Biomedical Engineering Reference
In-Depth Information
set of diseases arising in a variety of organs; however, these diseases share the
similar properties outlined here. Currently, approximately half of all cancers are
cured by surgical removal, radiation, or chemotherapy. The other half are lethal
because they have metastasized (and are thus not removable) and because they
are resistant to known therapies (a result of tumor cell heterogeneity).
What implications does the complex adaptive nature of cancer have for fu-
ture research and treatment? It may be possible to turn a molecular process of
therapeutic evolution against the evolutionary power of the cancer cell by de-
signing a therapeutic approach that mimics and counters tumor evolution at a
molecular level so that drug diversity can negate tumor cell heterogeneity and
take away the advantage the cancer cell has to overcome present treatments. At a
very simple level, the cancer could select its own drugs. This could be accom-
plished by using a randomized library of RNA sequences, termed aptamers, and
permit the lethal cancer cells to bind to the aptamers with the highest affinity
and specificity (49-55). These specific aptamers are amplified and then conju-
gated to radionuclides and cytotoxic drugs.
This is a novel approach to the treatment of resistant cancers. This tech-
nique essentially floods the cell with billions of random RNA sequences and
allows the cancer cell to select out specific molecules to bind that it is express-
ing. Aptamers are modified oligonucleotides that are isolated by the systematic
evolution of ligands by an exponential enrichment (SELEX) process. They are
globular molecules that can recognize and bind with high affinity to a variety of
cellular constituents. They are intermediate in size between small peptides and
single-chain antibody fragments. One of their main advantages for cancer target-
ing and therapy is their small size compared to antibodies, which can result in
improved cancer tissue permeation and delivery of lethal agents (54,55). Mo-
lecular evolution using random libraries of polymers might be used to select
high-affinity binding components specific for prostate tumor cells. This pitting
of molecular evolution against tumor evolution will permit a wide diversity of
tightly binding synthetic ligands to match the biological diversity of the tumor
cells. One type of these polymers that can be used includes highly diverse RNA
molecules synthesized with random sequences and that are relatively inert to
RNAse hydrolysis. A 15-mer of random nucleotides produces over a billion
different RNA aptamers. These mixtures of aptamers can be differentially se-
lected for their ability to bind tightly to cancer tissue while not binding to nor-
mal tissue. The specific tumor binding aptamers can then be amplified by
reverse transcriptase and PCR to enrich the population of tight binding aptamers
for the tumor cell. This process can be cycled over and over (see Figure 4). Lu-
pold and colleagues have applied this concept to target prostate cancer cells
(49). They were able to select two specific aptamers to an important prostate
cancer marker, prostate-specific membrane antigen, from an initial 40-mer li-
brary of approximately 6 + 10
14
random-sequence RNA molecules for their abil-
ity to bind to a recombinant protein representing the extracellular 706 amino
