To cite this article: Daniel H. In this study, mammalian expression vectors carrying bovine herpesvirus 1 (BHV-1) VP22 (BVP22) or herpes simplex virus type 1 (HSV-1) VP22 (HVP22) and equine herpesvirus type 4 (EHV-4) tk (Etk) were constructed in order to evaluate and compare the therapeutic potentials of BVP22 and HVP22 to enhance Etk/ganciclovir (Etk/GCV) suicide gene therapy for neuroblastomas by GCV cytotoxicity assays and noninvasive bioluminescent imaging in vitro and in vivo. Suicide gene therapy using herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) offers a potential treatment strategy for cancer and is undergoing preclinical trials for a variety of tumors. Background Ganciclovir (gan sye’ kloe vir) is an acyclic guanosine nucleoside analogue structurally related to acyclovir which has antiviral activity against many herpes viruses, including herpes simplex 1 and 2, Epstein-Barr virus and varicella-zoster, but is used largely in the therapy of cytomegalovirus (CMV) infections. The inhibition of PC-3 tumour growth in vivo induced by the Ad-CMV-TK/acyclovir suicide-gene system was assessed in separate and controlled experiments using human prostate cancer mouse models. One mutant, termed Q7530 TK, had a lower Km for GCV than thymidine. Lack of synergy between 131I-FIAU and GCV does not warrant further investigation of combination treatment with the two agents.

While neomycin selects for cells with integration, the marker HSVtk selects for homologous recombination (since it is usually included in the genome only during random integration). Terms Related to the Moving Wall Fixed walls: Journals with no new volumes being added to the archive. However, in combination gene therapy, the route of delivery for each gene may have implications for efficacy, especially if a cell suicide gene such as HSV-TK is employed. Patients with histologically confirmed malignant tumors refractory to standard treatment were eligible. Valganciclovir was approved for use in 2001 and is available in 450 mg tablets and as a powder for solution under the brand name of Valcyte. GFP-HSVtk expression levels relative to mCherry were practically identical in iPSCs with or without let7 regulation, showing that let7 regulation has no detectable effect in HSVtk expression in pluripotent cells (Supplementary Figure S2a). Valganciclovir has replaced oral ganciclovir in therapy and prophylaxis of CMV infections.

Side effects of ganciclovir and valganciclovir therapy include headache, dizziness, confusion, tremors, nausea, diarrhea, fever, renal dysfunction, bone marrow suppression and rash. Hepatotoxicity Intravenous administration of ganciclovir is associated with transient mild-to-moderate elevations in serum ALT levels in 2% of patients. These episodes have usually been asymptomatic and self-limited. CMV infection itself can cause liver enzyme elevations and may account for some abnormalities found during therapy. There is little evidence that either ganciclovir or valganciclovir can cause clinically apparent liver injury. Links to PubMed are also available for Selected References. Mechanism of Injury Ganciclovir is metabolized intracellularly in viral infected cells, hepatic metabolism is minimal, and it is excreted largely unchanged by the kidneys, perhaps accounting for the absence or rarity of hepatic injury.

The flare of hepatitis B that occurs when ganciclovir is stopped is probably caused by an immune reaction to the rapid return of HBV replication after therapy. Zimmerman HJ. Antiviral agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp.

621-3. (Expert review of antiviral agents and liver injury published in 1999; mentions that ganciclovir has not caused “overt hepatic injury”). Núñez M. Hepatotoxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed.

Amsterdam: Elsevier, 2013, pp. 505-18. (Review of hepatotoxicity of antiviral agents; ganciclovir and valganciclovir have been linked to serum enzyme elevations during therapy, and cases of clinically apparent liver injury have been reported to the sponsor). Acosta EP, Flexner C. Antiviral agents (nonretroviral). In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics.

12th ed. New York: McGraw-Hill, 2011, pp. 1593-1622. (Textbook of pharmacology and therapeutics). Styrt B, Freiman JP. Hepatotoxicity of antiviral agents. Gastroenterol Clin North Am 1995; 24: 839-52.

PubMed Citation  (Review of liver toxicity of antiviral agents; intravenous administration of ganciclovir has been reported to cause serum aminotransferase elevations in 2% of patients). Protein expression was detected by immunoblot by using polyclonal anti-TK and monoclonal anti-FADD antibodies. Liver failure caused by herpes simplex virus thymidine kinase plus ganciclovir therapy is associated with mitochondrial dysfunction and mitochondrial DNA depletion. Human Gene Ther 2003; 14: 463-72. PubMed Citation  (In a rat model, the adenoviral transfer of thymidine kinase followed by ganciclovir leads to acute hepatocellular injury with evidence of mitochondrial injury, lactic acid elevations and morphologic changes; this form of toxicity is only a concern for gene therapy studies in which there may be gene transfer of the viral kinase to normal hepatocytes). Reusser P. Oral valganciclovir: a new option for treatment of cytomegalovirus infection and disease in immunocompromised hosts.

Expert Opin Investig Drugs 2001; 10: 1745-53. PubMed Citation  (Review of valganciclovir, an oral prodrug of ganciclovir, which is active against CMV infection and disease; no mention of hepatotoxicity or ALT elevations with therapy). Shea BF, Hoffman S, Sesin GP, Hammer SM. Ganciclovir hepatotoxicity. Pharmacotherapy 1987; 7: 223-6. PubMed Citation  (33 year old man with HIV infection, CMV retinitis and mycobacterium avium intracellulare [MAC] infections developed increases in preexisting elevated enzyme levels without bilirubin elevations during two courses of ganciclovir [ALT 133 rising to ~500 U/L, AlkP 181 rising to 1014 U/L], peaking several weeks after stopping and then decreasing; liver biopsy showed MAC and no evidence of hepatitis). Hochster H, Dieterich D, Bozzette S, Reichman RC, Connor JD, Liebes L, Sonke RL, et al.

Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group Study. Ann Intern Med 1990; 113: 111-7. PubMed Citation  (40 patients with HIV and CMV infection were treated with zidovudine and intravenous ganciclovir; anemia and neutropenia were common; 1 patient developed hepatitis thought to be zidovudine-related, resolving on stopping and recurred on restarting zidovudine [timing and details not given]). Figge HL, Bailie GR, Briceland LL, Kowalsky SF. Possible ganciclovir-induced hepatotoxicity in patients with AIDS. Finally, Otero and Hope have shown that sequences from the HSV1 TK gene behave similarly to WPRE by enhancing levels of expression of another construct; this work was also restricted to in vitro plasmid DNA transfections (36).

PubMed Citation  (Retrospective review of 14 courses of ganciclovir in 11 patients with HIV infection identified 5 with associated elevations in AST [29-36 rising to 55-110 U/L] or Alk P [61 rising to 360 U/L], but all were receiving other potentially hepatotoxic agents and no patient was reported to develop hepatitis or jaundice). As a control (Fig 3B, lower panel), we observed that another abundant cytoplasmic protein, -actin, was not released from the cell into the medium (lanes 7–9) and was only minimally appreciable after lyase treatment (lanes 4–6), possibly as a consequence of marginal unspecific leakage. Synchrotron. A similar result previously obtained with tk when under the control of different cellular promoters was attributed to narrow selective limits imposed by HAT medium on cells expressing HSV-TK (20). PubMed Citation  (9 patients with recurrent hepatitis B after liver transplant were treated with ganciclovir for 3-10 months; serum HBV DNA and ALT levels decreased on therapy and flare occurred in 3 when ganciclovir was stopped, one becoming jaundiced and developing hepatic decompensation). After gel purification, these overlapping primary products were denatured and allowed to reanneal together, producing two possible heteroduplex products. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.

Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008; 8 were attributed to antiviral agents including one due to valacyclovir, but none were attributed to ganciclovir or valganciclovir). Witzke O, Hauser IA, Bartels M, Wolf G, Wolters H, Nitschke M; VIPP Study Group. Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial. Transplantation 2012; 93: 61-8. PubMed Citation  (Controlled trial of prophylaxis vs preemptive therapy of CMV infection in 296 renal allograft recipients; overall tolerability was good and no mention of ALT elevations or hepatotoxicity). Antiviral drugs.

Treat Guidel Med Lett 2013; 11 (127): 19-30. PubMed Citation  (Review of safety and efficacy of ganciclovir and valganciclovir treatment and prophylaxis against CMV infection; mentions that adverse effects include “abnormal liver function”).

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