acyclovir and Nasopharyngeal-Neoplasms

Herpes viruses are characterized by their ability to establish and maintain latent infections that can be reactivated. Several stimuli can trigger the reactivation of herpes viruses, which are perhaps best recognized in the recurrent blisters and ulcers associated with herpes simplex virus. We present two clinical cases of reactivation of herpes simplex virus during radiation therapy for management of cancers of the head and neck. Although the role of ionizing radiation in the reactivation of herpes simplex virus has not been established, we review the viral and host events associated with the establishment of orofacial herpes simplex virus infection, latency, and reactivation of the virus. We discuss current models of viral reactivation and suggest directions for further clinical research into the reactivation of orolabial herpes simplex virus during radiotherapy.

Topics: Acyclovir; Adult; Antiviral Agents; Carcinoma, Squamous Cell; Cerebellar Neoplasms; Head and Neck Neoplasms; Humans; Immunocompromised Host; Lymphoma, AIDS-Related; Lymphoma, B-Cell; Lymphoma, Large-Cell, Immunoblastic; Male; Middle Aged; Nasopharyngeal Neoplasms; Radiotherapy; Recurrence; Simplexvirus; Stomatitis, Herpetic; Virus Activation; Virus Latency

Topics: Acute Disease; Acyclovir; Antiviral Agents; Burkitt Lymphoma; Chronic Disease; Herpesvirus 4, Human; Humans; Infectious Mononucleosis; Nasopharyngeal Neoplasms; Recurrence; Tumor Virus Infections

The group of the human-pathogenic herpesviruses comprises five subgroups: Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). Primary infection with these ubiquitous herpesviruses usually occurs in childhood or during adolescence and frequently remains inapparent. However, it can also give rise to a variety of clinical pictures. Important clinical manifestations of herpesvirus infections are mucocutaneous lesions (HSV-1, HSV-2, VZV) self-limited, lymphoproliferative diseases (CMV, EBV) and congenital malformations (CMV). Primary infection with herpesviruses leads to a persistent infection of the host. This clinically silent condition of latency can be interrupted and may cause pathological symptoms to recur by reactivation of latent herpesviruses. A classical example of the clinical manifestation of herpesvirus reactivation is herpes zoster following an overcome varicella disease. The mechanism of herpesvirus reactivation has not yet been fully clarified. Reactivation of herpesviruses might be attributable to a weakening of the cellular immunodefence. For the control of viral infections mainly two cellular effector systems are responsible: unspecific, cytotoxic, natural killer (NK) cells and specific cytotoxic thymus-dependent (T) lymphocytes. The functional impairment of these cytotoxic active cells my cause herpesvirus reactivation in immunodeficient or immunosuppressed persons. Interference with the immunological control function may also contribute to the genesis of herpesvirus-associated tumours. Such an association between herpesviruses and human tumours is assumed to exist especially in the case of EBV. The frequently life-endangering severity of local or disseminated herpesvirus infections calls for suitable measures ensuring efficient prophylaxis and therapy. However, the possibilities of a specific immunoprophylaxis (vaccine, special immunoglobulins) against herpesvirus infections are still rather limited. The development of antiviral substances has greatly benefited from the introduction of new agents (Acyclovir) and the production of sufficient quantities of interferon (IFN) preparations during the last few years. Impressive results were obtained with the nucleoside-related substance Acyclovir in the prevention and therapy of primary or reactivated HSV-1 or HSV-2 infections. The use of Acyclovir as prophylactic agent produced the effect tha

Topics: Acyclovir; Antiviral Agents; Burkitt Lymphoma; Chickenpox; Cytomegalovirus; Cytomegalovirus Infections; Female; Herpes Genitalis; Herpes Simplex; Herpes Zoster; Herpesviridae; Herpesviridae Infections; Herpesvirus 3, Human; Herpesvirus 4, Human; Humans; Immunity, Cellular; Immunization, Passive; Infectious Mononucleosis; Male; Nasopharyngeal Neoplasms; Simplexvirus; Smallpox Vaccine; T-Lymphocytes; Vidarabine

In this study, we aimed to construct an effective and safe oncolytic adenoviral vector for cancer treatment with gene therapy. First, the promoter of the catalytic subunit of human telomerase (hTERTp), adenovirus early region 1a gene (E1A) and thymidine kinase gene of human herpes virus type 1 (HSV-1-TK) were amplified by using PCR from genomic DNA of 293A cells and wild-type HSV-1 (wHSV-1). These specially-prepared elements were inserted into an adenoviral shuttle vector in the opposite and the same directions of left inverted terminal repeat (L-ITR), respectively, to construct pENTR-E1A-IRES-TK-hTERTp (pEITH) and pENTR-hTERTp-E1A-IRES-TK (pHEIT). LR reaction between adenoviral shuttle vectors (pEITH and pHEIT) and the backbone vector DEST was carried out to establish adenoviral expression vectors pAd-E1A-IRES-TK-hTERTp (pAd-EITH) and pAd-hTERTp-E1A-IRES-TK (pAd-HEIT). Recombinant adenovirus Ad-EITH and Ad-HEIT were produced by transfecting 293A cells and purified for the subsequent studies of titer measurement, replication capability with and without acyclovir (ACV) and antitumor ability with and without ganciclovir (GCV) to evaluate the biological characteristics. Adenoviral shuttle vectors pEITH and pHEIT and expression vectors pAd-EITH and pAd-HEIT were successfully constructed, and recombinant adenoviruses Ad-EITH and Ad-HEIT with high titer were produced. The results of replication and cytotoxicity assays showed that Ad-EITH and Ad-HEIT replicated in the hTERTp (+) human nasopharyngeal carcinoma cell line CNE and expressed the TK gene effectively leading to the death of tumor cells. In addition, there were still some Ad-HEIT particles replicating in the hTERTp (-) human osteosarcoma U-2OS cells and human lung HFL-1 fibroblasts compared to Ad-EITH which was hardly able to replicate in U-2OS and HFL-1 cells. In addition, we also observed an interesting phenomenon, that the replication of Ad-EITH could be inhibited by antiviral drug ACV on account of the expression of HSV-1-TK gene making Ad-EITH sensitive to ACV. In conclusion, a novel oncolytic adenoviral vector Ad-EITH was produced which can be used for cancer-specific and efficient viral replication, and its safety is potentially improved as replication can be inhibited by ACV in vitro.

Topics: Acyclovir; Adenoviridae; Adenovirus E1A Proteins; Antiviral Agents; Bone Neoplasms; Carcinoma; Cell Line, Tumor; Fibroblasts; Ganciclovir; Gene Amplification; Gene Expression; Genetic Therapy; Genetic Vectors; Herpesvirus 1, Human; Humans; Lung; Nasopharyngeal Neoplasms; Osteosarcoma; Promoter Regions, Genetic; Recombinant Proteins; Telomerase; Terminal Repeat Sequences; Thymidine Kinase; Virus Replication

NPC-KT cl.S61, a subclone derived from an epithelial-nasopharyngeal carcinoma hybrid cell line NPC-KT, showed extensive Epstein-Barr virus (EBV) production and cell fusion when the EBV replicative cycle was induced by 5-iodo-2'-deoxyuridine. On the contrary, parental NPC-KT cells produced virus at a lower level and did not show cell fusion. Cell fusion in cl.S61 cells was blocked by 2-deoxyglucose and acyclovir, inhibitors of glycosylation and EBV DNA polymerase, respectively, with a concomitant decrease in the number of cells expressing EBV growth-associated antigens. However, the frequency of virus antigen expression in parental NPC-KT cells was not significantly affected by these drugs. This result suggests that efficient production of EBV from cl.S61 cells is due to the spreading of viral replicative cycle via cell fusion. It was also demonstrated by in situ autoradiography that cl.S61 cells producing virus fused to not only EBV receptor/CR2 positive Raji and BJAB cells, but also to receptor-negative Jurkat cells. The possible mechanism of EBV entry into cells devoid of virus receptor by cell fusion is discussed.

Topics: Acyclovir; Cell Fusion; Deoxyglucose; Herpesvirus 4, Human; Humans; Hybrid Cells; In Vitro Techniques; Nasopharyngeal Neoplasms; Receptors, Virus; Tumor Cells, Cultured; Virus Replication

NPC-KT cl.S61, a subclone derived from an epithelial-nasopharyngeal carcinoma hybrid cell line (NPC-KT), showed cytopathic changes characteristic of herpesvirus replication, including formation of multinucleated giant cells and inclusion bodies, when Epstein-Barr virus replicative cycle was induced by 5-iodo-2'-deoxyuridine. Acyclovir (an inhibitor of herpesvirus DNA polymerase), Epstein-Barr virus-immune human serum, or 2-deoxyglucose (an inhibitor of the glycosylation) interfered with syncytium formation, indicating that a virus-specified glycoprotein belonging to the late group is responsible for cell fusion induced by Epstein-Barr virus replication in cl.S61 cells.

Topics: Acyclovir; Antigens, Viral; Carcinoma, Squamous Cell; Cell Fusion; Cytopathogenic Effect, Viral; Deoxyglucose; DNA, Viral; Electrophoresis, Polyacrylamide Gel; Herpesvirus 4, Human; Humans; Hybrid Cells; Idoxuridine; Nasopharyngeal Neoplasms; Nucleic Acid Hybridization; Restriction Mapping; Tumor Cells, Cultured; Virus Replication