8a-tetrahydrocycloprop[1,2-c]pyrrolo[3,2-e]indol- 4(5H)-one (CPI), (+)-CC-1065, and agents incorporating the parent 1,2,7,7a-tetrahydrocycloprop[1,2-c]indol-4-one (CI) left-hand subunit. The CI subunit of the agents is a much more reactive alkylating agent than the natural CPI alkylation subunit of CC-1065. Consequently, simple derivatives of CI were found to alkylate double-stranded DNA under milder conditions than were simple derivatives of CPI, and the marked similarities in the CI and CPI DNA alkylation profiles illustrate that CI represents the minimum pharmacophore of CPI. Comparisons of the DNA alkylation profiles of (+)-N-butyloxycarbonyl-CPI, (+)-N-acetyl-CPI, and (+)-CC-1065 revealed distinctions in the CPI and (+)-CC-1065 sites of alkylation, whereas the incorporation of the reactive CI electrophile into an analog of CC-1065 (CI-CDPI2) (CDPI, N3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid) provided an agent that possesses the characteristic CC-1065 DNA alkylation profile (site selectivity and relative site intensity). These observations suggest that the noncovalent binding selectivity of the agents may restrict the number of available DNA alkylation sites and play a productive role in controlling the sequence-selective alkylation by effectively delivering the electrophile to A + T-rich minor groove regions of DNA possessing accessible adenine N-3 alkylation sites. In turn, the noncovalent binding selectivity may be derived from preferential binding within the narrower, sterically more accessible A + T-rich minor groove of double-stranded DNA.

Alkylation↗

PubMed1997

Molecular cloning and expression of a novel rat CC-chemokine receptor (rCCR10rR) that binds MCP-1 and MIP-1beta with high affinity.

Chemokines stimulate the migration and activation of leukocytes to areas of inflammation or tissue damage by binding to specific seven-transmembrane G protein-coupled receptors. We report the cloning of a novel rat CC-chemokine receptor, the rat CCR10-related receptor (rCCR10rR), with 72% amino acid identity to the human CC-chemokine receptor CCR10 and 30%-35% amino acid identity to the known human CC-chemokine receptors CCR1, CCR2, CCR3, CCR4, and CCR5. Multiple tissue northern analysis indicates that rCCR10rR is expressed at a higher level in spleen than in the other tissues assayed. The CC-chemokines MIP-1beta and MCP-1 bind with highest affinity to rCCR10rR, with K(D) = 0.4 and 0.7 nM, respectively. The CC-chemokines RANTES and MIP-1alpha were poor competitors for MIP-1beta binding, with IC50 values of 150 nM and 86 nM, respectively, but the K(D) for RANTES binding was still in the nanamolar range (4.8 nM). These results indicate that rCCR10rR is a true member of the CC-chemokine receptor family and may be involved in eliciting the responses to the CC-chemokines MIP-1beta and MCP-1.

Amino Acid Sequence↗

PubMed1986

Genotoxicity of the antitumor antibiotic CC-1065.

CC-1065, a very potent antitumor antibiotic, is active against several animal tumors, and against human tumors in the cloning assay at doses 50-1000 times lower than other agents such as adriamycin. It binds and alkylates DNA, and inhibits DNA synthesis, suggesting a potential for genotoxicity. Therefore, the genotoxic effects of CC-1065 were tested in several assay systems. CC-1065 was weakly mutagenic in the Ames Salmonella mutation assay (strain TA100) without S9 activation, but lacked mutagenic activity in TA98 with or without activation. CC-1065 was a very potent mutagen in the Salmonella forward mutation assay (induction of 8-azaguanine resistance), increasing the mutation frequency 19-fold over background at 0.1 ng/ml without activation. In mammalian (V79) cells it was a very potent mutagen without activation, increasing the mutation frequency 20-fold over background a 0.5 ng/ml. CC-1065 induced chromosome aberrations in V79 cells at very low (less than 0.1 ng/ml) doses, making this assay the most sensitive. CC-1065 increased the induction of micronuclei in rats 10- to 20-fold over the background at 200 and 400 micrograms/kg, but not at 100 micrograms/kg. CC-1065 failed to cause DNA breaks or DNA--protein cross-links as measured by the DNA damage/alkaline elution assay.

Animals↗

PubMed2006

The thalidomide analogue, CC-4047, induces apoptosis signaling and growth arrest in childhood acute lymphoblastic leukemia cells in vitro and in vivo.

PURPOSE: Thalidomide and its analogues have shown promise in the treatment of multiple myeloma but their therapeutic potential has not been evaluated in models of acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: We assessed the effects of the thalidomide analogue, CC-4047, on the growth and apoptosis signaling of human B cell precursor (BCP) ALL cell lines and freshly obtained childhood BCP-ALL cells grown with or without stromal cells. In addition, we studied the effects of CC-4047 on the progression and dissemination of xenotransplanted human BCP-ALL cells in nonobese diabetic/severe combined immunodeficiency mice. RESULTS: CC-4047 reduced the proliferation of human BCP-ALL cell lines in vitro. In contrast with the antileukemic effect of cytarabin, this was more pronounced when cell lines or freshly obtained childhood BCP-ALL cells were cocultured with stromal cells. CC-4047 induced the cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase in stroma-cocultured BCP-ALL cells. The inhibition of tumor growth, caspase-3 cleavage, and reduced microvessel density was observed in nonobese diabetic/severe combined immunodeficiency mice inoculated s.c. with childhood BCP-ALL cells upon CC-4047 treatment. After i.v. BCP-ALL xenotransplantation, CC-4047 reduced splenic dissemination. CONCLUSIONS: The thalidomide analogue, CC-4047, displays profound cytostatic effects on stroma-supported human ALL cells both in vitro and in vivo.

Animals↗

PubMed1981

Some aspects of the pathophysiology of homozygous Hb CC erythrocytes.

We have studied erythrocytes from homozygous CC patients in vitro and in perfused rat mesoappendix vasculature to answer some long-standing questions. By examination of wet whole blood preparations, and by comparing the cell distribution on isopycnic continuous density gradients of whole blood samples from a splenectomized CC patient with those from three intact CC patients, we have demonstrated the presence of a distinct crystal-containing band of cells that is present in the former, but totally absent from the latter. We conclude that Hb CC cells containing crystals circulate in Hb CC individuals, but in intact patients they are effectively removed by the spleen. By use of 31P nuclear magnetic resonance and viscosity measurements on cells, we have demonstrated that intracellular aggregation of hemoglobin C occurs on deoxygenation even when no crystal formation is detectable by morphological methods. These two observations are in apparent contradiction with the absence of clinical microcirculatory impairment found in both intact and splenectomized CC patients. The contradiction was resolved by rheological studies on isolated rat mesoappendix preparations and erythrocyte diameter measurements that lead to the conclusion that the hemorheological properties of CC cells in the microcirculation are nearly normal because their increased viscosity is offset by their smaller diameter and size.

Blood Viscosity↗

PubMed2005

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1.

CC-4047, an immunomodulatory analog of thalidomide, inhibits multiple myeloma with unknown effects on the human osteoclast lineage. Early osteoclast progenitors are of hematopoietic origin and differentiate into mature bone resorbing multinucleated osteoclasts. We investigated the effects of CC-4047 and thalidomide on human osteoclastogenesis, using in vitro receptor activator of NFkappa-B ligand/macrophage colony-stimulating factor-stimulated bone marrow cell cultures. Treating bone marrow cultures with CC-4047 for 3 weeks decreased osteoclast formation accompanied by complete inhibition of bone resorption. The inhibitory effect was similar when cultures were treated for 3 weeks or for only the first week (90% inhibition), indicating that CC-4047 inhibits early stages of osteoclast formation. Inhibition of osteoclastogenesis by CC-4047 was mediated by a shift of lineage commitment to granulocyte colony-forming units at the expense of granulocyte-macrophage colony-forming units. Further studies revealed that this shift in lineage commitment was mediated through down-regulation of PU.1. Treatment with thalidomide resulted in significantly less potent inhibition of osteoclast formation and bone resorption. These results provide evidence that CC-4047 blocks osteoclast differentiation during early phases of osteoclastogenesis. Therefore, CC-4047 might be a valuable drug for targeting both tumors and osteoclastic activity in patients with multiple myeloma and other diseases associated with osteolytic lesions.

Angiogenesis Inhibitors↗

PubMed2004

Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma.

PURPOSE: To assess the safety, efficacy, and immunomodulatory effects of CC-4047 (Actimid; Celgene, San Diego, CA) in patients with relapsed or refractory myeloma. PATIENTS AND METHODS: Twenty-four relapsed or refractory patients were treated with a dose-escalating regimen of oral CC-4047. Clinical responses and adverse effects were identified, and peripheral T-cell subsets, serum cytokines, and proangiogenic factors were evaluated. RESULTS: CC-4047 was tolerated with no serious nonhematologic adverse events. All patients were eligible for analysis. Toxicity criteria during the initial 4 weeks of study were used to define the maximum-tolerated dose (MTD). During this period, one patient withdrew with a deep vein thrombosis (DVT) probably caused by an undiagnosed primary melanoma with lymphadenopathy in the groin, one patient withdrew because of progressive disease (PD), and three patients discontinued with neutropenia. Nineteen of 24 patients continued on treatment beyond 4 weeks to PD or development of a serious adverse event. Three further patients developed a DVT at 4, 9, and 11 months. Treatment resulted in a greater than 25% reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a greater than 50% reduction in paraprotein, and four (17%) of 24 patients entered complete remission. The MTD was 2 mg/d. All patients showed increased CD45RO expression on CD4(+) and CD8(+) cells, with a concomitant decrease in CD45RA(+) cells. CC-4047 treatment was associated with significantly increased serum interleukin (IL)-2 receptor and IL-12 levels, which is consistent with activation of T cells and monocytes and macrophages. CONCLUSION: This study demonstrates the safety and efficacy of CC-4047. The MTD of CC-4047 orally was 2 mg/d. This is the first report demonstrating in vivo T-cell costimulation by this class of compound, supporting a potential role for CC-4047 as an immunostimulatory adjuvant treatment.

Administration, Oral↗

PubMed2005

Band 3 modifications in Plasmodium falciparum-infected AA and CC erythrocytes assayed by autocorrelation analysis using quantum dots.

The molecular stability of hemoglobin is critical for normal erythrocyte functions, including oxygen transport. Hemoglobin C (HbC) is a mutant hemoglobin that has increased oxidative susceptibility due to an amino acid substitution (beta6: Glu to Lys). The growth of Plasmodium falciparum is abnormal in homozygous CC erythrocytes in vitro, and CC individuals show innate protection against severe P. falciparum malaria. We investigated one possible mechanism of innate protection using a quantum dot technique to compare the distribution of host membrane band 3 molecules in genotypically normal (AA) to CC erythrocytes. The high photostability of quantum dots facilitated the construction of 3D cell images and the quantification of fluorescent signal intensity. Power spectra and 1D autocorrelation analyses showed band 3 clusters on the surface of infected AA and CC erythrocytes. These clusters became larger as the parasites matured and were more abundant in CC erythrocytes. Further, average cluster size (500 nm) in uninfected (native) CC erythrocytes was comparable with that of parasitized AA erythrocytes but was significantly larger (1 microm) in parasitized CC erythrocytes. Increased band 3 clustering may enhance recognition sites for autoantibodies, which could contribute to the protective effect of hemoglobin C against malaria.

Animals↗

PubMed1994

Primary structure of CC-III, the glycosylated cysteine proteinase from the latex of Carica candamarcensis Hook.

The amino acid sequence of the cysteine proteinase CC-III from the latex of the subtropical species Carica candamarcensis Hook has been determined with the exception of seven residues (pos. 180-186). It was deduced from the sequence analysis of the whole chain and peptides obtained by tryptic, chymotryptic, peptic and thermolysinolytic hydrolysis. CC-III consists of 214 amino acid residues. Out of a total of eight cysteine residues, six are located at positions involved in the formation of the three disulfide bridges stabilizing the structure of papain related enzymes. CC-III from Carica candamarcensis is a glycoprotein with the carbohydrate moiety bound to asparagine at position 44. Out of 210 residues compared with the sequences of the four cysteine proteinases of Carica papaya L., CC-III shares 125 identical ones (59.5%) with papain, 142 (67.6%) with papaya proteinase IV, 146 (69.5%) with papaya proteinase III and 156 (74.3%) with chymopapain. All amino acid residues constituting the active site and subsite S2 in chymopapain are conserved in CC-III with the exception of the substitution Leu157--> Val in the latter. This fact as well as the highest degree of identity between CC-III and chymopapain point to a similar specificity of both enzymes and thus CC-III might be a suitable substitute for chymopapain as a chemonucleolytic agent.

Amino Acid Sequence↗

PubMed1999

Comparison of 24-hour ambulatory blood pressure data in hypertensive patients switched from nifedipine-GITS to nifedipine-CC.

STUDY OBJECTIVE: To evaluate 24-hour blood pressure control and frequency of adverse effects in patients with mild to moderate hypertension switched from nifedipine gastrointestinal therapeutic system (Nif-GITS) to nifedipine coat core (Nif-CC). DESIGN: Open-label, prospective, switch study SETTING: University-affiliated outpatient cardiology clinic. SUBJECTS: Twenty patients with mild to moderate essential hypertension, who were taking Nif-GITS 30, 60, or 90 mg/day for 8 weeks or longer. INTERVENTIONS: Patients stabilized with Nif-GITS 30, 60, or 90 mg were monitored over 24 hours with an ambulatory blood pressure monitor and were then switched to an equivalent dosage of Nif-CC. After 8 weeks+/-1 week taking Nif-CC, they were again monitored with a 24-hour blood pressure monitor. The 24-hour blood pressure load (percentage of values > 135/85 mm Hg for 24 hrs), daytime blood pressure load (percentage of values > 140/90 mm Hg from 7:00 A.M.-10:00 P.M.), nighttime blood pressure load (percentage of values > 120/80 mm Hg from 10:00 P.M.-7:00 A.M.), diurnal blood pressure variation, average 24-hour blood pressure, daytime blood pressure, nighttime blood pressure, mean blood pressure for the first 4 hours, and last 8 hours of the dosing interval were measured. Adverse effects such as headache, dizziness, and edema were also reported. MEASUREMENTS AND MAIN RESULTS: No differences in average 24 hour-blood pressure readings were observed but significant differences in blood pressure control during the first 4 and last 8 hours of the dosing interval were seen. Systolic and diastolic blood pressures were higher after approximately 16 hours in patients switched from Nif-GITS to Nif-CC. Although Nif-CC caused a greater initial response, it was less effective than Nif-GITS after 16 hours. This could explain the lack of differences in average 24-hour blood pressure values between formulations. Of the 20 patients, 20% experienced increased headaches, 20% showed signs of increased peripheral edema, and 10% reported occasional dizziness after switching agents. Three patients discontinued Nif-CC, two as ordered by their primary care physician and one on his own due to headache. CONCLUSION: This study suggests that patients switched from Nif-GITS to Nif-CC could experience increased blood pressure during the night or toward the end of the dosing interval. They could also experience adverse effects such as headache, edema, and dizziness, which could result in more physician visits and put patients with other disease states such as coronary heart disease at increased risk.

Adult↗