The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo.
Patients with actively replicating human immunodeficiency virus (HIV) exhibit adverse reactions even to low irradiation doses. High levels of the virus-encoded viral protein R (Vpr) are believed to be one of the major underlying causes for increased radiosensitivity. As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined its efficacy as a drug for treatment of glioblastoma multiforme (GBM).In vitro, four glioblastoma-derived cell lines with and without methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2 to 6 Gy) or to combinations thereof. Vpr showed high rates of acute toxicities with median effective doses of 4.0±1.1 μM and 15.7±7.5 μM for U251 and U87 cells, respectively. Caspase assays revealed Vpr-induced apoptosis in U251, but not in U87 cells. Vpr also efficiently inhibited clonogenic survival in both U251 and U87 cells and acted additively with irradiation. In contrast to TMZ, Vpr acted independently of MGMT expression.Dose escalation in mice (n=12) was feasible and resulted in no evident renal or liver toxicity. Both, irradiation with 3x5 Gy (n=8) and treatment with Vpr (n=5) delayed intracerebral tumor growth and prolonged overall survival compared to untreated animals (n=5; p3x5 Gy<0.001 and pVpr=0.04; log-rank test).Our data show that the HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM.
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Jens
J
Kübler
Department of Neuroradiology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Stefanie
S
Kirschner
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Linda
L
Hartmann
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Grit
G
Welzel
Centre for Biomedicine and Medical Technology Mannheim (CBTM), Institute of Neuroanatomy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Maren
M
Engelhardt
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Carsten
C
Herskind
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Marlon R
MR
Veldwijk
Centre for Biomedicine and Medical Technology Mannheim (CBTM), Institute of Neuroanatomy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Christian
C
Schultz
Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Manuela
M
Felix
Medical Radiation Physics/Radiation Protection, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Gerhard
G
Glatting
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Patrick
P
Maier
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Frederik
F
Wenz
Department of Neuroradiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Marc A
MA
Brockmann
Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Frank A
FA
Giordano
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005910:Glioma / Q000473:pathology*; D006801:Humans; D051379:Mice; D023041:Xenograft Model Antitumor Assays; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
D000970:Antineoplastic Agents; D054325:vpr Gene Products, Human Immunodeficiency Virus
MGMT; glioblastoma; irradiation; temozolomide; viral protein R