Cytokinetics is the study of the kinetics of cellular growth, a
fundamental attribute of all multi-cellular life. Because oncology is
the study of malignant growth, it is rooted, in a very fundamental
sense, in this discipline. All the cardinal features of a cancer—its
proclivity to increase in size, to disseminate, and to destroy the
function of normal organs—are dependent on the reproduction of its
cells. For this reason, growth kinetic concepts pervade clinical
thinking in both overt and obscure ways. As evidence, we need only refer
to the everyday language of clinicians, which is replete with kinetic
terms: indolent growth, rapid growth, slow or no regression (“refractory
to therapy”), and brisk regression (“responsive to therapy”).
The
meanings of these descriptive terms seem intuitive. They are, however,
more complex and profound than a superficial familiarity would reveal.
Is indolent growth always slow, never to accelerate? Is rapid growth
always virulent, never to decelerate? How does the quantification of
cellular proliferation relate to macroscopic growth patterns? What are
the connections between growth rate and other attributes of cancer? Do
the presumed sites of action of anticancer drugs, the disruption of
mitosis, associate growth pattern with response to therapy? Is there a
difference in this regard between the impact of drugs on cancer cells
and on such rapidly proliferating host tissues as hematopoietic
progenitors and gastrointestinal mucosa? How do new markers of oncogene
expression, themselves related to multiple growth-related processes,
relate to prognosis, natural history, and response to therapy?
An
exciting development in the past decade has been the asking of these
various kinetic questions in experimental treatment protocols. Can
prognosis be predicted by pretreatment cytokinetic measurements? Does
drug resistance emerge rapidly between diagnosis and the first
opportunity to initiate chemotherapy? Is prognosis improved by shrinking
a tumor mass as rapidly as possible, even before surgical removal? What
is the optimal scheduling of non–cross-resistant chemotherapies? What
is the relationship between drug dose and the rate of tumor regression?
Can we use oncogene markers to plan treatment? These and similar issues
are important to both the scientist who studies cytokinetics in cells,
tissues, and tumors and the clinician who treats and studies patients.
The
field of cytokinetics actually comprises two intertwined disciplines.
The first is the study of cell proliferation. This is of interest not
primarily in the biologic sense of examining how cells divide (which is
discussed elsewhere in this volume), but in the numeric sense of
studying how fast they divide, how many are dividing, and how biologic
measurements, such as DNA content per cell and gene expression, relate
to these kinetic processes. The second aspect of cytokinetics is growth
curve analysis, the description of rates of change of cell number over
time in both the unperturbed and perturbed (therapeutic) situation. The
two disciplines are closely related, in that the kinetics of cellular
proliferation partially determine the kinetics of tumor growth. In
addition, both cellular proliferation and tumor growth are now thought
to relate to many biologic characteristics of a cancer, including its
tendency to invade, metastasize, and respond to drug therapy. Hence,
this chapter will consider both disciplines, their connections, and
their clinical implications.