Recombinant Baculovirus Containing the Diphtheria Toxin A Gene for Malignant Glioma Therapy

Abstract

Insect baculoviruses are capable of infecting mammalian glial cells in the central nervous system. We investigated in the current study the feasibility of using the viruses as toxin gene vectors to eliminate malignant glioma cells in the brain. We first confirmed that glioma cells were permissive to baculovirus infection, with variable transduction efficiencies at 100 viral particles per cell and ranging between 35% and 70% in seven human and rat glioma cell lines. We then developed a recombinant baculovirus vector accommodating the promoter of glial fibrillary acidic protein (GFAP) to minimize possible side effects caused by overexpression of a therapeutic gene in sensitive neurons. We placed the GFAP promoter into a baculovirus expression cassette, in which the enhancer of human cytomegalovirus immediate-early gene and the inverted terminal repeats of adeno-associated virus were employed to improve the relatively low transcriptional activity of the cellular promoter. This recombinant baculovirus significantly improved transduction in glioma cells, providing the efficiency in C6 rat glioma cells up to 96%. When used to produce the A-chain of diphtheria toxin intracellularly in a rat C6 glioma xenograft model, the baculovirus effectively suppressed tumor development. The new baculovirus vector circumvents some of the inherent problems associated with mammalian viral vectors and provides an additional option for cancer gene therapy. (Cancer Res 2006; 66(11): 5798-806)

Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas

“…56 Transcriptional regulation of transgene expression has been extensively used to express therapeutic transgenes in gliomas using the GFAP promoter. 10,11,18,[57][58][59] Reaching the goals of targeted gene expression will greatly increase the specificity and safety of gene therapy, thus getting us closer to the fulfillment of the expectations generated by this new branch of molecular medicine.…”

Baculovirus vectors for antiangiogenesis-based cancer gene therapy

“…34 Consequently, baculovirus has been exploited to treat cancers in liver, 33 skin, 34 lung 34 and brain. 18 This study adds a new dimension to the applications of baculovirus vectors to prostate cancer treatment.…”

“…[14][15][16][17] Moreover, recently recombinant baculovirus expressing Diphtheria Toxin A has been exploited to suppress the glioma xenograft growth in the rat brain. 18 Another baculovirus expressing the tumor antigen also confers protective antitumor effects in mice with brain tumors, 19 implicating the potential of baculovirus in cancer gene therapy. 20 Despite the wide spectrum of applications, the nonreplication nature of baculovirus results in genome degradation within the mammalian cells over time, leading to transient transgene expression and mitigating its potential for cancer therapies that necessitate sustained expression.…”

Baculovirus as a new gene delivery vector for stem cell engineering and bone tissue engineering

“…22 Another appealing application of baculovirus is in vivo gene delivery, but most previous in vivo studies delivered only reporter genes into animal models. 23 28 show that a baculovirus expressing diphtheria toxin A inhibits the glioma xenograft growth in the rat brain, suggesting the potentials of baculovirus in cancer therapy. However, the applications of baculovirus in mesenchymal stem cell engineering and bone repair have yet to be reported.…”