Page 1297 - Small Animal Internal Medicine, 6th Edition

CHAPTER 76
VetBooks.ir

Practical Chemotherapy

CELL AND TUMOR KINETICS Oncogenes serve as checkpoints between different phases
of the cell cycle.
To better understand the effects of chemotherapy on both Several terms must be defined before chemotherapy is
neoplastic and normal tissues, it is necessary to have a basic discussed. The mitotic index (MI) refers to the proportion of
understanding of cell biology and tumor kinetics. As a cells in the process of mitosis within a tumor; the pathologist
general rule, the biologic characteristics of neoplastic cells often provides information about the mitotic activity in a
are similar to those of their normal counterparts; however, given tumor sample, reported as the MI or as the number of
neoplastic cells usually do not undergo terminal differentia- mitoses per high-power field (or per 10 high-power fields).
tion or apoptosis (programmed cell death). Therefore the cell The growth fraction (GF) refers to the proportion of prolif-
cycles of normal and neoplastic cells are similar. erating cells within a tumor and cannot be quantified in a
Recently, Hanahan and Weinberg reviewed the original patient. The doubling time (DT) refers to the time it takes
hallmarks of cancer (Hanahan and Weinberg, 2011); these for a tumor to double in size; it can be calculated by using
hallmarks provide a framework to better understand cancer sequential measurements of the tumor volume [V = p/6′
3
cell biology. They include sustaining proliferative signaling, (mean diameter) ] seen on imaging or determined by direct
evading growth suppressors, resisting cell death, enabling palpation. In dogs the DT ranges from 2 days (for metastatic
replicative immortality, inducing angiogenesis, and activat- osteosarcoma) to 24 days (for metastatic melanoma), whereas
ing invasion and metastasis. Underlying these hallmarks is in humans it ranges from 29 days (for malignant lympho-
genome instability, which generates the genetic diversity that mas) to 83 days (for metastases from breast cancer). The DT
expedites their acquisition, and inflammation, which fosters depends on the time spent in mitosis, the cell cycle duration,
multiple hallmark functions. Research in the past few years the GF, and the cell loss resulting from death or metastasis;
added two emerging hallmarks—reprogramming of energy as a general rule, the shorter the DT, the more aggressive
metabolism and evading immune destruction. In addition to the tumor (and the more likely to respond to conventional
cancer cells, tumors exhibit another dimension of complex- chemotherapy). Given our knowledge of tumor kinetics,
ity: they contain a repertoire of recruited, ostensibly normal by the time a pulmonary metastatic nodule is visualized
cells that contribute to the acquisition of hallmark traits by on radiographs, it consists of more than 200 million cells,
creating the “tumor microenvironment.” Recognition of the weighs less than 150 mg, and the cells have already divided
9
widespread applicability of these concepts will increasingly 25 to 35 times. A 1-cm palpable nodule has 10 tumor cells
affect the development of new means to treat human cancer. (1 trillion) and weighs 1 g (Fig. 76.2). As a general rule, most
The mammalian cell cycle has two apparent phases: nonneoplastic tissues (with the exception of bone marrow
mitosis and the resting phase. The resting phase is actually stem cells and intestinal crypt epithelium) have a low GF,
composed of four phases (Fig. 76.1): low MI, and prolonged DT, whereas most neoplastic tissues
have a high MI, high GF, and short DT (at least initially; see
1. Synthesis phase (S): DNA is synthesized. Fig. 76.2).
2. Gap 1 phase (G1): RNA and the enzymes needed for DNA Surgical cytoreduction (debulking) of a tumor that has
production are synthesized. reached a plateau of growth decreases the total number of
3. Gap 2 phase (G2): The mitotic spindle apparatus forms. cells, thus increasing the MI and GF and shortening the DT
4. Gap 0 phase (G0): This is the true resting phase. through yet unknown mechanisms (Fig. 76.3). In theory, this
renders the neoplasm more susceptible to chemotherapy or
The mitosis phase is termed the M phase. radiotherapy.

1269