title: Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer.
abstract: The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, ST 2100, Houston, Texas 77030, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.forename: Bin S
authors.initials: BS
authors.lastname: Teh
authors.forename: Terry L
authors.initials: TL
authors.lastname: Timme
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Fujita
authors.forename: Takefumi
authors.initials: T
authors.lastname: Satoh
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Wei-Yuan
authors.initials: WY
authors.lastname: Mai
authors.forename: Maria T
authors.initials: MT
authors.lastname: Vlachaki
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Amato
authors.forename: Dov
authors.initials: D
authors.lastname: Kadmon
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Miles
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ayala
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wheeler
authors.forename: Estuardo
authors.initials: E
authors.lastname: Aguilar-Cordova
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.forename: E Brian
authors.initials: EB
authors.lastname: Butler
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000532:radiotherapy / Q000628:therapy*