Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA

Abstract

Breast cancer is the most common cause of cancer-related death worldwide, thus remaining a crucial health problem among women despite advances in conventional therapy. Therefore, new alternative strategies are needed for effective diagnosis and treatment. One approach is the use of oncolytic viruses for gene-directed enzyme prodrug therapy. Here, the lacZ-carrying vaccinia virus (VACV) strain GLV-1h68 was used in combination with a β-galactosidase-activatable prodrug derived from a seco-analog of the natural antibiotic duocarmycin SA. Tumor cell infection with the VACV strain GLV-1h68 led to production of β-galactosidase, essential for the conversion of the prodrug to the toxic compound. Furthermore, drug-dependent cell kill and induction of the intrinsic apoptosis pathway in tumor cells was also observed on combination therapy using the prodrug and the GLV-1h68 strain, despite the fact that VACV strains encode antiapoptotic proteins. Moreover, GI-101A breast cancer xenografts were effectively treated by the combination therapy. In conclusion, the combination of a β-galactosidase-activatable prodrug with a tumor-specific vaccinica virus strain encoding this enzyme, induced apoptosis in cultures of the human GI-101A breast cancer cells, in which a synergistic oncolytic effect was observed. Moreover, in vivo, additional prodrug treatment had beneficial effects on tumor regression in GLV-1h68-treated GI-101A-xenografted mice.

Novel 19F‐MRS β‐galactosidase reporter molecules incorporated nitrogen mustard analogues

“…The lacZ gene encoding β‐gal has been recognized as the standard means of assaying clonal insertion, transcriptional activation, protein expression and interaction in molecular/cellular biology, small animal investigations, and clinical trials . So when using fluorinated nitrogen mustards as aglycones, their β‐ D ‐galactosides would work as prodrugs.…”

Virus and tumor microenvironment induced ER stress and unfolded protein response: from complexity to therapeutics

“…Episomal vectors like adenovirus and HSV-1 deliver their genomes into the nucleus of the target cell, where they continue as separate extrachromosomal element. Vaccinia viral vectors have also been used for cancer gene therapy [ 97 , 98 ] because of proficient infectivity and gene expression in complex tumors [ 99 ]. Also, the safety profile of Vaccinia virus has already been determined due to its use as a vaccine for small pox in humans [ 99 ].…”

The Lister Strain of Vaccinia Virus as an Anticancer Therapeutic Agent

“…They have been used to deliver enzymes that mediate the conversion of a relatively safe prodrug into a highly potent cytotoxic one that, being restricted to the tumor, should produce minimum systemic toxicity [112]. Seubert et al employed a different prodrug/enzyme system in conjunction with the GLV-1h68 recombinant [114]. Replication-competent VVs armed with the transgene for the cytosine deaminase (CD) enzyme, which converts 5-fluorocytosine (5-FC) into the active metabolite 5-fluorouracil (5-FU), have demonstrated efficacy in vivo [113].…”