Page 276 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 15 Molecular/Targeted Therapy of Cancer 255

Activating enzyme
Prodrug
Gene-encoding
VetBooks.ir activating enzyme Cell death

Bystander
effect

Toxic compound

• Fig. 15.4 Gene-directed enzyme prodrug therapy. In gene-directed enzyme prodrug therapy (GDEPT),
an activating gene is delivered to the cancer cells. A relatively inactive prodrug is then given to the patient
systemically. In cells processing the activating gene, the prodrug is converted to a highly toxic drug, which
can kill the cancer cell. The advantage of this system is the evidence of bystander effect. In this, only a
small proportion of cancer cells need to receive the activating gene, as toxic metabolites leak across gap
junctions and kill surrounding cancer cells.

enzymatic inactivation and renal clearance. A number of deliv- mouse models, a distant bystander effect on tumor metastases
ery systems are in clinical trials, including nanoparticles for sys- has been demonstrated that is mediated through the patient’s
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temic use. At present, no clinical trials have been performed in immune system. The in situ destruction of tumor cells is medi-
veterinary species. ated through necrosis rather than apoptosis, creating an ideal
inflammatory environment for the exposure and presentation of
Gene-Directed Enzyme Prodrug Therapy tumor antigens to the immune system. This allows the patient’s
immune system to recognize tumor metastases and has caused
Gene-directed enzyme prodrug therapy (GDEPT) involves the regression in a number of preclinical model systems. Owing to
delivery of a “suicide” gene (usually viral or bacterial enzyme) the presence of this phenomenon, complete tumor regression
to cancer cells that has the ability to convert a relatively non- has been reported in model systems, even when only 10% of the
toxic prodrug to an active compound within the cancer cell (Fig. tumor cells have been transduced with suicide genes. To date,
15.4). At the clinical level, the gene would be delivered to the five basic mechanisms have been proposed as mediators of the
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patient’s tumor and the enzyme activity would be confined to bystander effect :
the cancer cells. These systems have been combined with tran- • Release of activated soluble toxic factors as cells die
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scriptionally targeted vectors (described previously) to improve • Passive diffusion of toxic factors from intact cells
the targeting and eventual therapeutic index. Once the • Transference of toxic compounds through gap junctions
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patient’s cells have been transduced, they would then be given a • Phagocytosis of apoptotic bodies released from transduced cells
prodrug systemically. In the cancer cells, this novel enzyme can • Stimulation of host immune response in the tumor microenvi-
convert the prodrug to a more active compound that has the ronment
ability to kill the cancer cell (see Fig. 15.4). A number of suc- It is likely that a combination of these mechanisms operates to
cessful approaches have been developed in vitro, based on this support bystander tumor cell killing.
system. For example, the Escherchia. coli nitroreductase gene has In reality, the use of GDEPT in human clinical trials has
been used in preclinical models to cause reduction of an inactive been disappointing, with many of the preclinical successes not
prodrug (CB1954, a weak alkylating agent) to promote cell kill- translated into large-scale clinical successes. Human clinical
ing in cancer cells. However, because of the low efficiency of trials have included colon, liver, lung, prostate, breast, gli-
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existing vectors, the success of this therapy will largely depend oma, and ovarian cancers with variable results ; however, it
on the extent of the bystander effect. In this, the activation of should be noted that the apparent safety concerns related to
the prodrug in the cell causes cell death and also leakage of toxic suicide gene therapy have often limited trials to patients with
metabolites to neighboring cells. Consequently, it is estimated highly aggressive tumors and poor clinical performance scores.
that only a small fraction of the cells need receive the gene for This may have significantly limited any potential for clinical
there to be a dramatic effect on tumor volume. Furthermore, in success.