LuIII Parvovirus Selectively and Efficiently Targets, Replicates in, and Kills Human Glioma Cells

Abstract

Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro. In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

Viruses of the Parvoviridae Family: Molecular Genetical Aspects of Reproduction and Medical Importance

“…Природный хозяин для TVX и LuIII не из-вестен. Геноварианты RoPV1 не патогенны для человека [32,59].…”

“…Rodent Protoparvovirus 1 выделяют на клеточ-ных линиях человека и животных: например вирус Н-1 -на U937, SK29-Mel-1; вирус TVX -на HeLa и линии клеток амниона человека [30,32,37,59,78].…”

“…Изоляты RoPV1 характеризуются выражен-ным онкотропизмом и реплицируются преиму-щественно в трансформированных клетках [30,32,59].…”

Autonomous Parvoviruses neither Stimulate nor Are Inhibited by the Type I Interferon Response in Human Normal or Cancer Cells

“…SW-R and SW-S are singlecell-derived subclones of human synovial sarcoma SW-982 which are VSV resistant and VSV susceptible, respectively, and were produced and characterized earlier (28). U87 and A172 are human glioma cell lines originally obtained from ATCC (Manassas, VA) (8). The preceding cells were all cultured in Dulbecco modified Eagle medium with 10% fetal bovine serum (FBS), penicillin-streptomycin, nonessential amino acids, and 25 mM HEPES.…”

“…Oncosuppressive efficacy with these three parvoviruses has been demonstrated in diverse in vivo models of tumors, including glioma (8,9), pancreatic cancer (10,11), and lymphoma (12); a clinical trial is under way for H-1 therapy of glioblastoma (ClinicalTrials.gov trial NCT01301430), and we recently reported that LuIII may hold even greater promise than H-1 for treatment of glioma in humans (8). These viruses are not associated with any pathogenicity in humans (13); in fact, their growth and toxicity are innately more selective for a variety of oncogenically transformed human cells than for their normal precursors (14).…”