title: Molecular imaging with bioluminescence and PET reveals viral oncolysis kinetics and tumor viability.
abstract: Viral oncolysis, the destruction of cancer cells by replicating virus, is an experimental cancer therapy that continues to be explored. The treatment paradigm for this therapy involves successive waves of lytic replication in cancer cells. At present, monitoring viral titer at sites of replication requires biopsy. However, repeat serial biopsies are not practically feasible for temporal monitoring of viral replication and tumor response in patients. Molecular imaging provides a noninvasive method to identify intracellular viral gene expression in real time. We imaged viral oncolysis and tumor response to oncolysis sequentially with bioluminescence and positron emission tomography (PET), revealing the kinetics of both processes in tumor xenografts. We demonstrate that virus replication cycles can be identified as successive waves of reporter expression that occur ∼2 days after the initial viral tumor infection peak. These waves correspond to virions that are released following a replication cycle. The viral and cellular kinetics were imaged with Fluc and Rluc bioluminescence reporters plus two 18F-labeled PET reporters FHBG [9-(4-18F-fluoro-3-[hydroxymethyl] butyl) guanine] and FLT (18F-3'-deoxy-3-'fluorothymidine), respectively. Correlative immunohistochemistry on tumor xenograft sections confirmed in vivo results. Our findings show how PET can be used to identify virus replication cycles and for real-time measurements of intratumoral replicating virus levels. This noninvasive imaging approach has potential utility for monitoring viral oncolysis therapy in patients.
authors.affiliation: Departments of Surgery and.
authors.forename: Darshini
authors.initials: D
authors.lastname: Kuruppu
authors.affiliation: Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Brownell
authors.affiliation: Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
authors.affiliation: Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.affiliation: Departments of Surgery and.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy / Q000821:virology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods*; D018328:Melanoma, Amelanotic / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D049268:Positron-Emission Tomography / Q000379:methods*; D014709:Vero Cells