PubMed Health⌕ Search

Biomedical subjects

C Cianci

Publications and source records attributed to C Cianci.

At least 19 recordsLinked to original sources
PubMed2001

An approach to the identification of potent inhibitors of influenza virus fusion using parallel synthesis methodology.

Structure-activity studies associated with the salicylic acid-derived inhibitor of influenza fusion, BMY-27709, were examined using a parallel synthesis approach. This SAR survey led to the discovery of potent influenza inhibitory activity in a series of aromatic amides and thioamides derived from 1,3,3-trimethyl-5-hydroxycyclohexylmethylamine. Select compounds were characterized as inhibitors of the H1 subtype of influenza A viruses that act by preventing the pH-induced fusion process, thereby blocking viral entry into host cells. In a plaque-reduction assay, the most potent inhibitors displayed EC(50) values of 0.02-0.14 microg/mL.

Amines↗
PubMed2000

Salicylamide inhibitors of influenza virus fusion.

Structural variation of the quinolizidine heterocycle of the influenza fusion inhibitor BMY-27709 was examined by several topological dissections in order to illuminate the critical features of the ring system. This exercise resulted in the identification of a series of synthetically more accessible decahydroquinolines that retained the structural elements of BMY-27709 important for antiviral activity. The 2-methyl-cis-decahydroquinoline 6f was the most potent influenza inhibitor identified that demonstrated an EC50 of 90 ng/mL in a plaque reduction assay.

Animals↗
PubMed1999

Novel quinolizidine salicylamide influenza fusion inhibitors.

A novel series of quinolizidine salicylamides was synthesized as specific inhibitors of the H1 subtype of influenza A viruses. These inhibitors inhibit the pH-induced fusion process, thereby blocking viral entry into host cells. Compound 16 was the most active inhibitor in this series with an EC50 of 0.25 microg/mL in plaque reduction assay. The synthesis and the SAR of these compounds are discussed.

Animals↗
PubMed1999

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study.

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus +/- LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m2 per day and the l-LV dose being 5 mg/m2 per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3-4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8-25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus +/- LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin.

Adult↗
PubMed1999

pH-dependent changes in photoaffinity labeling patterns of the H1 influenza virus hemagglutinin by using an inhibitor of viral fusion.

The hemagglutinin (HA) protein undergoes a low-pH-induced conformational change in the acidic milieu of the endosome, resulting in fusion of viral and cellular membranes. A class of compounds that specifically interact with the HA protein of H1 and H2 subtype viruses and inhibit this conformational change was recently described (G. X. Luo et al., Virology 226:66-76, 1996, and J. Virol. 71:4062-4070, 1997). In this study, purified HA trimers (bromelain-cleaved HA [BHA]) are used to examine the properties and binding characteristics of these inhibitors. Compounds were able to inhibit the low-pH-induced change of isolated trimers, as detected by resistance to digestion with trypsin. Protection from digestion was extremely stable, as BHA-inhibitor complexes could be incubated for 24 h in low pH with almost no change in BHA structure. One inhibitor was prepared as a radiolabeled photoaffinity analog and used to probe for specific drug interactions with the HA protein. Analysis of BHA after photoaffinity analog binding and UV cross-linking revealed that the HA2 subunit of the HA was specifically radiolabeled. Cross-linking of the photoaffinity analog to BHA under neutral (native) pH conditions identified a stretch of amino acids within the alpha-helix of HA2 that interact with the inhibitor. Interestingly, cross-linking of the analog under acidic conditions identified a different region within the HA2 N terminus which interacts with the photoaffinity compound. These attachment sites help to delineate a potential binding pocket and suggest a model whereby the BHA is able to undergo a partial, reversible structural change in the presence of inhibitor compound.

Amino Acid Sequence↗
PubMed1999

Conquering influenza: recent advances in anti-influenza drug discovery.

Morbidity and mortality associated with influenza virus infection have cut a wide swathe through medical history. Even with the development of killed virus vaccines, illness due to influenza virus infection continues to be a major health problem throughout the world. This may change over the next few years with the development of a new class of antiviral agents targeting the catalytic site of the viral neuraminidase enzyme. These agents have been demonstrated to be both efficacious and clinically beneficial. In addition, investigation into alternative anti-influenza targets continues. These include inhibitors of hemagglutinin-mediated functions, the viral polymerase and new inhibitors of M2 ion channel activity.

Journal Article↗
PubMed1998

Development of antivirals against influenza.

Morbidity and mortality due to influenza virus infections remain a major problem throughout the world. Yearly, medical costs and loss of productivity resulting from influenza infection are estimated to be in the range of 12 dollars bn in the USA. The predicted increases in the elderly and immune-deficient populations will make influenza an even greater threat in the future. Despite the availability of vaccines, they have been least effective in these high-risk populations. Coupled with the requirement for routine revaccination, the need for effective antiviral agents is illustrated. The currently approved drugs, amantadine, rimantadine and ribavirin (in some countries), have limitations. They are only inhibitory against influenza A viruses, are prone to adverse reactions and quickly give rise to resistant virus. This review examines current drug therapies, antivirals in development and possible future opportunities for anti-influenza drugs.

Journal Article↗
PubMed1997

Differential effect of modified capped RNA substrates on influenza virus transcription.

The RNA-dependent RNA polymerase of influenza virus transcribes messenger RNA through a unique cap scavenging mechanism. Viral enzyme binds to the cap structure of host mRNA, cleaves the molecule 9-15 bases downstream of the cap, and uses the short capped oligonucleotide as a primer for mRNA synthesis. Previously, we have shown that the viral polymerase can efficiently bind capped RNAs shorter than 9 nucleotides in length, but the viral enzyme can not utilize these RNAs as primers. For this reason, these short capped oligonucleotides are potent inhibitors of influenza virus transcription. In these studies, it is now shown that short capped oligomers inhibit capped-RNA dependent transcription at the initial step of cap binding. In contrast, low concentrations of these short capped RNAs can actually stimulate viral transcription primed with high concentrations of the dinucleotide ApG. Another capped RNA derivative containing phosphorothioate oligonucleotides was also investigated as a potential polymerase inhibitor. This longer capped RNA was able to bind to the polymerase, but could not be cleaved to primer length by the enzyme associated endonuclease. Thus, the capped phosphorothioate RNA inhibited cap-primed transcription at the step of cap binding. However, in contrast to the short capped oligonucleotide, it also inhibited ApG primed viral transcription.

Oligoribonucleotides↗
PubMed1997

Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus.

In the initial stages of influenza virus infection, the hemagglutinin (HA) protein of influenza virus mediates both adsorption and penetration of the virus into the host cell. Recently, we identified and characterized BMY-27709 as an inhibitor of the H1 and H2 subtypes of influenza A virus that specifically inhibits the HA function necessary for virus-cell membrane fusion (G.-X. Luo, R. Colonno, and M. Krystal, Virology 226:66-76, 1996). Studies presented herein show that the inhibition is mediated through specific interaction with the HA protein. This binding represses the low-pH-induced conformational change of the HA protein which is a prerequisite for membrane fusion. In an attempt to define the binding pocket within the HA molecule, a number of drug-resistant viruses have been isolated and characterized. Sequence analyses of the HA gene of these drug-resistant viruses mapped amino acid changes responsible for drug resistance to a region located near the amino terminus of HA2. In addition, we have identified inactive analogs of BMY-27709 which are able to compete out the inhibitory activity of BMY-27709. This finding suggests that inhibition of the HA-mediated membrane fusion by this class of compounds is not solely the result of binding within the HA molecule but requires specific interactions.

Animals↗
PubMed1996

Treatment of metastatic renal cell carcinoma with constant-rate floxuridine infusion plus recombinant alpha 2b-interferon.

BACKGROUND: Floxuridine (FUDR) and alpha-interferon (IFN) are active agents in advanced renal cell carcinoma, with different dose-limiting toxic effects and antitumor synergism in experimental models. The main purpose of this phase II study was to assess the activity and toxic effects of a combination of FUDR and alpha 2b-IFN in metastatic renal cell carcinoma. PATIENTS AND METHODS: Metastatic renal cell carcinoma patients with measurable disease entered the study. FUDR was administered as a constant-rate continuous infusion for 14 days every 28 days at a starting daily dose of 0.1 mg/kg and with dose escalations of 0.025 mg/kg/day at each subsequent cycle if WHO > or = 2 toxicity had not occurred. IFN-alpha 2b 10 x 10(6) I.U. was administered intramuscularly 3 times per week. RESULTS: Forty-two patients entered the study and a total of 272 cycles of FUDR + alpha 2b-IFN were administered. In 41 evaluable patients WHO grade III-IV toxic effects included nausea and vomiting (22%), diarrhea (32%), stomatitis (12%), fatigue (27%) and anorexia (12%). It was possible to increase the initial FUDR does in 21 (50%) patients; the median FUDR dose intensity was 0.35 mg/kg/week (range 0.18-0.54). Among 39 evaluable patients, 3 (7.5%) complete and 10 (25.5%) partial responses were observed (response rate 33%, 95% confidence interval (CI) 19%-50%) which lasted a median of 13 months (5.5-40+). Responses also occurred in liver (2), in patients pretreated with systemic therapy (5) and in patients who had other unfavourable prognostic characteristics (7). Median progression-free and survival times were 9 and 16 months, respectively. CONCLUSIONS: In this study FUDR + alpha 2b-IFN demonstrated interesting activity in metastatic renal cell carcinoma, showing promise also in patients with unfavourable prognostic characteristics. The antitumor activity of FUDR and alpha 2b-IFN seems to be cumulative, but cumulative toxicity is also observed. These results require confirmation in randomised trials.

Adult↗
PubMed1996

Inhibition of the influenza virus RNA-dependent RNA polymerase by antisera directed against the carboxy-terminal region of the PB2 subunit.

The influenza virus RNA polymerase consists of a heterotrimeric complex of the PB1, PB2 and PA proteins, with the PB2 subunit responsible for recognizing 5' cap structures on the host cell RNAs used as primers for virus mRNA synthesis. To investigate further the role PB2 plays in mRNA synthesis, a set of polyclonal antisera raised against defined regions of the protein were tested for their ability to inhibit the virion transcriptase. All five sera were of sufficient titre to immunoprecipitate PB2 and four were capable of recognizing polymerase complexes containing PB1 and PA. However, only the serum raised against the carboxy terminus of PB2 (F5) substantially inhibited polymerase activity. This serum drastically reduced synthesis primed by globin mRNA, but only partially inhibited transcription primed by the dinucleotide ApG, or ApG and cap analogue. The preferential inhibition of globin-primed synthesis did not result from interference with cap recognition, as serum F5 did not reduce labelling of PB2 in a photoaffinity cap-binding assay. However, IgG and Fab fragments from F5 were found to inhibit virion endonuclease activity. This suggests that the C terminus of PB2 plays a crucial role in transcription initiation and implicates PB2 in endonuclease activity.

Animals↗
PubMed1995

Suramin in patients with metastatic colorectal cancer pretreated with fluoropyrimidine-based chemotherapy. A phase II study.

BACKGROUND: The results of conventional chemotherapy in metastatic colorectal cancer are discouraging, making it a logical target for new treatment approaches a necessary consideration. Suramin is a polysulfonated naphthylurea that binds to several cellular growth factors and has in vitro activity against human colorectal cancer cells. Therefore, this Phase II study of patients with metastatic colorectal cancer was conducted to evaluate its clinical activity. METHODS: Suramin was administered as a 6-day continuous infusion every week for 8 consecutive weeks by using a computer-assisted dosing of Bayesan pharmacokinetics to maintain suramin plasma concentrations of 200-250 micrograms/ml. Twenty patients with metastatic colorectal cancer who were not responsive or in progression within 6 months after completing fluoropyrimidine-based chemotherapy entered the study. RESULTS: Toxicities included mostly Grade 1 and 2 fatigue, nausea and vomiting, peripheral neurotoxicity, creatinine elevation, and proteinuria. No objective responses were observed, but three of three patients who received 5-fluorouracil plus folinic acid after suramin achieved a partial response. CONCLUSIONS: These results indicate that suramin is inactive in patients with metastatic colorectal cancer pretreated with fluoropyrimidines. Pretreatment with suramin may have changed the biology of the tumor, sensitizing it to fluoropyrimidines. Studies to investigate this possibility are in progress.

Adult↗
PubMed1995

Differential activation of the influenza virus polymerase via template RNA binding.

Primary transcripts synthesized by the influenza virus polymerase contain the capped 5' ends of eukaryotic mRNAs. These sequences are derived from host mRNA and scavenged by the viral polymerase as a prerequisite to transcription. The first step in this reaction is the specific binding of the viral polymerase to the cap structure of the host RNA. The role that template RNA plays in this RNA binding reaction was examined in quantitative capped mRNA binding and endonuclease assays. Capped RNA binding was shown to be a template-dependent property of the influenza virus polymerase. Addition of only the 5' end of viral RNA stimulates capped mRNA binding by the viral polymerase, but endonuclease activity requires the addition of the 3' end. The addition of template RNA corresponding to the positive-sense complementary RNA replicative intermediate was also able to stimulate capped mRNA binding but was not able to efficiently activate the viral endonuclease. Thus, regulation of endonuclease activity by the influenza virus polymerase can be dependent on template RNA binding.

DNA-Directed RNA Polymerases↗
PubMed1994

Biochemical studies on capped RNA primers identify a class of oligonucleotide inhibitors of the influenza virus RNA polymerase.

A synthetic 67-nt RNA substrate, containing a 32P-labeled cap-1 structure (m7G32pppGm) was specifically cleaved by the influenza virus RNA polymerase (EC 2.7.7.48) to yield a single capped 11-nt fragment capable of directly priming transcription. An analysis of systematic truncations of this RNA substrate demonstrated that an additional nucleotide beyond this cleavage site was required for cleavage. The minimal RNA chain length required for priming activity was found to be 9 nt, while in contrast an RNA chain length of at least 4 nt was required for efficient binding to the viral polymerase. On the basis of these chain length requirements we show that a pool of capped oligonucleotides too short to prime transcription, but long enough to bind with high affinity to the viral polymerase, are potent inhibitors of cap-dependent transcription in vitro.

Base Sequence↗
PubMed1994

Synergistic antiproliferative activity of suramin and alpha 2A-interferon against human colorectal adenocarcinoma cell lines: in vitro studies.

Suramin, a polysulphonated naphthylurea proven to be an effective anticancer agent against selected tumours, and alpha 2A-interferon (alpha 2A-IFN) were investigated for their combined effects on HCT-8, HCT-15, CL-D, SW-480 and SW-620 human colorectal adenocarcinoma cell lines. All lines were sensitive to clinically achievable concentrations of suramin in a dose-dependent manner, while alpha 2A-IFN alone induced only a modest reduction of cell growth. Concomitant treatment with suramin and alpha 2A-IFN resulted in a synergistic inhibition of cell viability in each cell line at all doses tested. However, when suramin and alpha 2A-IFN were administered sequentially, inhibition of cell viability was clearly dependent on the timing of treatment schedule, with maximum effect obtained when alpha 2A-IFN was administered prior to suramin. In contrast, pretreatment with suramin was markedly inferior to the former one. In conclusion, suramin and alpha 2A-IFN exert a synergistic effect on human colorectal cell proliferation in vitro at clinically achievable concentrations. This observation may have clinical relevance although the mechanisms of interaction remain to be elucidated.

Adenocarcinoma↗