Optimisation of Cancer Drug Treatments Using Cell Population Dynamics - Mathematical Methods and Models in Biomedicine - page 258

Then, unless it may be repaired by specific enzymes—that are often
overexpressed in cancer cells—these impaired cells, blocked at a checkpoint, are
subsequently sent to “clean death” by the physiological mechanism of apoptosis
(also possibly impaired in cancer, resulting in abnormal cells bypassing these
checkpoints). As mentioned above, we define here this class of drugs that have
for their ultimate mission to kill cancer cells—even if their primary action is not
to directly damage the genome, but rather to damage cell cycle enzymes—as
cytotoxics .
We reserve the term cytostatic to those non-cell-killing drugs that merely slow
down proliferation, usually by maintaining cells in G 1 with possible exit to G 0 ,
that is by definition the quiescent phase, i.e., the subpopulation of cells that are
not committed in the cell division cycle. Indeed, before the restriction point inside
G 1 , cells may stop their progression in the cell cycle and go back to quiescence in
G 0 . This last category comprises all drugs that act as antagonists of growth factors,
which may be monoclonal antibodies or tyrosine kinase inhibitors.

2.3 Drugs That Act on the Peritumoral Environment

We might also attach to this “cytostatic” category drugs that act on the tumour
environment, such as anti-angiogenic drugs (that impoverish it in oxygen and
nutrients) or molecules that could be able to modify local pH in a sense unfavourable
to cancer cells, assuming that their action is not to entrain cell death, but to indirectly
slow down progression in the cell cycle, which is possible mainly, if not only, in the
G 1 phase.
Acting on cancer cell populations without killing any of these cells but only by
limiting their thriving, even inducing their decay, by unfavourable environmental
conditions is certainly an ideal therapy, which avoid cell killing also in healthy
cell populations, and it has been achieved in some rare cases in monotherapy,
e.g., by Imatinib (initially known as STI571) for chronic myelogenous leukaemia
(CML) [ 53 , 100 ]. Yet most treatments of cancer use combinations of cytotoxics and
cytostatics (e.g., irinotecan and cetuximab [ 44 ]), for non-cell-killing therapeutics
alone are seldom sufficient in advanced stages of cancers.
Another instance of such combination of cell-killing and non-cell-killing ther-
apeutics is the treatment of premyelocytic acute myeloblastic leukaemia (APL or
AML3) by combining an anthracyclin and a redifferentiating agent (for AML is
characterised by a blockade of differentiation in non-proliferating hematopoietic
cells, and redifferentiating agents such as All-TransRetinoic Acid (ATRA) lift such
blockade in the case of APL) [ 66 ]. Here, maturation, and not proliferation (i.e., not
the cell cycle, which is not affected by them), is the target of redifferentiating agents,
which may thus by no means be considered as cytostatic.