Section 3: Cancer drugs and Stem Cells

Since cancer is a heterogeneous disease, many drugs have been discovered and developed to
combat various aspects of cancer. Cancer therapies are discussed below along with how they can benefit
from utilizing stem cells.
3.1.1 Chemotherapy.
Chemotherapy is the most commonly used type of cancer drug. A few examples include
alkylating agents, anti-neoplastics, and anti-metabolites. They can be administered orally, intravenously,
and directly into tissues. Although chemotherapy is a systemic treatment and can combat metastasis, it
also affects all rapidly proliferating cells and will cause systemic toxicity resulting in side effects such as
fatigue, nausea, pain, depression, numbness, weakness, hair loss, and overall decrease in quality of life.
Side effects can be minimized through tumor targeting which will result in higher concentrations at
diseased sites and lower concentrations systemically. For example, antibody targeted chemotherapies
conjugating cytotoxic chemotherapeutics to tumor associated antigens have been shown to have tumor
specific cytotoxic effects[69]. Use of tumor specific antigens for targeting is imperfect, however, and is
not applicable to all sorts of cancers. Fortunately, stem cells are able to home to all sorts of tumors due to
the inherent characteristics of cancer. As such, engineering stem cells to secrete chemotherapeutics can
significantly increase efficacy and safety. However, some cancer cells are resistant to chemotherapeutics,
necessitating efforts which utilizing other pathways to treat cancer.
3.1.2 Anti-cancer stem cell drugs
Rather than target cancer in general, some drugs also specifically focus on targeting cancer stem
cells These cancer stem cells are oftentimes more resistant to chemotherapy and radiation therapies and
cancer relapse occurs if the traditional treatments fail to kill all cancer stem cells[70]. In relapsed patients,
cancer stem cells account for a greater proportion of the tumors which makes the cancer even more
difficult to treat in a breast cancer model, the population of breast cancer initiating cells has been shown
to increase from 9% to 74% in tumors after traditional treatments[71].
3.1.3 Pro-apoptotic proteins
Apoptosis is a pathway naturally found on cancer cells that can be triggered to induce cell death
and cancer regression. Most notably, tumor necrosis factor-related apoptosis induced ligand (TRAIL)
directly attaches to receptors on tumor cells and activates apoptosis proteases to kill the cancer cell [72].
This is highly effective against all cancers types but creating cancer specific pro-apoptosis proteins is
essential. Similar to other drugs, any non specific activation can be minimized through targeting using
stem cell vehicles. MSCs designed to deliver specially engineered secretable TRAIL have been showed to
cause apoptosis in in vivo glioma models. Importantly, it has been shown that MSCs are resistant to
apoptosis from TRAIL making them viable targeting candidates[73].
3.1.4 Prodrugs
Another way to increase cancer specificity in drugs is to utilize prodrugs. Prodrugs are normally
non toxic. However, they are designed to respond to tumor specific enzymes which activate the prodrug
into its toxic form[74]. Thus, prodrugs provide a more targeted approach towards cancer therapy since
greater concentrations of cytotoxic drug will be located at sites of cancer than in healthy tissues[75].
Another benefit of prodrug systems is the bystandard effect which kills all local cancer cells in a given
region through diffusion of the activated prodrug agent[76]. Stem cells can further increase local
concentration of drug at tumor sites and thus increase therapeutic efficiency. Prodrugs also exhibit higher
specificity than many conventional drugs which further reduces systemic toxicity even if stem cell
vehicles become lodged in organs such as the liver or lungs. The prodrug system can even be used in
cancers that do not have specific activating enxymes through suicide gene therapy (discussed in section
4.1.4).
3.1.5 Anti-angiogenesic agents
Aside from killing cancer cells, tumor growth can be hindered via antiangiogenic agents. As a
mass of proliferating cells, tumors require blood vessels to carry oxygen and nutrients to cells past the
oxygen diffusion limit which are at risk of hypoxia. Studies have shown that utilizing anti-angiogenic
VEGF receptor inhibitors transiently normalized tumor vessels in glioblastoma patients [77].
Intravenously delivered stem cells can be used as vehicles for these agents. In addition, since certain types
of stem cells, such as MSCs, can become embedded pericytes, using continuous release delivery
mechanisms can reduce the transience of anti-angiogenesis cancer therapy[78].
3.1.6 Growth factor limiting agents
Similar to angiogenic proteins, growth factors are also important to the development of cancer.
Many drugs such as NK4 which inhibits hepatocyte growth factor are used to combat cancer. Delivery of
NK4 using MSCs has been shown to significantly increase survival of mice in a lung metastasis
model[79].