Regression of Glioma in Rat Models by Intranasal Application of Parvovirus H-1

Abstract

Purpose: In previous studies, we have shown that the apathogenic rat parvovirus H-1 (H-1PV) is capable to induce regression of advanced symptomatic rat and human gliomas in a rat model, when the virus was injected in the tumor (intracranially) or intravenously. Infection with H-1PV did not provoke any pathology in nontumor tissue. This study addresses the question whether also intranasal application of this oncolytic virus is suitable and sufficient for treating gliomas in this animal model.Experimental Design: Rat (RG-2) or human (U87) glioma cells were grafted stereotactically in the brain of rats (Wistar or RNU, respectively), and after development of tumors visible by MRI, H-1PV was instilled intranasally. Tumor regression was monitored by MRI, and survival was analyzed by Kaplan-Meier analysis. Brains from sacrificed animals were analyzed for histologic alterations, presence of viral DNA and proteins and infectious virions. In addition, distribution of virus to other organs was determined.Results: A single intranasal instillation of H-1PV was sufficient to induce efficient regression of rat glioma, leading to significant prolongation of survival without any toxicity for other tissues. It is shown that the virus reaches brain and other tissues, and that the viral replication-associated (and oncolysis-associated) regulatory proteins are exclusively expressed in the tumor tissue. In rats with xenografts of human glioma, oncolytic activity of H-1PV was less pronounced, however, leading to significant prolongation of survival.Conclusion: In view of an ongoing clinical trial on the use of H-1PV for oncolytic virotherapy of glioma, the option of applying the virus intranasally may be a valuable alternative to invasive routes of infection.

Structural Characterization of H-1 Parvovirus: Comparison of Infectious Virions to Empty Capsids

“…In other studies, H-1PV was assessed for the killing of human neuroblastoma and hepatoma cells and demonstrated tumor-selective lytic effects and low toxicity for nontransformed cells (21,22). Local, intranasal, or systemic treatment of advanced rat and human gliomas in rat models with H-1PV was also reported to induce regression (23,24). These promising results set the stage for the first phase I/IIa clinical trial using replication-competent H-1PV in patients with progressive primary or recurrent glioblastoma multiforme (25).…”

Glioma-Parvovirus Interactions: Molecular Insights and Therapeutic Potential

“…Although a parallel study with the MVM and H-1 viruses has not being carefully addressed, several subsequent reports suggested that H-1 is a more powerful oncolytic agent against human glioblastoma, regarding the levels of both cytotoxicity and virus yield in culture (Herrero et al 2004;Di Piazza et al 2007). Further recent preclinical studies have convincingly supported H-1 as anti-glioblastoma agent for clinical purposes, as its infection synergized with radiation (Geletneky et al 2010a), and moreover it improved survival and remission of advanced intracranial U87MG human glioblastoma in rat models (Geletneky et al 2010b;Kiprianova et al 2011). However, as discussed below for MVM, there are particularly interesting aspects in the non-productive glioma-parvovirus interaction, as they may uncover molecular processes altered in glioma and helping to identify cellular targets for cancer treatments.…”

Intranasal Administration of Temozolomide Delayed the Development of Brain Tumors Initiated by Human Glioma Stem-Like Cell in Nude Mice

“…The intranasal route has been previously used to deliver hormones, Perillyl alcohol, telomerase inhibitors, neuropeptides and viruses into the brain [6][7][8][9][10][11], Recent works described the feasibility of the route to direct lipid-based nanoparticles of TMZ or treat glioma in rats [12,13]. The molecules intranasally infused are driven through the trigeminal and olfactory nerves anatomic connection between the nose and the brain.…”