title: Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy.
abstract: We conducted a Phase I study of in situ herpes simplex virus thymidine kinase (HSV-tk) plus ganciclovir (GCV) gene therapy, which was approved by the Japanese government as the first prostate cancer gene therapy trial. Major inclusion criteria were local recurrence of prostate cancer after hormonal therapy and no metastasis. Adv.HSV-tk was injected directly into the prostate in escalating doses from 10(9) to 10(10) infection units, followed by intravenous administration of GCV for 14 days. Eight patients received nine courses of this gene therapy. The detection of vector DNA in blood/urine was only transient and no remarkable adverse events were observed in any patient. With regard to clinical response, significant prolongation of the median serum prostate-specific antigen (PSA) doubling time from 2.9 to 6.2 months (P = 0.041) was detected. In five patients (six injections), a clear decrease of PSA values was observed. One patient showed repeated clinical response after repeated injections. Serum cytokine analysis showed no notable changes after treatment. Fluorescence-activated cell sorting analysis also showed no influence on phenotypic distribution in peripheral blood samples, except for an increasing trend of CD8(+)/HLA-DR(+) after therapy. This study confirmed the safety profile and possibility of clinical response at the surrogate marker level in a clinical trial of HSV-tk gene therapy for hormone-refractory prostate cancer.
authors.affiliation: Department of Urology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nasu
authors.forename: Takashi
authors.initials: T
authors.lastname: Saika
authors.forename: Shin
authors.initials: S
authors.lastname: Ebara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kusaka
authors.forename: Haruki
authors.initials: H
authors.lastname: Kaku
authors.forename: Fernando
authors.initials: F
authors.lastname: Abarzua
authors.forename: Daisuke
authors.initials: D
authors.lastname: Manabe
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000096:biosynthesis; D000998:Antiviral Agents / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide / Q000187:drug effects; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000276:immunology / Q000628:therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000276:immunology / Q000628:therapy; D009500:Neutralization Tests; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D012449:Safety; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D013937:Thymidine Kinase; D017430:Prostate-Specific Antigen; D015774:Ganciclovir