title: Sustained release of low-dose ganciclovir from a silicone formulation prolonged the survival of rats with gliosarcomas under herpes simplex virus thymidine kinase suicide gene therapy.
abstract: A silicone formulation of ganciclovir (GCV-pellet) was developed to enhance the cytotoxic effects of herpes simplex virus thymidine kinase suicide gene therapy. The effectiveness of this drug delivery system was assessed in a rat 9L gliosarcoma model. The GCV-pellets (1 mm in length and in diameter) used in this experiment contained a total amount of 0.15 mg of GCV. In vitro experiments demonstrated that GCV was gradually released over a period of 7 days. Five days after stereotactic tumor inoculation into the right caudate nucleus, a herpes simplex virus type 1 (HSV-1) vector expressing herpes simplex virus thymidine kinase (HSV-tk) (T1, 2x10(6) pfu) was administered at the same location. The survival rate of the group treated with the GCV-pellet was compared with that of the T1 group injected intraperitoneally (IP) with GCV (30 mg/kg/day for 7 days). The GCV-pellet-treated group had a significantly prolonged survival (a median of more than 80 days) compared with the GCV IP group (a median of 65 days) and with control groups (P<0.05). The control groups (untreated or receiving only the virus vector) had a survival of 35-38 days. The survival rate of the GCV-pellet group over 80 days was 75%, and all the rats that survived more than 80 days and did not show tumors upon histological examination of the brain were deemed cured. No toxic effects or immunological reactions were observed histologically around the pellet in brain sections from the rats treated with the GCV-pellet. After GCV-pellet inoculation into the tumor, drug concentrations were kept at 1-10 microg/g tissue for 3-4 days. When the same dose of GCV (0.15 mg) in aqueous solution was injected into the tumor, GCV concentrations reached a peak of 0.5 mg/g tissue after 30 min and decreased below measurable level within 12 h. After IP injections of 3 mg GCV, GCV concentrations in the tumor reached a peak of 5.7 microg/g tissue after 30 min and also decreased below measurable level within 12 h. This sustained release of a low and effective GCV dose with the silicone formulation significantly prolonged survival in combinations with HSV-tk expression if compared to IP administration of GCV. Histological examination suggests that the treatment appears to be safe.
authors.affiliation: Department of Neurosurgery, Osaka University Medical School, Osaka, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Miura
authors.forename: S
authors.initials: S
authors.lastname: Moriuchi
authors.forename: M
authors.initials: M
authors.lastname: Maeda
authors.forename: A
authors.initials: A
authors.lastname: Sano
authors.forename: M
authors.initials: M
authors.lastname: Maruno
authors.forename: A M
authors.initials: AM
authors.lastname: Tsanaclis
authors.forename: R
authors.initials: R
authors.lastname: Marino
authors.forename: J C
authors.initials: JC
authors.lastname: Glorioso
authors.forename: T
authors.initials: T
authors.lastname: Yoshimine
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000032:analysis; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D024201:Bystander Effect; D002421:Caudate Nucleus; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage* / Q000032:analysis; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D018316:Gliosarcoma / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D023421:Models, Animal; D051381:Rats; D011916:Rats, Inbred F344; D012828:Silicones; D015996:Survival Rate; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D012828:Silicones; D013937:Thymidine Kinase; D015774:Ganciclovir