Page 1268 - Clinical Small Animal Internal Medicine

1206 Section 11 Oncologic Disease

studies of canine osteosarcoma, B cell lymphoma, mam- to the treatment during mitosis and most resistant when
VetBooks.ir mary carcinoma, prostate carcinoma, and mast cell tumors, in the S phase. If treated in or prior to G 1 or G 2 phase, a
temporary arrest or “block” in the cell cycle occurs. It is
as well as feline vaccine‐associated fibrosarcomas.
There are several fields of study devoted to under-
repair damage done to fragile DNA prior to duplication of
standing the uncontrolled nature of tumor cell replica- felt that the G 1 and G 2 blocks are necessary in order to
tion. An underlying mechanism by which a cell regulates a faulty template or distribution of defective genes to a
the number of divisions tolerable over time is through daughter cell in mitosis. These transient delays are also
the integrity of chromosomal telomeres. Telomeres are known as checkpoints. These checkpoints exist as safety
specialized nucleoprotein complexes that “cap” and pro- mechanisms to limit the propagation of heritable errors
tect the end of every eukaryotic chromosome against and promote the survival of the cell. A well‐known tumor
chromosomal fusion, recombination, and terminal DNA suppressor protein, p53, plays a critical role in the G 1
degradation. Telomeres become progressively shorter checkpoint and controlling the fate of injured cells. It has
with each doubling until they reach a critically short been determined that a majority of cancers are affected
length and induce replicative senescence. The enzyme with mutated p53, which allows cells that have been dam-
telomerase maintains telomeres by synthesizing and aged to proceed through the cell cycle and replicate, cre-
replenishing telomeric DNA. Cancer cells exploit this ating daughter cells with flawed genetic content.
function by expressing telomerase and perpetually Chemotherapy drugs can be defined as cell cycle phase
replace their telomeres. It is through this mechanism that specific or cell cycle phase nonspecific. Examples of
most cancer cells gain replicative immortality. It has been chemotherapeutics that are cell cycle phase specific
shown in dogs that telomerase activity is upregulated in a include antimetabolites (i.e., gemcitabine, cytosine arabi-
majority of cancers and is absent in normal adult tissue. noside, 5‐fluorouracil), which are S phase specific, inter-
In fact, according to veterinary oncologic studies, telom- fering with the incorporation of nucleotides during DNA
erase is present in greater than 90% of canine cancers and synthesis, and vinca alkaloids (i.e., vincristine, vinblastine)
is absent from most normal tissues, with the exception of which are M phase specific, as they disrupt the assembly
germ cells. Further, it has been suggested that a different of tubulin into microtubules and inhibit cell division.
form of telomere maintenance, known as alternative Understanding these interactions, combination treat-
lengthening of telomeres (ALT) via homologous recom- ment plans, in which chemotherapy and radiation ther-
bination, may occur in canine osteosarcoma cells. apy are administered concurrently, can exploit the
Important to the concept of replicative immortality, sensitive phases of the cell cycle, with the goal of improv-
there has been great interest in studying cancer stem ing therapeutic efficacy. A clinical illustration of this
cells. The basis of the cancer stem cell model is that practice is the combination of gemcitabine, which kills
tumor development relies on a subset of stem cells that cells specifically in S phase, with radiation therapy, where
have the ability to self‐renew and generate the diverse cells in S phase are the most resistant. The chemotherapy
cells that comprise the tumor through differentiation. dose must be reduced with this approach to limit the
As such, the tumor exists as a heterogenous structure, severity of normal tissue toxicity; however, the combina-
maintained by cancer stem cells, which are inherently tion has been reported for treatment of canine sinonasal
resistant to traditional chemotherapy and radiotherapy. carcinoma and feline oral squamous cell carcinoma.
Recently, cancer stem cells have been identified, isolated,
and characterized from canine osteosarcoma cells in vitro.
Resisting Cell Death

Evading Growth Suppressors Conventional cancer therapeutics may kill cells by
inducing a lethal, cellular division, known as mitotic
The cell cycle is an organized balance of signals promot- catastrophe, or triggering an organized, controlled
ing and restricting replication and division; however, cell death, known as apoptosis.
neoplastic cells exist with dysfunctional growth control Playing a dual role, the p53 tumor suppressor gene,
mechanisms. The basic phases of the cell cycle have been which was described in the previous section as control-
defined as S phase (DNA synthesis), M phase (mitosis), ling the G 1 checkpoint in managing the cell cycle, is also
and gaps, G 1 (between M and S), G 2 (between S and M), critical in activating the apoptotic response following
G 0 (senescence). cellular damage. As it is very common for malignancies
When cells are exposed to damaging agents, such as to exist with mutant p53, cancer cells are adept at
ionizing radiation or certain chemotherapy drugs, the avoiding death by apoptosis. For example, the incidence
therapeutic efficacy varies with respect to the phase of the of p53 mutations in canine osteosarcoma varies from
cell cycle. For example, irradiated cells are most sensitive 24% to 47%.