Br J Cancer 2000 May;82(10):1619-24
Department of Cellular and Molecular Sciences, St George's Hospital Medical School, Tooting, London, UK.
J Clin Invest 2000 May;105(9):1173-6 [Texto completo]
Immunomodulation of cancer: potential use of selectively replicating agents.
Agha-Mohammadi S, Lotze MT
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15261, USA.
J Clin Invest 2000 May;105(9):1169-72 [Texto completo]
Gene delivery from replication-selective viruses: arming guided missiles in the war against cancer.
Onyx Pharmaceuticals, 3031 Research Drive, Richmond, California 94925, USA. firstname.lastname@example.org
Ann Intern Med 2000 Apr 18;132(8):649-60
Gene therapy for lung disease: hype or hope?
Albelda SM, Wiewrodt R, Zuckerman JB
University of Pennsylvania Medical Center, Philadelphia, USA. email@example.com
Gene therapy, the treatment of any disorder or pathophysiologic state on the basis of the transfer of genetic information, was a
high-priority goal in the 1990s. The lung is a major target of gene therapy for genetic disorders, such as cystic fibrosis and
alpha1-antitrypsin deficiency, and for other diseases, including lung cancer, malignant mesothelioma, pulmonary inflammation,
surfactant deficiency, and pulmonary hypertension. This paper examines general concepts in gene therapy, summarizes the
results of published clinical trials, and highlights areas of research aimed at overcoming challenges in the field. Although
progress has been slower than anticipated, gene transfer has been safely achieved in patients with lung diseases. Recent
advancements in understanding of the molecular basis of lung disease and the development of improved vector systems make
it likely that gene therapy will be an important tool for the 21st-century clinician.
Urol Clin North Am 2000 Feb;27(1):103-13, ix
The potential role of gene therapy in the treatment of bladder cancer.
Hsieh JT, Dinney CP, Chung LW
Department of Urology, UT Southwestern Medical Center, Dallas, Texas, USA.
Based on understanding the molecular mechanism of bladder carcinogenesis, cancer gene therapy may well become a novel
therapy in the near future. Currently, a viral vector system appears to be a better vehicle to deliver genes into target cells.
Exploring different therapeutic strategies has generated promising results from preclinical bladder cancer models. Phase I
clinical trials are underway to study the feasibility of this treatment for human bladder cancer patients. However, several
potential problems associated with effective gene delivery need to be further refined.
Hum Cell 1999 Sep;12(3):115-23
[Gene therapy using anticancer drug-resistance genes].
[Article in Japanese]
Division of Experimental Chemotherapy, Japanese Foundation for Cancer Research, Tokyo, Japan.
Myelosuppression is a major dose-limiting factor in cancer chemotherapy. Introduction of drug-resistance genes into bone
marrow cells of cancer patients has been proposed to overcome this limitation. In theory, any gene whose expression protects
cells against the toxic effects of chemotherapy should be useful in vivo for this purpose. Among such genes, human
multidrug-resistance gene (MDR1) has been studied most extensively for this purpose, and clinical trials of drug-resistance
gene therapy have been started in the US for cancer patients who undergo high-dose chemotherapy with autologous
hematopoietic stem cell transplantation. In Japan, our clinical protocol of MDR1 gene therapy "A clinical study of
drug-resistance gene therapy to improve the efficacy and safety of chemotherapy against breast cancer" has been submitted to
the government. To improve the efficacy and safety of this drug-resistance gene therapy, we have constructed a series of
MDR1-bicistronic retrovirus vectors using a retrovirus backbone of Harvey murine sarcoma virus and internal ribosome entry
site (IRES) from picornavirus to co-express a second gene with the MDR1 gene. MDR1-MGMT bicistronic vectors can be
used to protect bone marrow cells of cancer patients from combination chemotherapy with MDR1-related anticancer agents
and nitrosoureas. In addition, MDR1-bicistronic retrovirus vectors can be designed to use the MDR1 gene as an in vivo
selectable marker to enrich the transduced cells which express therapeutic genes, if disease is curable by the expression of a
single-peptide gene in any types of bone marrow cells or peripheral blood cells.
Ann Med 1999 Dec;31(6):421-9
In situ use of suicide genes for therapy of brain tumours.
Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
20892-1851, USA. firstname.lastname@example.org
Suicide gene therapy represents a new therapeutic approach to the treatment of patients with otherwise incurable malignant
brain tumours. This strategy involves the introduction of a gene that renders the tumour cell susceptible to an otherwise
nontoxic prodrug. The most often used genetic prodrug activation system is the herpes simplex virus thymidine
kinase/ganciclovir (HSV-tk/GCV) paradigm. An important aspect of this system is the 'bystander effect', the extension of
cytotoxic effects to untransduced cells. For gene delivery, retroviral, adenoviral vectors and HSV-1 mutants have been used.
Clinical studies have revealed that the HSV-tk/GCV approach is safe, but also that responses are observed only in very small
brain tumours, indicating insufficient vector distribution and very low transduction efficiency with replication-deficient vector
systems. To improve treatment efficacy, the use of replication-competent oncolytic vectors in combination with new or
improved prodrug-suicide gene systems as a part of a multimodal approach is warranted. In the context of
replication-competent vectors, suicide genes might also be used as fail-safe genes in the case of runaway infection.
Ann Oncol 1999;10 Suppl 6:149-53
New approaches in cancer treatment.
Stanford University School of Medicine, California, USA. email@example.com
Major advances in cellular biology, genetics, pharmacology and immunology in the past decade are beginning to be translated
into progress in cancer treatment. This progress is manifested by new cytotoxic drugs which have recently entered clinical
practice (taxanes, topoisomerase I inhibitors, gemcitabine, vinorelbine, new purines), as well as the efficacy of monoclonal
antibody therapies against the CD-20 antigen of B-cell lymphomas and the Her2/neu oncogene in breast cancer. Several new
drugs in development are targeted at reversal or prevention of the multidrug resistance mechanism caused by expression of the
MDR1 gene (P-glycoprotein). Tumour angiogenesis as a target is being studied in several early clinical trials. As with many
other biological therapies, the evaluation of these compounds and their integration with standard therapies presents a major
challenge to clinical investigators. The emerging field of genomics and gene expression micro-arrays will provide enormous
information about the biology of cancers. This technology offers great opportunities for the discovery of new therapeutic
targets, which should provide a basis for the design and evaluation of many new agents in the coming decade.
Forum (Genova) 1999 Jul-Sep;9(3):225-36
Different approaches in the gene therapy of cancer.
Gough MJ, Vile RG
Molecular Medicine Program, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
The requirements of gene therapy for cancer are distinct from those of gene therapy for hereditary monogenic diseases. In
cancer the aim is to kill, not cure tumour cells. Also issues such as duration of gene expression and immunogenicity of vector
systems are of less relevance than efficiency of delivery to all tumour cells. In this light, we discuss the vector systems currently
available and the methods to target transgenes to tumour cells. In view of the current limitations in both vector systems and
targeting of tumours, we discuss the strategies that may be applied to increase the effectiveness of inefficient delivery, such as
immune activation, bystander cytotoxicity and replication-competent viruses.
Semin Oncol 1999 Aug;26(4):455-71
Gene therapy for prostate cancer.
Hrouda D, Perry M, Dalgleish AG
Department of Oncology, St George's Hospital Medical School, London, UK.
Prostate cancer is one of the leading causes of cancer deaths in the western hemisphere. A number of different gene therapy
strategies are currently being evaluated. The ex vivo and many of the in vivo therapies involve stimulating a specific antitumor
immune response. Autologous vaccines involving interleukin-2 (IL-2)- or granulocyte-macrophage colony-stimulating factor
(GM-CSF)-transduced whole tumor cells showed great promise in animal models. Clinical trials of these and other vaccine
strategies are underway. In vivo gene therapies involving the replacement of mutant tumor-suppressor genes, antisense
strategies, and the insertion of suicide genes are also being evaluated in prostate cancer.
Ann Oncol 1999;10 Suppl 4:188-92
Gene therapy for pancreatic and biliary malignancies.
Aspinall RJ, Lemoine NR
Imperial Cancer Research Fund Molecular Oncology Unit, Hammersmith Hospital, London, United Kingdom.
Advances in our understanding of the molecular genetics of pancreatic and biliary cancers have given us new targets for
therapy using molecular and genetic approaches. Replacement of tumour suppressor gene function using adenoviruses to
transfer wild-type p53 and p16 genes can produce dramatic anti-tumour effects, both in vitro and in vivo. Blockade of
dominant oncogene function using dominant negative technology may have a particular application for mutated K-ras which
occurs almost ubiquitously in pancreatic adenocarcinoma. Genetic prodrug activation therapy using tumour-selective gene
promoters to drive the expression of so-called suicide genes is showing remarkable promise. Targeted delivery of such
therapeutic constructs may also be possible through knowledge of the expression of surface receptors by particular tumour
cell types. Genetic immunomodulation using cytokine genes as well as specific vaccines against tumour-associated antigens are
now being brought into clinical trials.