Gene Therapy

The best way of treating a cancer would be to find a way of genetically modifying the tumour cells, correcting the genetic defect. This technique is known as ‘gene therapy’, It is regarded as a potential revolution in medicine because gene therapy is aimed at treating or eliminating causes of disease, whereas most current drugs treat the symptoms.

Gene therapy for cancer accounts for the majority of gene therapy clinical trials. Targets for

this include replacement of tumor suppressor genes, ‘‘suicide genes’’ to activate prodrugs, antiangiogenic gene therapy, cytokine-based gene transfer, and delivery of drug resistance genes to hematopoietic stem cells to protect them from the bone marrow toxicity of chemotherapeutic agents.

Suicide gene therapy approaches include transfection of tumor cells with herpes simplex

virus-thymidine kinase (HSV-TK) to activate the prodrug ganciclovir and cytosine deaminase

to convert the nontoxic compound 5-fluorocytosine into cytotoxic 5-fluorouracil .

Suicide gene clinical trials have been carried out in prostate cancer, mesothelioma, and glioblastoma. Cytokine gene therapy approaches have included gene transfer via tumor-homing lymphocytes bearing genes encoding interleukins (IL-1B, IL-2, IL-4, IL- 12), GM-CSF, and interferon-g (IFN-g). Clinical trials include IL-12 delivered by a vaccinia virus vector for mesothelioma and GM-CSF and IFN-g delivered in retroviral vectors for melanoma. Some clinical responses have been observed in these trials with small numbers of patients.

The tumor suppressor gene p53 is the most commonly mutated gene in human cancers.

Hence, it is a good target for gene replacement  therapy. Re-expression of p53 in human colon cancer cell lines bearing a mutated gene inhibits tumor cell proliferation. In a murine model of p53-mutated colon cancer, injection of an adenoviral vector encoding the WT p53 gene into tumors resulted in tumor regression and enhanced survival . Clinical trials with p53 gene replacement have been initiated for a number of cancers including colon and

head and neck cancers. In general, the procedures were well tolerated. The main side effects were fever and transient liver enzyme abnormalities. One key question for this and other gene therapy approaches to cancer is how many cells in a tumor need to be transfected to get a therapeutic effect? There is some evidence for ‘‘bystander’’

effects from p53 transfection, probably due to an antiangogenesis effect.620 Other potential tumor suppressor gene targets for which there is at least preclinical demonstration of efficacy are PTEN, E-cadherin, C-CAM, BRCA-1, and pHyde.