Phase I Study of Replication-competent Adenovirus-mediated Double Suicide Gene Therapy for the Treatment of Locally Recurrent Prostate Cancer

摘要: Adenovirus-mediated suicide gene therapy may hold promise in the treatment of human cancer.We have developed a novel approach that utilizes lytic, replication-competent adenovirus (Ad5-CD/TK rep ) to deliver cytosine deaminase/herpes simplex virus-1 thymidine kinase fusion tumors. The deaminase and herpes genes render malignant cells sensitive specific pharmacological agents and, importantly, sensitize them radiation. Phase I study described here represents first trial which virus was used therapeutic humans. indication is local recurrence prostate cancer after definitive radiation therapy. An escalating dose (1010, 1011, 1012 viral particles) Ad5-CD/TK injected intraprostatically under transrectal ultrasound guidance into 16 patients four cohorts. Two days later, were given 5-fluorocytosine ganciclovir prodrug for 1 (cohorts 1–3) or 2 (cohort 4) weeks. There no dose-limiting toxicities, maximum tolerated vector not defined. Ninety-four percent adverse events observed mild moderate (grade 1/2) nature. Seven (44%) demonstrated ≥25% decrease serum prostate-specific antigen, 3 (19%) ≥50% antigen. Transgene expression tumor destruction at injection site confirmed by sextant needle biopsy negative adenocarcinoma year follow-up. Although DNA could be detected blood as far out day 76, infectious patient urine. Together, results demonstrate intraprostatic administration followed weeks can safely applied humans showing signs biological activity.