Biomedical Engineering Reference
In-Depth Information
episodes. In most instances so far, this strategy has been carried out in practice by removal of tar-
get cells from the body, culture in vitro , introduction of the desired gene (mainly using retroviral
vectors), followed by reintroduction of the altered cells into the body.
An alternative anti-cancer strategy entails insertion of a copy of a tumour suppresser gene into
cancer cells. For example, a defi ciency in one such gene product, p53, has been directly implicated
in the development of various human cancers. It has been shown in vitro that insertion of a p53
gene in some p53-defi cient tumour cell lines induces the death of such cells. A potential weakness
of such an approach, however, is that 100 per cent of the transformed cells would have to be suc-
cessfully treated to fully cure the cancer. Tumour suppressor-based gene therapy in combination
with conventional approaches (chemotherapy or radiotherapy) may, therefore, prove most effi ca-
cious, and the sole gene-therapy-based medicine approved to date (in China only) is based upon
this approach (Box 14.2).
Yet another strategy that may prove useful is the introduction into tumour cells of a 'sensitivity'
gene. This concept dictates that the gene product should harbour the ability to convert a non-toxic
pro-drug into a toxic substance within the cells - thus leading to their selective destruction. The
model system most used to appraise such an approach entails the use of the thymidine kinase gene
of the herpes simplex virus (Figure 14.12).
Tumor cell
Active drug
(toxic)
'Sensitivity'
gene product
(a)
Pro-drug
Pro-drug
GCV-TP
(toxic)
Cellular
kinases
(b)
GCV-MP
HSVtk
GCV
GCV
Figure 14.12 Schematic representation of the therapeutic rationale underpinning the introduction of a
'sensitivity' gene into tumour cells in order to promote their selective destruction. As depicted in (a), the
gene product should be capable of converting an inactive pro-drug into a toxic drug capable of killing the cell.
A specifi c example of this approach is presented in (b): introduction of the herpes simplex thymidine kinase
(HSVtk) gene confers sensitivity to the anti-herpes drug, Ganciclovir (GCV) on the cell. GCV is converted by
HSVtk into a monophosphorylated form (GCV-MP). This, in turn, is phosphorylated by endogenous kinases,
yielding ganciclovir triphosphate (GCV-TP). GCV-TP induces cell death by inhibiting DNA polymerase. A poten-
tial advantage of this system is that some adjacent tumour cells (which themselves lack the HSVtk gene) are
also destroyed. This is most likely due to diffusion of the GCV-MP or GCV-TP (perhaps via gap junctions) into
such adjacent cells. This so-called 'bystander effect' means that all the transformed cells in a tumour would
not necessarily need to be transduced for the therapy to be successful
Search WWH ::




Custom Search