brivudine and Disease-Models--Animal

5-Vinylpyrimidine nucleosides can be readily synthesized via organometallic intermediates from commercially available nucleosides. Highly potent and selective inhibitors of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) are (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and some related analogs such as (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU) and (E)-5-(2-bromovinyl)-2'-deoxycytidine (BVDC). The selective antiviral action of BVDU is based upon a specific phosphorylation by the virus-encoded deoxythymidine kinase (TK), inhibition of the viral DNA polymerase and/or incorporation into viral DNA. The efficacy of BVDU against HSV-1 and VZV infections has been demonstrated in animal models and phase I clinical trials. Possible limitations in the clinical usefulness of 5-vinylpyrimidine nucleosides in general and BVDU in particular are discussed.

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Cell Line; Chemical Phenomena; Chemistry; Disease Models, Animal; Drug Resistance, Microbial; Fibroblasts; Herpesvirus 3, Human; Humans; Mice; Pyrimidine Nucleosides; Rabbits; Simplexvirus; Structure-Activity Relationship

Several reports describe the importance of the chaperone HSP27 (HSPB1) in cancer progression, and the demand for drugs that modulate HSPB1-activity is increasing rapidly. We reported earlier that RP101 (Bromovinyldeoxyuridine, BVDU, Brivudine) improves the efficacy of chemotherapy in pancreatic cancer.. Chemistry: Binding of RP101 and HSPB1 was discovered by affinity chromatography. Molecular and cell biology: HSPB1 in vitro transcription/translation (TNT), Pull down using RP101-coupled magnetic beads, Immuno Co-precipitations, Structural modeling of HSP27 (HSPB1), Introduction of point mutations into linear expression templates by PCR, Heat shock, Tumor Invasion. Animal experiments: Treatment of AH13r Sarcomas in SD-rats. Clinical Studies with late-stage pancreatic cancer patients: Pilot study, Dose finding study, Phase II study (NCT00550004).. Here, we report that RP101 binds in vitro to the heat shock protein HSPB1 and inhibits interaction with its binding partners. As a result, more activated CASP9 was detected in RP101-treated cancer cells. We modeled HSPB1-structure and identified the RP101 binding site. When we tested RP101 as an anti-cancer drug in a rat model, we found that it improved chemotherapy. In clinical studies with late-stage pancreatic cancer patients, the dose of 500 mg/day was safe and efficient, but 760 mg/day turned out to be too high for lightweight patients.. The development of RP101 as a cancer drug represents a truly novel approach for prevention of chemoresistance and enhancement of chemosensitivity.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bromodeoxyuridine; Disease Models, Animal; Dose-Response Relationship, Drug; Double-Blind Method; Drug Evaluation, Preclinical; Female; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; Humans; Male; Middle Aged; Models, Molecular; Molecular Chaperones; Pancreatic Neoplasms; Pilot Projects; Placebos; Rats; Rats, Sprague-Dawley; Sarcoma; Survival Analysis

The in vivo administration of enzyme-inhibiting drugs for cancer and infectious disease often results in overexpression of the targeted enzyme. We have developed an enzyme-catalyzed therapeutic agent (ECTA) approach in which an enzyme overexpressed within the resistant cells is recruited as an intracellular catalyst for converting a relatively non-toxic substrate to a toxic product. We have investigated the potential of the ECTA approach to circumvent the thymidylate synthase (TS) overexpression-based resistance of tumor cells to conventional fluoropyrimidine [i.e. 5-fluorouracil (5-FU)] cancer chemotherapy. (E)-5-(2-Bromovinyl)-2'-deoxy-5'-uridyl phenyl L-methoxyalaninylphosphoramidate (NB1011) is a pronucleotide analogue of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), an antiviral agent known to be a substrate for TS when in the 5'-monophosphorylated form. NB1011 was synthesized and found to be at least 10-fold more cytotoxic to 5-FU-resistant, TS-overexpressing colorectal tumor cells than to normal cells. This finding demonstrates that the ECTA approach to the design of novel chemotherapeutics results in compounds that are selectively cytotoxic to tumor cell lines that overexpress the target enzyme, TS, and therefore may be useful in the treatment of fluoropyrimidine-resistant cancer.

Topics: Animals; Antineoplastic Agents; Bromodeoxyuridine; Deoxyuracil Nucleotides; Disease Models, Animal; Drug Design; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Nude; Prodrugs; Thymidylate Synthase; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The animal model of necrotic hepatitis caused by HSV-1 infection in juvenile mice was used to compare the efficacies of the oral antiherpes agents famciclovir (FCV), valaciclovir (VACV) and brivudin (BVDU). The experimental infection allows the measurement of viral replication in the liver by macroscopic lesions and the evaluation of mortality from encephalitis. Mice intravenously inoculated with a highly virulent clinical HSV-1 isolate were orally treated by gavage over a period of 3 days starting on day 2 post infection. The reference drug acyclovir (ACV) was administered subcutaneously. Necrotic hepatitis was significantly (p < 0.01) reduced by treatment with FCV, VACV and ACV at a dose of 50 mg/kg per day divided into 3 doses. No significant effect was achieved with BVDU at 200 mg/kg per day. Treatment with FCV at 50 mg/kg per day, ACV at 100 mg/kg per day, and VACV at 200 mg/kg per day significantly (p < 0.001) decreased mortality in mice. BVDU treatment at 200 mg/kg per day did not reduce mortality but significantly prolonged (p < 0.05) the survival time.

Topics: 2-Aminopurine; Acyclovir; Animals; Antiviral Agents; Bromodeoxyuridine; Cell Line; Disease Models, Animal; Famciclovir; Hepatitis, Animal; Herpes Zoster; Herpesvirus 1, Human; Liver; Mice; Mice, Inbred BALB C; Valacyclovir; Valine; Viral Plaque Assay; Virus Replication

The acyclic nucleoside phosphonate analogue PMEA [9-(2-phosphonylmethoxyethyl)adenine] is a broad spectrum antiviral agent effective against DNA viruses and retroviruses. It is particularly active against the human immunodeficiency virus and, like other phosphonylmethoxyalkyl derivatives, it also inhibits HSV-1, TK- HSV-1 and HSV-2. We have evaluated the therapeutic efficacy of PMEA in the HSV-1 and TK- HSV-1 experimental keratitis models using BVDU (bromovinyldeoxyuridine) as the reference compound. As compared to placebo eyedrops, PMEA 0.2% and BVDU 0.2% eyedrops induced a rapid and significant healing (P less than 0.005) of keratitis caused by TK+ HSV-1. Treatment with PMEA 0.2% eyedrops also reduced the severity of keratitis caused by the TK- HSV-1 (P less than 0.05), whereas BVDU 0.2% eyedrops did not affect the course of TK- HSV-1 keratitis.

Topics: Adenine; Administration, Topical; Animals; Antiviral Agents; Bromodeoxyuridine; Disease Models, Animal; Keratitis, Dendritic; Organophosphonates; Rabbits; Simplexvirus

The phosphonylmethoxyalkyl derivative, (S)-1-(3-hydroxy-2-phosphonyl methoxypropyl)cytosine (HPMPC), was evaluated for its efficacy in the topical treatment of experimental keratitis caused by thymidine kinase-positive (TK+) or thymidine kinase-deficient (TK-) herpes simplex virus type 1 (HSV-1) strains. The HPMPC 0.2% eyedrops were as effective as the reference compound, (E)-5-(2-bromovinyl)-2'-deoxyuridine, (BVDU) 0.2% eyedrops in stimulating the healing of epithelial disease caused by the HSV-1 TK+ strain. Both drugs achieved a significant (P less than 0.005) healing effect compared with placebo eyedrops. No significant differences were noted in the efficacy of HPMPC 0.2% eyedrops when instilled one, three, or nine times a day. In the treatment of keratitis caused by the HSV-1 TK- strain, 0.2% BVDU eyedrops were similar to placebo; 0.2% HPMPC eyedrops again had a brisk and significant healing effect (P less than 0.005).

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Cidofovir; Cytosine; Disease Models, Animal; Drug Administration Schedule; Female; Keratitis, Dendritic; Male; Ophthalmic Solutions; Organophosphonates; Organophosphorus Compounds; Rabbits; Random Allocation; Simplexvirus; Thymidine Kinase

Two compounds, bromovinyldeoxyuridine ([E]-5-[2-bromovinyl]-2'-deoxyuridine) and trifluridine (5-trifluoromethyl-2' deoxyuridine) were compared for their efficacy in the topical treatment of experimental stroma herpetic keratitis produced by the injection of live herpes simplex virus, type 1, into the corneal stroma of rabbits. The trifluridine was used as 1% eyedrops, whereas bromovinyldeoxyuridine was used as either 0.1% or 0.5% eyedrops. All three treatment regimens caused a substantial healing of stroma disease in comparison with placebo treatment. The bromovinyldeoxyuridine (whether used as 0.1% or 0.5%) proved superior to 1% trifluridine eyedrops when the treatment was started one day after virus inoculation. However, bromovinyldeoxyuridine and trifluridine were equally effective if the treatment was started seven days after infection. The 0.5% bromovinyldeoxyuridine eyedrops seemed to be more effective in controlling the complicating severe iritis and secondary glaucoma than either 0.1% bromovinyldeoxyuridine or 1% trifluridine. No toxic effects were observed with bromovinyldeoxyuridine in any eye, whereas 1% trifluridine produced punctate epitheliopathy in some eyes.

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; Corneal Diseases; Disease Models, Animal; Drug Administration Schedule; Keratitis, Dendritic; Ophthalmic Solutions; Rabbits; Thymidine; Trifluridine