Gene therapy strategies to improve the effectiveness of cancer radiotherapy.
Having the ability to alter the genetic makeup of a cancer cell by gene transfer is a potentially powerful strategy for treating human cancer. However, a low efficiency of gene delivery in vivo and poor tumour specificity has prevented the widespread implementation of this technology in the clinic. Despite these formidable obstacles, the first successful application of gene therapy in the treatment of cancer may occur when it is combined with local modalities such as radiation therapy. A small number of gene therapy strategies have been evaluated in clinical trials in combination with external beam radiation therapy. The combined therapy has been well-tolerated and has not exacerbated the side effects of radiation therapy. Gene transfer and tumour cell destruction has been demonstrated in vivo. Although the results await confirmation in larger, prospective Phase III trials, there is suggestive evidence that the combined therapies may be demonstrating better than expected antitumour activity. Our vast knowledge of the molecular defects that drive the cancer process, coupled with our expanding understanding of the genes responsible for tumour cell radioresistance, have spawned the development of rational, targeted gene therapies designed to increase tumour cell radiosensitivity. Here, the results of the clinical trials conducted so far will be reviewed, followed by a description of new approaches under development at present.
Freytag
Svend O
SO
Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202-3405, USA. sfreyta1@hfhs.org
Kim
Jae Ho
JH
Brown
Stephen L
SL
Barton
Kenneth
K
Lu
Mei
M
Chung
Myung
M
D000256:Adenoviridae / Q000502:physiology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D024201:Bystander Effect; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D004249:DNA Damage; D004260:DNA Repair; D041722:Genes, Transgenic, Suicide; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D014409:Tumor Necrosis Factor-alpha