title: Preclinical safety, toxicology, and biodistribution study of adenoviral gene therapy with sVEGFR-2 and sVEGFR-3 combined with chemotherapy for ovarian cancer.
abstract: Abstract Antiangiogenic and antilymphangiogenic gene therapy with soluble vascular endothelial growth factor receptor-2 (VEGFR-2) and soluble VEGFR-3 in combination with chemotherapy is a potential new treatment for ovarian carcinoma. We evaluated the safety, toxicology, and biodistribution of intravenous AdsVEGFR-2 and AdsVEGFR-3 combined with chemotherapy in healthy rats (n=90) before entering a clinical setting. The study groups were: AdLacZ and AdLacZ with chemotherapy as control groups, low dose AdsVEGFR-2 and AdsVEGFR-3, high dose AdsVEGFR-2 and AdsVEGFR-3, combination of low dose AdsVEGFR-2 and AdsVEGFR-3 with chemotherapy, combination of high dose AdsVEGFR-2 and AdVEGFR-3 with chemotherapy, and chemotherapy only. The follow-up time was 4 weeks. Safety and toxicology were assessed by monitoring the clinical status of the animals and by histological, hematological, and clinical chemistry parameters. For the biodistribution studies, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used. Low dose (2×10(10) vp) AdsVEGFR-2 and AdsVEGFR-3 gene therapy was well tolerated, even when gene therapy was combined with chemotherapy. Notably, only transient elevation of liver enzymes and mild regenerative changes were seen in liver after the gene transfer in the groups that received high doses (2×10(11) vp) of AdsVEGFR-2 and AdsVEGFR-3 with or without chemotherapy. No life-threatening adverse effects were noticed in any of the treatment groups. The highest protein concentration of soluble VEGFR-2 (sVEGFR-2) in circulation was seen 1 week after the gene transfer. The combination of chemotherapy to gene therapy seemed to prolong the time of detectable transgene protein at least 1 week in the circulation. The expression of AdsVEGFR-2 and AdsVEGFR-3 transgenes was mainly seen in the liver and spleen as detected by qRT-PCR. According to these results, AdsVEGFR-2 and AdsVEGFR-3 gene therapy combined with chemotherapy is safe and can be brought to clinical testing in ovarian cancer patients.
authors.affiliation: Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, FIN-70211, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Tuppurainen
authors.forename: Hanna
authors.initials: H
authors.lastname: Sallinen
authors.forename: Emmi
authors.initials: E
authors.lastname: Kokki
authors.forename: Jonna
authors.initials: J
authors.lastname: Koponen
authors.forename: Maarit
authors.initials: M
authors.lastname: Anttila
authors.forename: Kati
authors.initials: K
authors.lastname: Pulkkinen
authors.forename: Tommi
authors.initials: T
authors.lastname: Heikura
authors.forename: Pyry
authors.initials: P
authors.lastname: Toivanen
authors.forename: Kirsi
authors.initials: K
authors.lastname: Hämäläinen
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.forename: Seppo
authors.initials: S
authors.lastname: Heinonen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001774:Blood Chemical Analysis; D004353:Drug Evaluation, Preclinical; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D051381:Rats; D014018:Tissue Distribution; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3