July 20, 2012 in
Medications Imagine millions of cancer cells organized in thousands of small
divots. Hit these cells with drugs and when some cells die, you have a
candidate for a cancer drug. But a review published this week in the journal
Expert Opinion on Drug Discovery argues that these 2D models in fact offer very
little information about a potential drug's effects in the body and may often
give researchers misleading results. "Up until the 1980s animal models
were the standard for cancer drug discovery. However, with the increase in the
number of compounds available for testing and the advent of high-throughput
screening (HTS), the use of animals to discover cancer drugs became too costly
and unethical. Consequently, 2D cell culture models have become the mainstay
for drug discovery or to explore a drug's mechanism of action," says Dan
LaBarbera, PhD, investigator at the University of Colorado Cancer Center and
the University of Colorado Skaggs School of Pharmacy and Pharmaceutical
Sciences. LaBarbera is principal investigator of the recent review, on which he
collaborated with Skaggs colleagues Brian Reid, PhD, and Byong Hoon Yoo, PhD.
LaBarbera cites the gap between results in 2D cells and effects in tumors
themselves as a contributing factor for the declining rate of drugs passing FDA
approval. In particular, only 5 percent of investigational new drugs targeting
cancer make it through clinical trials, at a cost of about $800 million per
drug. When you factor in the inevitable failures at various points in
development, each approved drug costs an average $1.5 billion. To increase the
drug success rate, LaBarbera suggests something called the multicellular tumor
spheroid (MCTS) model. In these models, instead of 2D monolayers, cancer cells
are cultured as 3D spheroids. One of the advantages of the MCTS model is that
when spheroids reach a critical diameter, they begin to form an outer
proliferating zone, an inner quiescent zone, and a central necrotic core – more
faithfully mimicking the microenvironments of human tumors. Additionally,
spheroids can be grown in the presence of compounds that mimic extra cellular
matrix – the environment that surrounds and very much affects the growth and
behaviors of human tumors. Why pay more? Save on Quality Monoclonal Antibodies
& much more! - www.anogen.ca Instead of indiscriminately killing cells,
modern cancer drugs tend to target cells with very specific genetic mutations
that turn on and off very specific growth and survival mechanisms that in turn
very frequently depend on everything else going on in and around the cells.
Using MCTS models, researchers can ask questions about how a drug will
penetrate a tumor's heterogeneous 3D structure and how a drug will interact
with the environment surrounding these tiny tumors. "Though these MCTS
models have been around since the 1970s, only recently has technology made it
possible to use them in place of 2D models for the high-throughput screening
used in drug discovery," LaBarbera says. Remember those millions of cancer
cells organized in independent divots that researchers hit with drugs? We're
fairly tied to the technology that reads the results of these divots. But
micro-technologies now allow multicellular tumor spheroids to be cultured in
place of 2D cell cultures using high-throughput micro-well plates – we can use
the same drug testing machinery on these new models. Likewise, materials
science technology now exists to grow cells within semipermeable membranes,
helping researchers define the shape of the eventual spheres. And as futuristic
as it undoubtedly sounds, magnetic cell levitation can help alleviate the
problem of cells sticking to the plastic well surface, which limits spheroid
growth. The recent practicality of high-throughput MCTS screening leads
LaBarbera to call today a "renaissance" for the technique. Of course,
this 3D testing is initially more expensive and more challenging. "A lot
of researchers try to get cost down to pennies per well – you can see how
screening millions of compounds equals millions of dollars – but this often
leads to a higher cost down the road due to a lower success rate. Yes, it may
cost more to do HTS with 3D models, but in the long run it may lead to higher
success rates and so decreased costs," LaBarbera says. LaBarbera suggests
that another use of the systems biology approach made possible by 3D models
like MCTS is to bridge the gap between high-volume, low-accuracy screens and
more involved testing in animal models. "We envision a future in which
MCTS arrays enable a convergence of systems biology and chemical biology,
improving the success rate of drugs in the pipeline of discovery,"
LaBarbera says. Provided by University
of Colorado Denver
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