HSV-1 TK

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Overview

Enzymes that are not present in mammalian cells are present in some viruses, bacteria or fungi, and these enzymes catalyze the transformation of non-toxic or low-toxic precursor drugs into highly toxic drugs. Since human cells lack the enzyme system to catalyze precursor drugs, precursor drugs are activated only in tumor cells transfected with suicide genes (i.e., drug-sensitive genes), without damaging normal cells. Suicide gene therapy is the transfer of such genes into tumor cells to make them metabolically sensitive to the precursor drug. When the suicide gene is transferred into the tumor cell, the toxicity of the precursor drug to patient treatment is confined to the transformed cell and its microenvironment without significant systemic toxicity. In addition, suicide genes can kill untransfected tumor cells adjacent to transfected cells through a bystander effect. The bystander effect was found to be more pronounced in tumor cells with more gap junctions or cellular channels.

Suicide genes

The main suicide genes identified so far include: herpes simplex virus thymidine kinase (HSV-TK) gene, cytomidine deaminase gene, varicella zoster virus thymidine kinase gene, E. coli nitroreductase gene, E. coli guanosine-xanthine phosphate ribosyltransferase gene and E. coli deoxyribose genes, etc. The most studied gene is HSV-TK gene.

HSV-TK

HSV-TK, herpes simplex virus thymidine kinase, is a commonly used suicide gene in oncogene therapy research. Herpes simplex virus thymidine kinase (HSV-TK) gene works because certain specific enzyme protein genes such as HSV-TK and CD genes encode enzyme proteins that can convert some non-toxic or low-toxic prodrugs into strong cytotoxic substances that kill tumor cells. These genes are also known as suicide genes.

Antivirals

Thymidine kinase from herpesvirus is a subfamily of thymidine kinases. It is present in herpesvirus-infected cells and is used to activate a range of antiviral drugs against herpesvirus infection, and is therefore specifically targeted for treatment that targets only infected cells.

Such antivirals include:

• Purine analogues of guanine: acyclovir, famciclovir, ganciclovir, penciclovir, vaxilovir, valganciclovir
• Adenosine
• Pyrimidine analogs of uridine: Idoxuridine, trifluridine
• Bromovudine

Mutations in the gene encoding thymidine kinase in herpesviruses can confer viral resistance to acyclovir. Alternative drugs available in these cases include other guanine analogues such as famciclovir, valacyclovir and penciclovir.

Suicide Gene-Mediated Targeted Tumor Therapy

The thymidine kinase encoded by the HSV-TK gene phosphorylates not only thymidine but also purine pentosidine and various nucleoside analogs that cannot be phosphorylated by intracellular kinases, such as acyclic guanosine and uridine derivatives. Acyclic guanosine and uridine derivatives are phosphorylated by thymidine kinase to monophosphates, which are then phosphorylated by intracellular kinase to diphosphates and triphosphates, which inhibit DNA polymerase and thus block cellular DNA synthesis. HSV-Tk gene is used as a suicide gene to transfect tumors, and acyclic guanosine or uridine derivatives can be used to treat tumors. Studies have shown that HSV-TK gene can effectively treat prostate cancer, ovarian cancer and melanoma, etc.

Marker substrates

It is generally accepted that HSV-TK marker substrates enter cells via a variety of cell membrane transporters, especially peptide transporters, and therefore the entry of HSV-TK marker substrates into target cells reflects not only enzymatic activity but also cell membrane transport activities. By selecting the ideal HSV-TK marker matrix as a probe and choosing a specific vector, it is possible to achieve the goal of gene targeting therapy as well as to monitor the gene expression and therapeutic effect by visualization.