Tumor Development Under Combination Treatments with Anti-angiogenic Therapies - Mathematical Methods and Models in Biomedicine - page 304

chemotherapy . The use of chemotherapies in oncology, indeed, has been one of
the major steps forward in the so-called “war against cancer” [ 4 ]. There not only
exists a huge body of experimental and clinical literature that has been produced in
the last 60 years, but chemotherapy also triggered a large amount of theoretical
research in connection with its apparently simple translation into mathematical
models (e.g., [ 1 , 23 - 25 , 51 , 54 , 58 - 61 , 64 , 65 , 68 ]). Also, and unlike in other fields of
biomedicine, on this topic there has been a small, but important interplay between
theoretical and experimental-clinical scientists [ 14 , 38 , 67 ].
Broadly speaking, we may consider two major classes of actions of
chemo-therapeutic drugs: cytostatic , where the chemical decelerates or blocks
the tumor cells' proliferation, and cytotoxic , where the agent kills the neoplastic
cell. This, of course, is a highly idealized description and often it is not clear how to
classify the actions of a specific drug. For example, paclitaxel, still one of the more
commonly used drugs in chemotherapy, binds to tubulin which locks microtubules
in place and thus prevents cell-duplication. In principle, this is a blocking action.
However, generally, a drug that prevents the further duplication of cancer cells
indefinitely is considered cytotoxic even when it does not induce apoptosis.
The main adverse effects of chemotherapy are due to the fact that drugs are
rarely selective to identify tumor cells, but, especially in the first stages of modern
chemotherapy, target all or at least large classes of proliferating cells. The mecha-
nism of action for these drugs is to interfere with one or more biochemical pathways
and thus the more the targeted pathway is specific to cancer cells, the less severe
side effects are. Since its first use, it has been plain that for this reason—the scarce
selectivity of chemotherapeutic agents—a number of serious side effects are related
to the use of cytotoxic chemicals to cure tumors. They simply also kill a more or
less wide range of physiologically proliferating cells important for life.
Even when side effects are limited, a high number of failures of chemotherapy
due to both intrinsic and acquired drug resistance plagues this treatment approach.
Cancer cells often are genetically unstable and, coupled with high proliferation
rates, this leads to significantly higher mutation rates than in healthy cells [ 14 ]. If a
mutated cell has a biochemical structure that invalidates the mechanism of attack
of the chemotherapeutic agent, these cells have acquired drug resistance. Indeed,
the response of tumor cells to chemotherapy is characterized by a considerable
evolutionary ability to enhance the cell survival in an environment that is becoming
hostile. Moreover, and more importantly, because of the tremendous heterogeneity
of cancer cells, often small sub-populations of cells are intrinsically not sensitive
to the treatment ab initio (intrinsic resistance). In this case, as the sensitive cells
are killed by the treatment, a tiny fraction of remaining, intrinsically resistant
tumor cells can grow to become the dominant remaining population leading to
the failure of therapy, possibly only after many years of seeming remission of the
cancer. Considerable research efforts thus have been, and still are being devoted
to finding means to overcome drug resistance [ 13 ]. Tumor anti-angiogenic therapy
falls into the realm of these procedures [ 20 , 21 ] and, for this reason, combinations
of chemotherapy with anti-angiogenic treatments offer synergistic advantages.