acyclovir and Laryngeal-Neoplasms

The most extensively investigated strategy of suicide gene therapy for treatment of cancer is the transfer of the herpes simplex virus thymidine kinase (HSV-TK) gene followed by administration of antiviral prodrugs such as acyclovir (ACV) and ganciclovir (GCV). The choice of the agent that can stimulate HSV-TK enzymatic activity is one of the determinants of the usefulness of this strategy. Previously, we found that a diterpenoid, scopadulciol (SDC), produced a significant increase in the active metabolite of ACV. This suggests that SDC may play a role in the HSV-TK/prodrug administration system.. The anticancer effect of SDC was evaluated in HSV-TK-expressing (TK+) cancer cells and nude mice bearing TK+ tumors. In vitro and in vivo enzyme assays were performed using TK+ cells and tumors. The phosphorylation of ACV monophosphate (ACV-MP) was measured in TK- cell lysates. The pharmacokinetics of prodrugs was evaluated by calculating area-under-the-concentration-time-curve values.. SDC stimulated HSV-TK activity in TK+ cells and tumors, and increased GCV-TP levels, while no effect of SDC was observed on the phosphorylation of ACV-MP to ACV-TP by cellular kinases. The SDC/prodrug combination altered the pharmacokinetics of the prodrugs. In accord with these findings, SDC enhanced significantly the cell-killing activity of prodrugs. The bystander effect was also significantly augmented by the combined treatment of ACV/GCV and SDC.. SDC was shown to be effective in the HSV-TK/prodrug administration system and improved the efficiency of the bystander effect of ACV and GCV. The findings will be considerably valuable with respect to the use of GCV in lower doses and less toxic ACV. This novel strategy of drug combination could provide benefit to HSV-TK/prodrug gene therapy.

Topics: Abietanes; Acyclovir; Animals; Antiviral Agents; Biological Availability; Carcinoma; Cell Line, Tumor; Female; Ganciclovir; Genes, Neoplasm; Genetic Therapy; Glioblastoma; HeLa Cells; Herpes Simplex; Herpesvirus 1, Human; Humans; Laryngeal Neoplasms; Mice; Mice, Nude; Molecular Structure; Plasmids; Prodrugs; Thymidine Kinase; Transfection; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

A series of synthetic spongiane-type diterpenes have been tested in vitro for their potential antitumor and antiherpetic activity. Although the antiviral activity of these compounds against herpes simplex virus type 2 (HSV-2) was very weak, some compounds exhibited relevant cytotoxicity in the human tumor cell lines HeLa and HEp-2. The biological activity of formyl spongianes is reported for the first time. With the present study, some structure-activity trends are suggested for the cytotoxic activity of these sponge-derived natural products.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cricetinae; Cricetulus; Diterpenes; Drug Screening Assays, Antitumor; Ear; Fibroblasts; HeLa Cells; Herpesvirus 2, Human; Humans; Inhibitory Concentration 50; Laryngeal Neoplasms; Molecular Structure; Porifera; Skin; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured

Fourteen semisynthetic compounds derived from the natural scopadulane-type diterpenes thyrsiflorin A (4), B (5), and C (6), including several precursors, have been examined in vitro for their antiherpetic activity against Herpes simplex virus type II (HSV-2) and cytotoxicity against two human tumor cell lines. Four of these compounds showed moderate antiherpetic activity, but none of them exhibited a significant cytotoxicity against the cell lines used. Some structure-activity relationships have been identified for the antiviral activity in these scopadulane derivatives as well as important structural features for the cytotoxic activity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antiviral Agents; Cattle; Cell Survival; Cells, Cultured; Chlorocebus aethiops; CHO Cells; Cricetinae; Diterpenes; Ear; Female; HeLa Cells; Herpesvirus 2, Human; Humans; Inhibitory Concentration 50; Kidney; Laryngeal Neoplasms; Ovary; Plants, Medicinal; Skin; Structure-Activity Relationship; Tumor Cells, Cultured; Uterine Cervical Neoplasms; Vero Cells

Herpes simplex viruses (HSV) are ubiquitous pathogens causing a variety of diseases ranging from mild illness to severe life-threatening infections. HSV utilize cellular signaling pathways and transcription factors to promote their replication. Here we report that HSV type 1 (HSV-1) induces persistent activation of transcription factor NF-kappa B, a critical regulator of genes involved in inflammation, by activating the I kappa B kinase (IKK) in the early phase of infection. Activated NF-kappa B enhances HSV-1 gene expression. HSV-1-induced NF-kappa B activation is dependent on viral early protein synthesis and is not blocked by the anti-herpetic drug acyclovir. IKK inhibition by the anti-inflammatory cyclopentenone prostaglandin A(1) blocks HSV-1 gene expression and reduces virus yield by more than 3000-fold. The results identify IKK as a potential target for anti-herpetic drugs and suggest that cyclopentenone prostaglandins or their derivatives could be used in the treatment of HSV infection.

Topics: Acyclovir; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Chlorocebus aethiops; Cycloheximide; Dactinomycin; Drug Design; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Fungal; Herpesvirus 1, Human; Humans; I-kappa B Kinase; Kinetics; Laryngeal Neoplasms; Methionine; Neuroblastoma; NF-kappa B; Prostaglandins A; Protein Serine-Threonine Kinases; Recombinant Proteins; Transfection; Tumor Cells, Cultured; Vero Cells; Virus Replication

Multiple papilloma of larynx is caused by human papilloma virus. We treated sixteen such cases (10 males and six females) in the last 10 years. All presented with hoarseness while six presented with difficulty in respiration. Three patients needed tracheostomy, all had difficult decanulation, and one developed laryngotracheal stenosis and could not be decanulated. All were treated by surgical excision; ten had recurrence. Four patients were treated with post operative Acyclovir with no recurrence in three cases.

Topics: Acyclovir; Child; Child, Preschool; Female; Humans; Laryngeal Neoplasms; Laryngoscopy; Male; Papilloma; Papillomavirus Infections; Prognosis; Retrospective Studies; Tracheostomy; Tumor Virus Infections

Six patients with severe, recalcitrant, juvenile-onset recurrent respiratory papillomatosis were treated with 7 independent trials of acyclovir. In 2 trials, patients received acyclovir in place of interferon-alpha; the remaining 5 trials were in patients not otherwise receiving chemotherapy. Quantitative analysis of overall disease extent, laryngeal involvement, and degree of glottic obstruction for the 6 months prior to acyclovir administration and during acyclovir administration demonstrated a statistically significant decrease in all parameters evaluated in those patients who were otherwise unmediated. The 2 patients who discontinued interferon-alpha immediately prior to beginning acyclovir demonstrated worsening disease, consistent with the well-recognized rebound phenomenon associated with stopping interferon. This study suggests that acyclovir decreases the extent of respiratory papillomatosis in patients with recalcitrant disease. The beneficial effect of acyclovir appears to be insufficient to counteract the rebound of disease when interferon is stopped abruptly.

Topics: Acyclovir; Drug Administration Schedule; Humans; Laryngeal Neoplasms; Neoplasm Recurrence, Local; Papilloma; Pilot Projects; Treatment Outcome

Four patients with aggressive respiratory papillomatosis have been treated with oral Acyclovir as adjuvant therapy while continuing to undergo regular endoscopy and laser treatment to the lesions. The duration of Acyclovir administration ranged from 2 weeks to 3 months. Two patients had papillomatosis confined to the larynx and two in addition had disease in the lower respiratory tract. One of the four patients had less aggressive disease during the treatment period. Acyclovir does not appear to significantly influence respiratory papillomatosis. Acyclovir's activity is dependent upon the presence of virally encoded thymidine kinase. This enzyme is not known to be encoded by papilloma viruses. Acyclovir is not recommended in the treatment of juvenile respiratory papillomatosis.

Topics: Acyclovir; Child; Child, Preschool; Female; Humans; Laryngeal Neoplasms; Male; Neoplasms, Multiple Primary; Papilloma; Respiratory Tract Neoplasms

We report the results obtained in a study of 3 young patients with laryngeal papillomatosis, who were treated with acyclovir after tumor excision using forceps was performed under microlaryngoscopy. No recurrence of the papillomatosis occurred between 18 and 42 months post-therapy. Laryngeal papillomatosis is the most common proliferative laryngeal lesion in children. Different non-surgical therapies have been used to prevent its recurrence but with poor results. Acyclovir is a drug with proved efficacy in DNA viral diseases. Since papillomata of the larynx is most likely a viral disease which is imputed to have a DNA virus etiology, acyclovir may be effective to control it.

Topics: Acyclovir; Child; Child, Preschool; Combined Modality Therapy; Female; Glottis; Humans; Laryngeal Neoplasms; Laryngoscopy; Male; Neoplasm Recurrence, Local; Papilloma; Vocal Cords

Topics: Acyclovir; Herpes Zoster; Humans; Injections, Intravenous; Laryngeal Neoplasms; Neoplasms

Topics: Acyclovir; Deglutition Disorders; Herpes Zoster; Humans; Laryngeal Diseases; Laryngeal Neoplasms; Sleep Apnea Syndromes; Tracheal Diseases; Tracheal Stenosis