Adenoviral Vector-based Suicide Gene Therapy Development
Molecular chemotherapy is a gene therapy approach aimed at achieving selective eradication of cancer cells via a genetically expressed toxin. This method is often denoted as "suicide gene therapy". Adenovirus vector-mediated suicide gene therapy has achieved a positive effect on cancer treatment. Creative Biolabs is dedicated to establishing the most exquisite service platform for our clients and our one-stop adenovirus vector construction services can provide comprehensive technical support for the treatment of human diseases.
Introduction of Suicide Gene Therapy
Suicide gene therapy attracts special attention because it allows selective conversion of non-toxic compounds into cytotoxic drugs inside cancer cells. A number of suicide gene systems have been identified, including the herpes simplex virus thymidine kinase (HSV-TK) gene, the cytosine deaminase (CD) gene, the nitroreductase gene, and the Escherichia coli Deo gene.
- HSV-TK and Ganciclovir System
HSV-TK is the most widely studied enzyme that is used for suicide gene strategies. The prodrug for HSV-TK is ganciclovir (GCV), and herpes simplex virus type 1 (HSV-1) produces HSV-TK. Phosphorylation of GCV by HSV-TK into a monophosphate form (GCV-MP) is the rate-limiting step in the generation of a cytotoxic drug. Guanylate kinase metabolizes the monophosphate to the diphosphate form (GCV-DP) and then to the triphosphate form (GCV-TP). The triphosphate form is highly toxic to cells by inhibiting DNA polymerase and by incorporation into DNA with chain termination. Therefore, GCV in the presence of HSV-TK is a prodrug that causes cell death.
- CD and 5-Fluorocytosine System
CD is an enzyme that catalyzes the deamination of cytosine to uracil. This reaction converts an inert prodrug, 5-fluorocytosine (5-FC), to a highly toxic chemotherapeutic agent, 5-fluorouracil (5-FU). The cytotoxic effects of 5-FU occur following its conversion to 5-fluoro-2'-deoxyuridine-5'-monophosphate (5-FdUMP) (through a de novo pyrimidine pathway). 5-FdUMP is an irreversible inhibitor of thymidylate synthase and thus inhibits DNA synthesis by deoxythymidine triphosphate (dTTP) deprivation.
- Nitroreductase and CB1954 System
The Escherichia coli enzyme nitroreductase in combination with the prodrug CB1954 [5-(aziridine-1-yl)-2,4-dinitrobenzamide] is the most promising suicide gene systems. CB1954 is a weak, monofunctional alkylating agent. The nitroreductase enzyme DT diaphorase converts CB1954 to its 4-hydroxylamino derivative, which afters acetylation via thioesters such as acetyl coenzyme A (CoA), then becomes a powerful bifunctional alkylating agent. The activated prodrug is then capable of forming poorly repaired DNA crosslinks. The advantage of the nitroreductase-CB1954 suicide gene system is that killing mediated by activated CB1954 is not dependent on the cell cycle phase, potentially allowing quiescent tumor cells to be killed.
- Escherichia coli Deo and 6-Methylpurine Deoxyriboside System
The Escherichia coli Deo gene codes for an enzyme, purine nucleoside phosphorylase (PNP), not found in human cells. The PNP enzyme cleaves 6-methyl purine deoxyriboside (MEP) to liberate 6-methyl purine, a potent, membrane-permeant and freely diffusible toxin. The hallmarks of this approach are strong bystander killing in human colon, melanoma, and glioma cancer cells in vitro. The ability of the activated prodrug in killing both proliferating and non-proliferating cancer cells is attributed to its mechanism of action which is independent of DNA synthesis.
Figure 1. Schematic representation of the two-step process in suicide gene therapy. (Karjoo, 2018)
Service
Currently, adenoviral vector has shown its efficacy for treating a number of diseases in human. The major challenges to the translation of gene therapy technology to humans are the development of better vectors and specific suicide gene. Therefore, we offer a variety of adenoviral vector-based suicide gene therapy development services, including but not limited to, HSV-TK system, CD system, nitroreductase system, and Escherichia coli Deo system.
Creative Biolabs has focused on the development of gene therapies for years, and we whole-heartedly cooperate with you to accomplish our shared goals. Our team provides you with outstanding support and meets your specific needs with a professional technology platform. If you are interested in our services, please contact us or send an inquiry.
Reference
- Karjoo, Z.; et al. (2016). Progress and problems with the use of suicide genes for targeted cancer therapy. Adv Drug Deliv Rev. 99(Pt A):113-128.
