acyclovir and Brain-Neoplasms

Herpes simplex virus encephalitis (HSE) is the most common cause of letal encephalitis and its prevalence appears higher among oncologic patients who undergo brain radiotherapy (RT). We describe a case of 76-year-old woman with glioblastoma multiforme (GBM) who developed HSE shortly after brain RT. Cerebrospinal fluid analysis (CSF) was normal and the diagnosis was driven by brain MRI and EEG. Prompt introduction of antiviral therapy improved the clinical picture. We highlight the importance of EEG and brain MRI for the diagnosis and suggest the possibility of antiviral profilaxys in oncologic patients who undergo brain RT.

Topics: Acyclovir; Aged; Brain Neoplasms; Cranial Irradiation; Electroencephalography; Encephalitis, Herpes Simplex; Female; Glioblastoma; Herpesvirus 1, Human; Humans; Magnetic Resonance Imaging; Prognosis; Risk Assessment; Treatment Outcome

Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients.. Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection.. Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms.. GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas.. ClinicalTrials.gov NCT00589875.

Topics: Acyclovir; Adenoviridae; Adult; Aged; Antiviral Agents; Brain Neoplasms; Chemotherapy, Adjuvant; Genetic Therapy; Genetic Vectors; Glioma; Humans; Immunotherapy; Middle Aged; Simplexvirus; Survival Analysis; Thymidine Kinase; Treatment Outcome; Valacyclovir; Valine

Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect.. Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10), 1 × 10(11), or 3 × 10(11) vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment.. Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3(+) T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months.. AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.

Topics: Acyclovir; Adenoviridae; Adjuvants, Immunologic; Adult; Aged; Antineoplastic Agents, Alkylating; Antiviral Agents; Brain Neoplasms; Cancer Vaccines; Combined Modality Therapy; Dacarbazine; Genetic Therapy; Genetic Vectors; Glioma; Herpesvirus 1, Human; Humans; Immunotherapy; Middle Aged; O(6)-Methylguanine-DNA Methyltransferase; Temozolomide; Thymidine Kinase; Treatment Outcome; Valacyclovir; Valine

We have previously demonstrated safety of G207, a doubly mutated (deletion of both gamma(1)34.5 loci, insertional inactivation of U(L)39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score >or=70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 x 10(9) plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.

Topics: Acyclovir; Adult; Aged; Antibodies, Viral; Brain Neoplasms; Female; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Simplexvirus; Treatment Outcome; Virus Replication

Topics: Acyclovir; Adrenal Cortex Hormones; Anti-Bacterial Agents; Antiviral Agents; Brain Neoplasms; Ceftriaxone; Dexamethasone; Diagnosis, Differential; Electroencephalography; Emergency Service, Hospital; Encephalitis, Herpes Simplex; Fever; Humans; Hypnotics and Sedatives; Infarction; Levetiracetam; Male; Massachusetts; Middle Aged; Phenytoin; Piracetam; Propofol; Status Epilepticus; Temporal Lobe; Tomography, X-Ray Computed; Unconsciousness; Vancomycin

Topics: Acyclovir; Aged; Antiviral Agents; Brain Neoplasms; Diagnosis, Differential; Encephalitis, Varicella Zoster; Glioma; Gliosis; Humans; Immunocompetence; Magnetic Resonance Imaging; Male; Middle Aged; Valacyclovir; Valine; Young Adult

To describe herpes simplex virus encephalitis despite normal cell count in the cerebrospinal fluid in patients with malignoma after whole brain irradiation.. Blood and cerebrospinal fluid analysis and magnetic resonance imaging.. Three male and two female patients with malignoma and a recent history of whole-brain irradiation presented with impaired consciousness with or without epileptic seizure. Although cerebrospinal fluid analysis revealed a normal cell count, herpes simplex virus DNA was detected in all samples by polymerase chain reaction.. In patients with impaired consciousness, epileptic seizure, or temporal lobe symptoms of new onset and a recent history of brain irradiation with normal cerebrospinal fluid, an atypical anergic course of herpes simplex virus encephalitis should be considered. Herpes simplex virus polymerase chain reaction should be used as method of choice to detect herpes simplex virus genomes as early as possible rather than relying on routine cerebrospinal fluid parameters. Importantly, antiviral therapy should be started without delay in any case of faint suspicion and should be continued until herpes simplex virus encephalitis is clearly ruled out.

Topics: Acyclovir; Aged; Antiviral Agents; Brain Neoplasms; Encephalitis, Herpes Simplex; Fatal Outcome; Female; Herpesvirus 1, Human; Humans; Immunocompromised Host; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging

The case of a 14-year-old girl who developed Epstein-Barr virus-related lymphoproliferative disorder, cytomegalovirus reactivation, and Varicella zoster virus encephalitis during treatment for medulloblastoma is described. The patient was diagnosed with a cerebral medulloblastoma and treated with systemic chemotherapy, intrathecal chemotherapy, and radiotherapy. Six months later, she developed persistent low-grade fever, abdominal pain, and vomiting. Several mucosal or ulcerated lesions of the stomach and colon were found on fiberscopy. The infiltrating cells were positive for CD20 and EBER1, and the diagnosis of lymphoproliferative disorder was made. CMV antigen was found in the peripheral lymphocytes at that time. At the same time, it was noted that the patient's language was inappropriate for her age, and a facial and abdominal rash, as well as a right facial palsy, had developed. She was then diagnosed as having VZV encephalitis, because VZV was detected in the CSF. She was treated subsequently with acyclovir and oral steroid, and the VZV encephalitis resolved. The lymphoproliferative disorder improved gradually with rituximab, ganciclovir, and total nutritional support. At the time of the development of the lymphoproliferative disorder and VZV encephalitis, the patient had severe lymphopenia and this may have caused these rare phenomena in a non-transplant setting.

Topics: Acyclovir; Adolescent; Antibodies, Monoclonal, Murine-Derived; Antiviral Agents; Brain Neoplasms; Combined Modality Therapy; Cytomegalovirus Infections; Encephalitis, Varicella Zoster; Epstein-Barr Virus Infections; Female; Ganciclovir; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunosuppression Therapy; Lymphopenia; Lymphoproliferative Disorders; Medulloblastoma; Rituximab; Virus Activation

Herpesviruses can cause an acute, subacute, or chronic disease state in both immunocompetent and immunocompromised individuals. Herpes simplex virus (HSV) encephalitis is most often an acute monophasic disease process. Rarely, however, it may progress to a chronic state, and more rarely still to a granulomatous encephalitis. Prior studies have suggested that antiviral immunity with Toll-like receptors determines susceptibility to herpesviruses. The authors report the case of a 14-year-old girl with a remote history of treated HSV encephalitis, who had intractable seizures and worsening MR imaging changes that were concerning for either a neoplastic or an inflammatory process. She was found to have granulomatous herpes simplex encephalitis and had a low cytokine response to Toll-like receptor 3 stimulation.

Topics: Acyclovir; Adolescent; Antiviral Agents; Brain Neoplasms; Contrast Media; Cytokines; Demyelinating Autoimmune Diseases, CNS; Diagnosis, Differential; Encephalitis, Herpes Simplex; Female; Granuloma; Humans; Magnetic Resonance Imaging; Seizures; Toll-Like Receptor 3; Treatment Outcome

Granulocytic sarcomas, or chloromas, are extramedullary collections of immature granulocytes. Central nervous system involvement is rare and of those cases described, most are complications of acute myelogenous leukemia.. A 40-year-old man with chronic myelogenous leukemia presented with seizure and encephalopathy. Magnetic resonance imaging of the brain revealed temporal T2 hyperintensities with gyriform cortical enhancement. Cerebrospinal fluid showed mild pleocytosis and elevated protein. Electroencephalography demonstrated periodic lateralized epileptiform discharges. Acyclovir was initiated for herpes simplex encephalitis, however, follow-up MRI showed extension of the lesion. MR spectroscopy suggested tumor, confirmed by brain biopsy. Postradiation MRI showed a significant decrease in lesion size.. Granulocytic sarcoma can present as intraparenchymal cerebral lesions in patients with chronic myelogenous leukemia and may mimic herpes simplex encephalitis.

Topics: Acyclovir; Adult; Antiviral Agents; Biopsy; Brain; Brain Neoplasms; Diagnosis, Differential; Electroencephalography; Encephalitis, Herpes Simplex; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Magnetic Resonance Imaging; Male; Sarcoma, Myeloid

Topics: Acyclovir; Antibodies, Viral; Brain Neoplasms; Clinical Trials as Topic; Glioblastoma; Humans; Neoplasm Recurrence, Local; Simplexvirus; Treatment Outcome; Virus Replication

We report a case of a 73-year-old patient with complete ophthalmoplegia following an episode of ophthalmic herpes zoster. MRI showed an associated ipsilateral temporal meningioma with cavernous sinus extension. We discuss the possible responsibility of these two conditions in the ocular motor signs.

Topics: Acyclovir; Aged; Anisocoria; Anti-Inflammatory Agents; Antiviral Agents; Blepharoptosis; Brain Neoplasms; Female; Herpes Zoster Ophthalmicus; Humans; Magnetic Resonance Imaging; Meningioma; Methylprednisolone; Ophthalmoplegia; Temporal Lobe; Valacyclovir; Valine; Visual Acuity

Topics: Acyclovir; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Transitional Cell; Cisplatin; Combined Modality Therapy; Drug Eruptions; Female; Fluorouracil; Humans; Interferons; Middle Aged; Urinary Bladder Neoplasms

The authors report a fatal outcome in a 4-year-old boy with herpes simplex virus (HSV) pneumonia and ependymoma. The patient had respiratory distress that worsened despite antibiotic treatment. Bronchoalveolar lavage showed intranuclear viral inclusions, and culture was positive for HSV type 1. His T-cell count was significantly decreased. Although acyclovir and foscarnet were given, the patient died. Postmortem examination showed HSV pneumonitis with severe alveolar damage and severe involutional changes of the thymus with absence of Hassall's corpuscles. HSV must be considered in the differential diagnosis of patients with interstitial pneumonia and T-cell deficiency, especially after craniospinal irradiation.

Topics: Acyclovir; Antiviral Agents; Brain Neoplasms; Child, Preschool; Drug Therapy, Combination; Ependymoma; Fatal Outcome; Foscarnet; Herpes Simplex; Herpesvirus 1, Human; Humans; Immunity, Cellular; Male; Neoplasm Recurrence, Local; Pneumonia, Viral; T-Lymphocytes

We recently demonstrated in vitro that a mutant HSV-TK (mutant 75) expressed from an adenovirus (AdCMV-TK75) radiosensitized rat RT2 glioma cells significantly better than wild type HSV-TK (AdCMV-TK) in combination with acyclovir (ACV). To examine whether a similar improvement could also be observed in vivo, we tested these viruses in a syngeneic rat glioma tumor model (RT2/Fischer 344). First, we demonstrate that treatment with AdCMV-TK and ACV significantly radiosensitizes implanted gliomas and roughly doubles the mean survival time to 37 days, compared to 20 days for control animals implanted with Adbetagal-transduced cells (P<.02). Second, it was important to first examine the effect of AdCMV-TK75 and ACV on survival without any irradiation. We found that AdCMV-TK75 appeared to sensitize gliomas more efficiently than AdCMV-TK, although this difference was not significant ( P= .19 ). Third, and most importantly, in combined HSV-TK, ACV and irradiation experiments, we demonstrate that AdCMV-TK75 is superior over AdCMV-TK and significantly (P<.005) prolonged the survival of treated animals. Our results suggest that AdCMV-TK75 is far more efficient than AdCMV-TK in radiosensitizing rat glioma when administered in combination with ACV.

Topics: Acyclovir; Adenoviridae; Animals; Antiviral Agents; Apoptosis; Blotting, Western; Brain; Brain Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Genetic Vectors; Glioma; Mutation; Neoplasm Transplantation; Radiation-Sensitizing Agents; Rats; Rats, Inbred F344; Simplexvirus; Survival Rate; Thymidine Kinase; Transduction, Genetic; Tumor Cells, Cultured

Glioblastoma multiforme is one of the most aggressive and frequently occurring forms of brain cancer. It originates from astrocytes and is characterized by a loss of cell cycle control frequently involving mutations in tumor suppressor genes, such as p53 and p16. Nucleoside analogs, such as acyclovir (ACV), are currently being used in the treatment of viral diseases, such as those caused by members of the herpes family. Further, ACV in combination with type I interferons (IFN) has been shown to be more effective at lower doses in treatment of viral diseases. We show here that ACV at high concentrations (up to 500 microg/ml) inhibited growth in tissue culture of the human glioblastoma cell lines T98G, SNB-19, and U-373 by as much as 68.3% while inhibiting normal human astrocytes by only 38.3%. Related to this, the tumor cells were more than sevenfold more efficient in phosphorylation of ACV to the active phosphate form than normal human astrocytes. Analogous to treatment of virus-infected cells, suboptimal concentrations of ACV were as effective as high concentrations when used in conjunction with low concentrations of IFN-gamma in inhibition of tumor cell growth. At the cellular level, ACV and IFN-gamma inhibited the cell cycle in both the G1 and S phases. The cooperative effect of ACV and IFN-gamma against the glioblastomas appears to be due to direct inhibition of DNA synthesis by ACV in the S phase of the cell cycle and induction by IFN-gamma of the tumor suppressor gene p21wAF1/CIP1, which in turn acts at the level of proliferating cell nuclear antigen (PCNA) and cyclin E/cyclin-dependent kinase 2 (Cdk2) binding and inhibition of function. These studies show that the combination of IFN-gamma and ACV at suboptimal concentrations elicits significant antiproliferative effects on the glioblastoma cell lines T98G, SNB-19, and U-373 while having very little effect on normal human astrocyte cell proliferation.

Topics: Acyclovir; Antiviral Agents; Astrocytes; Brain Neoplasms; CDC2-CDC28 Kinases; Cell Cycle; Cell Division; Cell Line; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; Drug Synergism; Glioblastoma; Humans; Interferon-gamma; Proliferating Cell Nuclear Antigen; Protein Serine-Threonine Kinases; Recombinant Proteins; Tumor Cells, Cultured

Adenovirus expressing herpes simplex virus-thymidine kinase (HSV-TK) sensitizes internal rat glioma cells to radiation in combination with acyclovir (ACV). However, relatively high concentrations of ACV (>10 microM) are required to obtain significant radiosensitization. Serum levels rarely reach more than the lower micromolar range, preventing the full use of this genetic approach to radiosensitize cells in vivo. To better use the lower concentrations of ACV available in sera, we constructed an adenovirus expressing a mutant HSV-TK (HSV-TK(75)) isolated for its approximately 20 times greater sensitivity to ACV than wild-type (wt) HSV-TK. We demonstrate that rat RT2 glioma cells infected with adenovirus AdCMV-TK(75) and exposed to either ACV or ganciclovir become more sensitive to lower concentrations (1-3 microM) of the drugs compared with cells infected with AdCMV-TK(wt), which expresses wt HSV-TK. Most importantly, the RT2 cells become more sensitive to low doses (2-4 Gy) of 60Co radiation than cells infected with an adenovirus expressing wt HSV-TK. This sensitization is accompanied by an increased rate of apoptosis. In summary, we show that infection of rat glioma cells with an adenovirus expressing a mutant HSV-TK sensitizes the cells to low doses of radiation after exposure to ACV at lower concentrations than those required for wt HSV-TK. This finding suggests that this mutant adenovirus may improve the in vivo efficacy of HSV-TK-based cancer gene therapy approaches.

Topics: Acyclovir; Adenoviridae; Animals; Antiviral Agents; Apoptosis; Blotting, Western; Brain Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Genetic Vectors; Glioma; Mutation; Rats; Rats, Inbred F344; Simplexvirus; Thymidine Kinase; Tumor Cells, Cultured

The effect of acyclovir (ACV) on the metabolism of rat 9L-gliosarcoma cells expressing the herpes simplex virus-thymidine kinase gene was studied using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and L-[methyl-11C]methionine. Though the average weight of the tumors treated with ACV was significantly lower than that of the saline-injected control group, FDG and methionine uptake per weight of tumor tissue was not different between the two groups. This result exhibits a striking contrast to the metabolic pattern observed after radiation therapy, suggesting the different pathways regarding tumor cell death between the therapies.

Topics: Acyclovir; Animals; Antiviral Agents; Biological Transport; Brain Neoplasms; Carbon Radioisotopes; Fluorodeoxyglucose F18; Genetic Therapy; Gliosarcoma; Glucose; Male; Methionine; Prodrugs; Radiopharmaceuticals; Rats; Rats, Inbred F344; Simplexvirus; Thymidine Kinase

To establish the replicated-deficient recombinant adenovirus-mediated thymidine kinase/acyclovir (Adtk/ACV) system and to evaluate its suicide effect on rat C6 brain gliomas in vitro and in vivo.. The plasmid pAdtk and pJM17 were co-infected into 293 cells (adenovector packaging cells) and the results were identified by polymerase chain reaction (PCR) assay. After the glioma C6 cells were transduced by Adtk at different multiplicity of infection (MOI) and exposed to different concentrations of ACV or gancyclovir (GCV), the cell survival curves were studied, and the cell surface was observed with scanning electronic microscopy (SEM). C6 gliomas in vivo at different inoculation days were injected with Adtk intratumorally and ACV intraperitoneally daily, and the survival duration and histologic changes of the rats were observed.. The infectious Adtk virions had a suicide effect which was enhanced with the increase in MOIs of Adtk and ACV doses along with bystander effect. Under scanning electronic microscope, special pathologic changes were observed. ACV had a similar effect as GCV but a higher dose was used. The survival duration in day 3, day 6 and day 8 groups exceeded 90 days, and the rats in day 10 group survived 28.5 +/- 4.6 days, but the survival duration in untreated C6 group and AdLacZ/ACV (adenovirus-mediated LacZ/ACV) treated group were 16.8 +/- 3.1 and 14.0 +/- 2.2 days respectively.. Adtk/ACV system can effectively kill the rat brain gliomas in vitro and in vivo.

Topics: Acyclovir; Adenoviruses, Human; Animals; Brain Neoplasms; Ganciclovir; Gene Transfer Techniques; Genetic Therapy; Glioma; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Thymidine Kinase; Tumor Cells, Cultured

Earlier studies have shown that genetically engineered herpes simplex viruses (e.g., HSV-1) are effective in killing malignant tumor cells both in vitro and in various murine tumor models. This report focuses on a panel of five genetically engineered viral mutants of the gamma(1)34.5 gene, which was shown previously to cause reduction in viral replication and associated neurovirulence of HSV. These include R3616, which has both copies of gamma(1)34.5 deleted, R4009, which has a stop codon inserted after codon 28 in both copies of the gamma(1)34.5 gene, R849, which contains a lacZ gene inserted in place of the gamma(1)34.5, R908, which lacks 41 codons in frame after codon 72 of the gamma(1)34.5, and R939, which carries a stop codon precluding the translation of the COOH-terminal domain of the gamma(1)34.5 gene. We report the following: (a) all five mutant HSVs were avirulent in experimental animals but were cytotoxic for human tumor cells in vitro and in vivo; (b) the gamma(1)34.5- HSV replicated in human glioma cells almost as efficiently as wild-type HSV-1(F) based on replication assays, in situ hybridization for viral DNA, and expression of infected cell protein 27; (c) capacity of mutant HSVs to kill human cells derived from glioblastoma multiforme (CH-235MG, D-37MG, D-54MG, D-65MG, U-251MG, U-373MG, and SK-MG-1), anaplastic astrocytoma (Hs-683), anaplastic glioma (U-87MG and U-138MG), gliosarcoma (D-32GS), or normal human astrocytes demonstrated that glioma cells varied in their susceptibility to HSV-mediated cytotoxicity and that cultured astrocytes were two to three orders of magnitude less susceptible to killing than were malignant glia; and (d) scid mice, which received 0.5 or 5 x 10(6) plaque-forming units of R4009, either were coinoculated at the time of intracranial transplantation with 106 U251MG or D-54MG human glioma cells or received the cells intratumorally 5 days after tumor induction and experienced significant increases in median survivals, with no histopathological indication of an infectious encephalitic process. Genetically engineered gamma(1)34.5- HSV mutants appear to be a potentially safe biotherapeutic agent for experimental treatment of uniformly fatal malignant brain tumors.

Topics: Acyclovir; Animals; Antiviral Agents; Astrocytes; Brain Neoplasms; Chlorocebus aethiops; Cytopathogenic Effect, Viral; DNA, Viral; Genetic Engineering; Glioma; Herpesvirus 1, Human; Humans; Immediate-Early Proteins; Mice; Mice, SCID; Transplantation, Heterologous; Vero Cells; Virus Replication

The antiviral drug acyclovir, an analogue of purine, was found to selectively enhance the radiosensitivity of rodent tumor cells which were transduced with the herpes simplex virus thymidine kinase gene (HSV-tk). 9L rat glioma cells transduced with HSV-tk and treated with acyclovir (20 micrograms/ml) for 24 hr before or after irradiation were highly sensitive to radiation, as compared with non-transduced glioma cells. When 9L cells transduced with HSV-tk gene were exposed to acyclovir and radiation, the sensitizer enhancement ratio (SER) was 1.6. In vivo, a significant increase in the median survival time of rats with 9L-tk tumors was observed when acyclovir was administered before and after single-dose irradiation, relative to the survival time of similar rats receiving radiation alone. The results show that an antiviral agent can selectively enhance cell killing by radiation in cells transduced with the HSV-tk, and suggest that the addition of HSV-tk gene therapy to standard radiation therapy will improve the effectiveness of treatment for brain tumors.

Topics: Acyclovir; Animals; Antiviral Agents; Brain Neoplasms; Cell Survival; Ganciclovir; Genetic Therapy; Glioma; Male; Radiation-Sensitizing Agents; Rats; Rats, Inbred F344; Simplexvirus; Thymidine Kinase; Transduction, Genetic

We present a case of subacute focal encephalitis in a 62-year-old man whose clinical manifestations, neuroradiological findings and histopathological features mimicked those of a patient with malignant lymphoma of the central nervous system (CNS). In addition to routine histopathological examination, extensive studies including serological examination for encephalitic viruses, immunohistochemistry and DNA analysis were required to distinguish focal encephalitis from lymphoma of the CNS, clinical entities which differ in treatment.

Topics: Acyclovir; Antiviral Agents; Blotting, Southern; Brain Neoplasms; Diagnosis, Differential; Encephalitis, Viral; Herpes Simplex; Humans; Lymphoma; Magnetic Resonance Imaging; Male; Middle Aged

The paper reports the construction of retroviral vector pLNTK carrying HSV-tk gene driven by PGK promoter and the successful transfer into human glioma cell SHG44. The in vitro study confirmed that ayclovir (ACV) sensitive level of the gene-transferred glioma cell (SHGLNTK) was 1,000 times that of SHG44. 3H-TdR incorporation confirmed that the DNA replication in SHGLNTK was considerably suppressed when treated with ACV. The in vivo study confirmed that ACV could suppress tumor formation of the SHGLNTK cells. In situ gene transfer treatment of nude mice carrying SHG44 tumor showed good therapeutic results. Such treatment may be used as an innovative method for brain tumor therapy.

Topics: Acyclovir; Animals; Antimetabolites; Brain Neoplasms; DNA, Neoplasm; Gene Transfer Techniques; Genetic Therapy; Glioma; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Thymidine Kinase; Tumor Cells, Cultured

To demonstrate in a well-characterized tumor model that the radiosensitivity of tumor cells transduced with a herpes simplex virus thymidine kinase gene (HS-tk) would be selectively enhanced by antiviral agents.. Rat 9L gliosarcoma cells transduced with a retroviral vector containing an HS-tk gene, 9L-tk cells were exposed to various doses of irradiation under either in vitro or in vivo conditions. The radiation sensitizing potential of two antiviral drugs, bromovinyl deoxyuridine (BVdU) and dihydroxymethyl ethyl methyl guanine (acyclovir), was evaluated in vitro. The radiosensitizing ability of BVdU was also evaluated with a 9L-tk tumor growing in the rat brain. Tumors growing in the right hemisphere of rat brains were irradiated stereotactically with single-dose irradiation.. The radiation response of 9L-tk cells was selectively enhanced by antiviral agents relative to nontransduced cells. In the cell culture, when a 24-h drug exposure (20 micrograms/ml) preceded radiation, the sensitizer enhancement ratio (SER) for BVdU and acyclovir was 1.4 +/- 0.1 and 1.3 +/- 0.1, respectively. Exposure of cells to 10 micrograms/ml acyclovir for two 24-h periods both pre- and postirradiation resulted in a SER of 1.6 +/- 0.1. In vivo, a significant increase in median survival time of rats with 9L-tk tumors was found when BVdU was administered prior to single-dose irradiation relative to the survival time of similar rats receiving radiation alone.. An antiviral agent can enhance cell killing by radiation with selective action in cells transduced with the herpes simplex virus thymidine kinase gene. The results suggest that the three-pronged therapy of HS-tk gene transduction, systemically administered antiviral drug, and stereotactically targeted radiation therapy will improve the effectiveness of radiation therapy for the treatment of radioresistant tumors.

Topics: Acyclovir; Animals; Antiviral Agents; Brain Neoplasms; Bromodeoxyuridine; Gliosarcoma; Male; Radiation-Sensitizing Agents; Rats; Rats, Inbred F344; Simplexvirus; Thymidine Kinase; Transfection; Tumor Cells, Cultured

The antiviral agents ganciclovir, 1-beta-D-arabinofuranosylthymine (araT), acyclovir, and 5-iodo-5'-amino-2',5'-dideoxyuridine were cytotoxic to rat C6 glioma cells expressing retrovirally transferred herpes simplex virus (HSV) type 1 thymidine kinase (TK) coding sequence, with concentrations that inhibited cell survival by 50% (IC50 values) of 0.06, 3, 13, and 23 mumol/L, respectively. In C6 cells not expressing HSV-TK, the IC50 value for ganciclovir was 140 mumol/L and a concentration of 1 mmol/L killed more than 99% of the cells. The other antiviral agents tested were less toxic in nontransduced cells. Compared with retrovirally transduced cells, transduction of C6BU1 cells with an adenovirus vector containing the coding sequence for HSV-TK (Ad.RSVtk) increased the cellular activity of the viral kinase up to 600-fold with increasing multiplicity of infection (MOl). Cells transduced with Ad.RSVtk exhibited as much as a fivefold and 12-fold decrease in IC50 value for ganciclovir and araT, respectively, compared with retrovirally transduced cells. Sensitivity to antiviral drugs increased with increasing exposure to Ad.RSVtk, with IC50 values of 0.6 and 0.005 mumol/L for araT and ganciclovir, respectively, at an MOl of 1000. These data suggest that adenoviral transfer of HSV-TK will allow the use of less toxic drugs or lower concentrations of toxic drugs such as ganciclovir for directed antitumor therapy in vivo.

Topics: Acyclovir; Adenoviruses, Human; Animals; Arabinonucleosides; Avian Sarcoma Viruses; Brain Neoplasms; Drug Resistance; Ganciclovir; Genes, Viral; Genetic Vectors; Glioma; Promoter Regions, Genetic; Rats; Recombinant Fusion Proteins; Simplexvirus; Thymidine; Thymidine Kinase; Transfection; Tumor Cells, Cultured

Malignant gliomas are the most common malignant brain tumors and are almost universally fatal. A genetically engineered herpes simplex virus-1 mutant with decreased neurovirulence, dlsptk, has been shown to kill human glioma cells in culture and in animal models. However, intracranial inoculation of dlsptk is limited by fatal encephalitis at higher doses. Therefore, additional engineered and recombinant herpes simplex mutants with demonstrated reduced neurovirulence (AraAr9, AraAr13, RE6, R3616) were examined as antiglioma agents. One long-term human glioma cell line and two early-passage human gliomas in culture were destroyed by all four viruses tested. In a subcutaneous glioma model, AraAr13, RE6, and R3616 retained substantial antineoplastic effects in nude mice when compared with controls (one-sided Wilcoxon rank test, P < 0.05 for one or more doses each). When tested in a nude mouse intracranial glioma model, both RE6 and R3616 significantly prolonged average survival without producing premature encephalitic deaths at two doses (log-rank statistic, P < 0.007). Histopathological studies of the brains of surviving animals revealed minimal focal encephalitis in two of three RE6-treated animals and no evidence of encephalitis in either one of three RE6-treated or in three of three R3616-treated animals. No evidence of residual tumor was seen in four of the six surviving animals. Additionally, both RE6 and R3616 were found to be susceptible to the common antiherpetic agent acyclovir, adding to their safety as potential antiglioma agents. Recombinant and engineered viruses that minimize host toxicity and maximize tumoricidal activity merit further study as antineoplastic agents.

Topics: Acyclovir; Animals; Brain Neoplasms; Encephalitis; Female; Glioma; Herpes Simplex; Humans; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; Simplexvirus; Transplantation, Heterologous; Tumor Cells, Cultured

Twelve cases of malignant gliomas (anaplastic astrocytoma 4, glioblastoma 8, recurrent 3, primary 9) were treated with ACNU and radiation with sensitizing agents after the surgical removal of the tumor. BUdR, Vidarabine (Ara-A), Aciclovir (ACV) were applied for sensitizing agents. BUdR was administrated intraarterially prior to radiation (380 rad, two times a week), and Ara-A and ACV intravenously during and after the radiation. Total dosage of the radiation was 50-60 Grey for each case. All recurrent and eight primary patients died. The mean survival time of the recurrent patients was 17.7 months, while that of the primary patients was 13.4 months. One of the primary patient was glioblastoma and is still surviving more than 24 months by now. The complete response (CR) rate of the primary tumor patients observed by computerized tomography (CT) scan was 5/9. We can expect the availability of this trial for malignant gliomas because of high CR rate in primary tumor cases.

Topics: Acyclovir; Adolescent; Adult; Aged; Brain Neoplasms; Bromodeoxyuridine; Combined Modality Therapy; Evaluation Studies as Topic; Female; Glioma; Humans; Male; Middle Aged; Nimustine; Radiation Injuries; Radiation-Sensitizing Agents; Radiotherapy Dosage; Remission Induction; Vidarabine