PubMed Health⌕ Search

Biomedical subjects

R Snoeck

Publications and source records attributed to R Snoeck.

At least 73 records · Page 4Linked to original sources
PubMed1999

Novel potential agents for human cytomegalovirus infection: synthesis and antiviral activity evaluation of benzothiadiazine dioxide acyclonucleosides.

The first acyclonucleosides based on the benzothiadiazine dioxide system were synthesized following the silylation procedure. Several acyclic moieties, including acetoxyethoxymethyl, benzyloxymethyl, and propargyloxymethyl groups, were introduced. Two synthetic strategies were designed to selectively obtain the N-1 or N-3 derivatives. Lipase-mediated deacylation was used for the deprotection of the acyclonucleosides. Some of the benzothiadiazine dioxide acyclonucleosides, in particular 16, proved active against human cytomegalovirus (CMV) at concentrations slightly higher than that found for ganciclovir [50% inhibitory concentration (IC50) = 3. 5-3.7 micrograms/mL, cytotoxicity (CC50) >/= 40 micrograms/mL, MCC = 20 micrograms/mL]. Additionally, compound 16 inhibited the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in CEM cells at concentrations that were 5-fold lower than its cytotoxic concentration.

Anti-HIV Agents↗
PubMed1999

Imidazothiadiazine dioxides: synthesis and antiviral activity.

A new series of imidazothiadiazine dioxides, including the first acyclonucleosides derived from this heterocycle moiety, has been synthesized. A wide-spectrum antiviral screening was performed. Some of the N-1 benzyl imidazothiadiazines and the new acyclonucleosides showed interesting anti-CMV or anti-HIV activity. These structures could be considered as new lead compounds for antiviral drug research.

Antiviral Agents↗
PubMed1999

Chronic verrucous varicella zoster virus skin lesions: clinical, histological, molecular and therapeutic aspects.

The outbreak of HIV infection introduced a new phenomenon in varicella zoster virus (VZV) pathology, namely the long-standing wart-like skin lesions that are frequently associated with resistance to thymidine kinase (TK)-dependent antiviral agents. This paper reviews the clinical, histological, and molecular aspects and the therapeutic management of these verrucous lesions. The majority of lesions are characterized by chronically evolving, unique or multiple wart-like cutaneous lesions. The main histopathological features include hyperkeratosis, verruciform acanthosis and VZV-induced cytopathic changes with scant or absent cytolysis of infected keratinocytes. The mechanism that establishes the chronic nature of the lesions appears to be associated with a particular pattern of VZV gene expression exhibiting reduced or nondetectable gE and gB synthesis. Drug resistance to TK-dependent antiviral agents is a result of nonfunctional or deficient viral TK. This necessitates alternative therapeutic management using antiviral agents that target the viral DNA polymerase.

Acyclovir↗
PubMed1999

Synthesis and antiviral activity of 6-benzoyl-benzoxazolin-2-one and 6-benzoyl-benzothiazolin-2-one derivatives.

The synthesis and antiviral activity of an original series of 6-benzoyl-benzoxazolin-2-one and 6-benzoyl-benzothiazolin-2-one derivatives are described. Several compounds were found to have a selective inhibitory activity against human cytomegalovirus (HCMV) and varicella-zoster virus (VZV) in vitro, being inactive against a variety of other DNA and RNA viruses. 6-(3-fluorobenzoyl)benzoxazolin-2-one, 6-(3-fluorobenzoyl)benzothiazolin-2-one, 6-(3-bromobenzoyl)benzothiazolin-2-one, 6-(3-iodobenzoyl)benzothiazolin-2-one, 3-methyl-6-(3-fluorobenzoyl)benzothiazolin-2-one, 3-benzyl-6-benzoyl-benzothiazolin-2-one, 3-benzyl-6-(3-fluorobenzoyl)benzothiazolin-2-one and 3-benzoyl-6-(3-fluorobenzoyl)benzothiazolin-2-one were the most active of the series against HCMV and VZV with a selectivity index (CC50/IC50) ranging from 10 to 20. They displayed similar activity against thymidine kinase competent (TK+) and deficient (TK-) VZV strains, and also proved to be active against clinical HCMV isolates that were resistant to ganciclovir (GCV). Time-of-addition experiments revealed a site of interaction with the HCMV replicative cycle that may be close or similar to that of GCV and cidofovir (HPMPC). The compounds showed poor, if any, activity against herpes simplex virus type 1 (HSV-1) and HSV-2, and were not inhibitory against human immunodeficiency virus and other DNA and RNA viruses. Therefore, these compounds may represent a novel lead for the development of specific HCMV and VZV drugs.

Antiviral Agents↗
PubMed1999

In vitro sensitivity of Kaposi's sarcoma cells to various chemotherapeutic agents including acyclic nucleoside phosphonates.

The involvement of a viral agent in the pathogenesis of Kaposi's sarcoma (KS) points to antiviral agents as possible therapeutic and/or prophylactic options in the management of the disease. In the present study we investigated the antiproliferative effects of various chemotherapeutic agents, including acyclic nucleoside phosphonates, on the growth of KS-derived cells. Nested PCR amplification demonstrated that these cells do not contain human herpesvirus 8 (HHV-8) DNA sequences. The cytotoxicity of the chemotherapeutic compounds was less pronounced in KS cells than in human dermal microvascular endothelial cells, which are considered to be the normal counterpart of KS cells. Stimulation of KS cells with basic fibroblast growth factor (bFGF) and correction of the IC50 values by the doubling times revealed that the apparent chemotherapeutic resistance of KS cells could mainly be attributed to the long doubling times of these cells. bFGF-stimulated KS cells still exhibited no particular sensitivity to the acyclic nucleoside phosphonates whose activity extends to HHV-8, which is consistent with the absence of linear HHV-8 DNA synthesis in these cells. Our data suggest that neither anti-cancer agents nor antiviral agents such as the acyclic nucleoside phosphonates can discriminate efficiently between KS cells and normal endothelial cells.

Antineoplastic Agents↗
PubMed1999

Current pharmacological approaches to the therapy of varicella zoster virus infections: a guide to treatment.

Varicella zoster virus (VZV), a member of the herpesvirus family, is responsible for both primary (varicella, chickenpox) as well as reactivation (zoster, shingles) infections. In immunocompetent patients, the course of varicella is generally benign. For varicella zoster, post-herpetic neuralgia is the most common complication. In immunocompromised patients (particularly those with AIDS), transplant recipients and cancer patients, VZV infections can be life-threatening. For these patients and also for immunocompetent patients at risk such as pregnant women or premature infants, the current treatment of choice is based on either intravenous or oral aciclovir (acyclovir). The low oral bioavailability of aciclovir, as well as the emergence of drug-resistant virus strains, have stimulated efforts towards the development of new compounds for the treatment of individuals with VZV infections. Among these new compounds, penciclovir, its oral prodrug form famciclovir and the oral pro-drug form of aciclovir (valaciclovir), rank among the most promising. As with aciclovir itself, all of these drugs are dependent on the virus-encoded thymidine kinase (TK) for their intracellular activation (phosphorylation), and, upon conversion to their triphosphate form, they act as inhibitors/alternative substrate of the viral DNA polymerase. Therefore, cross-resistance to these drugs may be expected for those virus mutants that are TK-deficient and thus resistant to aciclovir. Other classes of nucleoside analogues dependent for their phosphorylation on the viral TK that have been pursued for the treatment of VZV infections include sorivudine, brivudine, fialuridine, fiacitabine and netivudine. Among oxetanocins, which are partially dependent on viral TK, lobucavir is now under clinical evaluation. Foscarnet, which does not require any previous metabolism to interact with the viral DNA polymerase, is used in the clinic when TK-deficient VZV mutants emerge during aciclovir treatment. TK-deficient mutants are also sensitive to the acyclic nucleoside phosphonates (i.e. [s]-1-[3-hydroxy-2-phosphonylmethoxypropyl]cytosine; HPMPC); these agents do not depend on the virus-encoded TK for their phosphorylation but depend on cellular enzymes for conversion to their diphosphoryl derivatives which then inhibit viral DNA synthesis. Vaccination for VZV has now come of age. It is recommended for healthy children, patients with leukaemia, and patients receiving immunosuppressive therapy or those with chronic diseases. The protection induced by the vaccine seems, to some extent, to include zoster and associated neuralgia. Passive immuniatin based on specific immunoglobulins does not effectively prevent VZV infection and is therefore restricted to high risk individuals (i.e. immunocompromised children and pregnant women).

Antiviral Agents↗
PubMed1998

Iron as a potential co-factor in the pathogenesis of Kaposi's sarcoma?

The role of iron in the pathogenesis of several tumours is being increasingly investigated. In particular, its involvement in the pathogenesis of Kaposi's sarcoma (KS) is suggested by the distribution of the endemic form of KS corresponding to continental rifts and associated iron-oxide-rich volcanic clays. We investigated in vitro to what extent iron supplementation or withdrawal could affect the growth of KS-derived cells, by analysing the effects of adding iron salts (iron chloride and ferric nitrilotriacetate) and/or reducing iron by iron chelators (desferrioxamine) on KS-derived cell cultures. The addition of iron salts strongly stimulated the growth of KS cells, as reflected by increase in thymidine incorporation and cell number. Conversely, desferrioxamine and deferiprone inhibited cell growth. The inhibitory effect of iron chelation was more pronounced on rapidly dividing basic fibroblast-growth-factor-stimulated cells. These results may point to a novel therapeutic approach to KS.

Carcinogens↗
PubMed1998

Polyanion inhibitors of HIV and other viruses. 7. Polyanionic compounds and polyzwitterionic compounds derived from cyclodextrins as inhibitors of HIV transmission.

New polyanionic compounds were obtained from radical addition of thiomalic acid and mercaptopropionic acid onto perallylated cyclodextrins (CDs) under UV irradiation with a catalytic amount of alpha,alpha'-azobis(isobutyronitrile). All these polyanions, bearing 18-48 carboxylate groups, inhibited human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-4 cells at a 50% inhibitory concentration (IC50) of 0.1-2.9 microM, while not being toxic to the host cells at concentrations up to 62 microM. These compounds were also active against a clinical HIV-1 isolate (HE) at >/=4-fold higher concentrations. Only some compounds showed activity against the two HIV-2 strains (ROD and EHO) but at higher concentrations than those required to inhibit HIV-1 (IIIB and HE) replication. In addition, these compounds were not active against the M-tropic HIV-1 strain BaL but were active against simian immunodeficiency virus [SIV (MAC251)]. These compounds were also inhibitory to the replication of human cytomegalovirus at an IC50 of 1-10 microM, but not herpes simplex virus (type 1 and type 2) or other (picorna-, toga-, reo-, orthomyxo-, paramyxo-, bunya-, rhabdo-, and poxvirus) viruses. Radical addition on perallylated CDs of a protected cysteine gave polyzwitterionic compounds. None of these last compounds proved inhibitory to the replication of HIV-1, HIV-2, or any of the other viruses tested.

Animals↗
PubMed1998

Synthesis of imidazo[1,2-a]pyridines as antiviral agents.

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and their antiviral activity are reported. From the synthesized compounds, 4, 15, and 21 were highly active against human cytomegalovirus with a therapeutic index superior to 150. These compounds also showed pronounced activity against varicella-zoster virus. Their structure-activity relationship is discussed.

Animals↗
PubMed1998

Treatment of severe laryngeal papillomatosis with intralesional injections of cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine].

Respiratory papillomatosis is a rare and often severe disease, usually localized in the larynx. It may cause respiratory distress and even life-threatening obstruction of the airways. Treatment is generally based on the evaporation of the lesions with a CO2 laser, but microsurgery, cytotoxic and/or cytostatic drugs, interferons, and vaccines are also used. Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] (HPMPC) was shown to suppress the growth of tumors induced by rabbit papillomavirus as well as human papillomavirus (HPV). The efficacy of cidofovir was assessed in 17 patients with severe respiratory papillomatosis. Cidofovir at a concentration of 2.5 mg/ml was injected directly in the different laryngeal papillomatous lesions during microlaryngoscopy under general anesthesia. Biopsies were taken before the treatment was started both for anatomopathology and viral typing. HPMPC kinetics in serum was monitored in three patients, the drug levels being determined by high-performance liquid chromatography. Complete disappearance of the papillomatosis was observed in 14 patients. Four patients relapsed and were successfully treated again with cidofovir. Of the three remaining patients, one progressed while under treatment with cidofovir, after an initial marked response. One patient had a partial remission and remained stable for more than 1 year after the last injection. He had a very aggressive and extensive disease originally. Finally, one patient was lost to follow-up after four injections. Intratumoral injections of cidofovir for the treatment of severe laryngeal papillomatosis is a powerful new therapeutic approach for this disease. Treatment was well tolerated, and no significant side effects were noted.

Adolescent↗
PubMed1998

Novel carbocyclic nucleosides containing a cyclobutyl ring. Guanosine and adenosine analogues.

(1R,cis)-2-(3-Amino-2,2-dimethylcyclobutyl)ethanol (4) was used as a precursor in the synthesis of cyclobutyl nucleoside analogues containing guanine, 8-azaguanine, adenine or 8-azaadenine. All the compounds were evaluated as antiviral agents in a variety of assay systems. Some activity was noted for compound 13, 17, 19 and 20 against vaccinia virus and for compounds 11, 12, 13, 17, 19 and 20 against herpes simplex virus, at concentrations that were up to 10-fold below the cytotoxic concentrations for the host cells.

Acids, Carbocyclic↗
PubMed1998

Specific therapies for human papilloma virus infections.

Human papillomavirus induces the hyperproliferation of epithelial cells, leading to a broad spectrum of human diseases, ranging from benign warts to malignant neoplasms, depending on the location of the lesion, the immune status of the patient and the type of human papillomavirus. Current therapies for human papillomavirus-associated diseases are based on the excision or ablation of dysplastic or malignant tissue, and are associated with a high frequency of recurrent disease, discomfort and costs. A better understanding of the viral replicative cycle and of the interaction between the virus and the host cell, particularly the cell cycle regulation, has opened new perspectives. Recently, new treatment modalities for human papillomavirus-induced lesions have been identified, including the use of antiviral/immunomodulatory therapies, such as cidofovir, antisense oligonucleotides, imiquimod and human papillomavirus vaccines.

Journal Article↗
PubMed1998

Intracellular metabolism of the N7-substituted acyclic nucleoside analog 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine, a potent inhibitor of herpesvirus replication.

We investigated the intracellular metabolism of S2242 (2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine), the only known antivirally active acyclic nucleoside analogue with the side chain substituted at the N7 position of the purine ring. Uptake of S2242 by CEM cells increased linearly with increasing extracellular concentrations of the compound and was blocked by inhibitors of nucleoside transport. S2242 was phosphorylated in a time- and concentration-dependent manner to its monophosphates, diphosphates, and triphosphates. Intracellular half-life of the diphosphates and triphosphates in CEM cells was approximately 3-6 hr. A strong correlation was found between the cytostatic action of the compound and its phosphorylation in different cell lines. In accord with the findings that (1) the cytostatic potential of S2242 is reversed by deoxycytidine (dCyd) and (2) the growth of deoxycytidine kinase-deficient (dCK-) cells is refractory to the inhibitory effect of S2242, the amount of metabolites formed from S2242 in the dCK- cell line was approximately one hundredth of that in the wild-type cells. The observation that purified dCK phosphorylates S2242 to its monophosphate further corroborates these results. The activity of S2242 against herpes simplex virus, varicella-zoster virus, and human herpesvirus type 6 was reversed by 50-100-fold on the addition of exogenous dCyd. Compound S2242 was not preferentially phosphorylated in herpes simplex virus 1-, varicella-zoster virus-, or human herpesvirus type 6-infected cells (Vero, human embryonic lung, and HSB-2 cells, respectively), and exogenously added dCyd reduced substantially the formation of S2242 metabolites in these cells. In human cytomegalovirus (HCMV)-infected human embryonic lung cells, a 5-25-fold increase in S2242 metabolite formation was observed compared with the noninfected cells, suggesting that an HCMV-encoded or -induced enzyme causes the specific phosphorylation of S2242. Exogenously added dCyd had little effect on the activity of S2242 against HCMV and on the phosphorylation of the compound in HCMV-infected cells. S2242 was not specifically phosphorylated by the HCMV-encoded UL-97 kinase in cells infected with a vaccinia/UL-97 recombinant. S2242 was found to be a substrate (K(m) = 90 microM) for purified human deoxyguanosine kinase; the latter enzyme was stimulated 3-4-fold in HCMV-infected cells.

Alkaline Phosphatase↗
PubMed1998

Broad-spectrum antiviral activity and mechanism of antiviral action of the fluoroquinolone derivative K-12.

The fluoroquinolone derivatives have been shown to inhibit human immunodeficiency virus (HIV) replication at the transcriptional level. We confirmed the anti-HIV activity of the most potent congener, 8-difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2- methoxyphenyl)-1-piperazinyl]-4-quinolone-3-carboxylic acid (K-12), in both acutely and chronically infected cells. K-12 was active against different strains of HIV-1 (including AZT- and ritonavir-resistant HIV-1 strains), HIV-2 and simian immunodeficiency virus, in MT-4, CEM, C8166 and peripheral blood mononuclear cells. In all of these antiviral assay systems, K-12 showed a similar activity (EC50 0.2-0.6 microM). K-12 inhibited Moloney murine sarcoma virus-induced transformation of C3H/3T3 cells with an EC50 of 6.9 microM. Also, K-12 proved inhibitory to herpesvirus saimiri, human cytomegalovirus, varicella-zoster virus and herpes simplex virus types 1 and 2 (in order of decreasing sensitivity), but was not inhibitory (at subtoxic concentrations) to human herpesvirus type 8 (as evaluated in BCBL-1 cells), vaccinia virus, Sindbis virus, vesicular stomatitis virus, respiratory syncytial virus, Coxsackie virus, Punta Toro virus, parainfluenza virus or reovirus. Time-of-addition experiments and quantitative transactivation bioassays indicated that K-12 inhibits the Tat-mediated transactivation process in HIV-infected cells.

Anti-HIV Agents↗
PubMed1998

Antiproliferative effects of acyclic nucleoside phosphonates on human papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell lines.

Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum activity against DNA viruses and retroviruses. HPMPC (cidofovir) has proved to be effective in the treatment of HPV-associated diseases. We have evaluated the effects of various ANPs [i.e., 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC); 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir), guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP (cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV), ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant mycophenolic acid (MPA) on the proliferation of human cervical keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa). In vitro incubation of these cell lines with ANPs resulted in a concentration- and time-dependent inhibition of cell proliferation. This inhibitory effect was most striking for HPMPC. The 50% inhibitory concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to 0.6-2 microg/ml at day 7. When the IC50 values of the ANPs for the various HPV-harboring cells were compared with those for primary human keratinocytes isolated from normal cervix, HPMPC emerged as the most selective ANP, with a selectivity index (SI) in the range of 15-42. When IC50 values as a function of time were determined for several tumor cell lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs again showed an antiproliferative effect as a function of time, although of a lower extent (5- to 25-fold decrease in the IC50 values between days 3 and 7) than for the HPV-positive cells. Treatment of SV40- and adenovirus-transformed cells with ANPs resulted in the inhibition of cell proliferation as a function of time, similar to that observed with HPV-positive cells, HPMPC and cHPMPC being the most potent antiproliferative agents. These results suggest that the antiproliferative activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may be explained, at least in part, by a specific inhibitory effect on rapidly proliferating cells, and the presence of the HPV genome might enhance the sensitivity of cells to HPMPC due to interactions of the viral-transforming proteins with products of the tumor suppressor genes.

Animals↗
PubMed1998

Inhibiting effects of cidofovir (HPMPC) on the growth of the human cervical carcinoma (SiHa) xenografts in athymic nude mice.

At present more than 70 human papillomaviruses (HPV) genotypes have been described and each shows a predilection for a cutaneous or mucosal surface. There is a strong association between infection with specific genital viruses (i.e., types 16 and 18) and the development of cervical cancer. Thus, intervention with the natural history of HPV infection in the genital tract may form the basis for an effective anticancer strategy. We have shown that treatment of cell lines derived from human cervical carcinomas [i.e., SiHa and CaSki (HPV-16-positive)] and HeLa (HPV-18-positive)] with HPMPC (cidofovir) results in a concentration- and time-dependent inhibition of cell proliferation. We report here the effects of HPMPC on the growth of cervical carcinoma (SiHa) xenografts in athymic nude mice. Athymic mice between the age of 6 and 8 weeks were injected SC with 5 to 10x10(6) cells. Once tumors were established, the mice were injected with PBS (placebo), HPMPC, or cytarabine (AraC) at the tumor site. Animals that were injected intratumorally with HPMPC at a dose of 5 mg/ml (0.25 mg/injection) or 10 mg/ml (0.5 mg/injection) three or five times per week, once daily, during 4 weeks showed a statistically significant reduction in tumor size compared to the placebo group or AraC group. However, when HMPC was administered topically (as a cream) or systemically (intraperitoneally), no reduction of tumor growth was observed at nontoxic concentrations, suggesting that a high local concentration of HPMPC is required to achieve a significant decrease of tumor growth.

Animals↗
PubMed1998

Treatment of classical Kaposi's sarcoma with intralesional injections of cidofovir: report of a case.

The effect of intralesional injections of cidofovir, a nucleotide analog with potent in vitro activity against human herpesvirus 8 (HHV-8), was studied in vivo in an HIV-negative patient with classical Kaposi's sarcoma (KS). After five weekly injections of the drug, no clinical, histological, immunohistological, or virological changes could be detected in comparison with saline-injected lesions. These findings suggest that, once the KS tumor has developed, active viral replication is no longer involved in the pathogenesis of the disease. Alternative hypotheses are that HHV-8 replication in blood-borne cells may foster growth of spindle cells in the skin, or that blocking HHV-8 may not affect existing lesions but may prevent new lesions from developing.

Aged↗