Gene therapy of cancer
Gene therapy is being pursued as a possible approach to modifying
the genetic program of cancer cells as well as for treatment of
metabolic diseases. The field of cancer gene therapy utilizes a variety of strategies, ranging from replacement of mutated or deleted tumor suppressor genes to enhancement of immune responses to cancer cells Indeed. in preclinical models. approaches such
as replacement of tumor suppressor genes leads to growth arrest or apoptosis . However. the translation of these findings into clinically useful tools presents special challenges
One of the main difficulties in getting gene therapy technology
from the laboratory to the clinic is the lack of a perfect delivery an ideal vector would be administered through a noninvasive route and would transduce all of the cancer cells and none of the normal cells. Furthermore. the ideal vector would have a high degree of activity. that is. it would produce an adequate amount of the desired gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect. cancer requires either that the therapeutic gene is delivered to all of the cancer cells. or that a therapeutic effect is achieved on nontransfected
cells as well as transfected cells through a "bystander effect." On the other band. treatment of a metabolic disease requires prolonged gene expression. while transient expression may be sufficient for cancer therapy. one of the promising approaches to increase the number of tumor cells transduced is the use of a replication-competent virus,such as a parvovirus, human reovirus, or vesicular stomatitis virus, that
selectively replicates within malignant cells and lyses them more efficiently than it does normal cells.another strategy to kill tumor cells with suicide genes exploits tumor-specific expression elements, such as the MUC-I. PSA. CEA. or VEGF promoers. that can be utilized to achieve tissue-specific or tumor-specific expression of the desired gene.
As the goal in cancer therapy is to eradicate systemic disease, optimization of delivery systems is the key to success for gene therapy strategies. Gene therapy is likely to be most successful when combined with standard therapies. but it will provide the advantage of customization of therapy based on the molecular status of an individual's tumor.
Examples for Vector for Cancer Gene Therapy
Retrovirus
his advantages are small genome stable colinear intergration efficient gene transfer non toxic to host cells infects dividing cells
disadvantages are requires activity dividing cells carries small DNA sequences only low titre transient expression labile in vivo
Adenovirus
his advantages are high viral titres highly efficient gene transfer non toxic to host cells infects dividing and non dividing cells
his advantages are high viral titres highly efficient gene transfer non toxic to host cells infects dividing and non dividing cells
disadvantages are transient expression carries small DNA sequences only immunogenic
his advahtages are highly efficient gene transfer and expression safe for immunosuppressed patients
disadvantages are strongly immunogenic transient gene expression
Adeno-associated virus
his advantages are small genome integrates into chromosome 19 efficient gene transfer nono pathognic to human infects dividing and non dividing cells weakly immumogenic
disadvantages are carries small DNA sequences only safety questionable loss if non random integration over time low viral titers
his advantages are infects dividing and non dividing cells neurotropic high viral titers large insert size potential for prolonged gene expression
disadvantages are toxicity related to lytic infection safety questionable
Protein|DNAcomplex
his advantages are cell specific targeting unlimited size
disadvantages are inefficient gene transfer safety questionable
Liposomes
his advantages synthetic unlimited size
disadvantage inefficient gene transfer
Non viral plasmid his few safety concerns and inefficient gene transfer
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