Page 203 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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Cancer Chemotherapy

DANIEL L. GUSTAFSON AND DENNIS B. BAILEY

General Principles of Cancer Chemotherapy Processes in cell division not involving DNA replication are also

Mechanism of Cancer Therapy targets for anticancer agents. The most prominent of these targets
is tubulin, with several classes of drugs having antitubulin activity.
The use of chemical elixirs for the treatment of cancer can be traced The mechanism of action of these agents involves either inhibit-
through the medicinal customs and practices of multiple cultures. ing the polymerization of tubulin or stabilizing the polymerized
The modern use of pharmacologic agents to treat cancer began in form so that depolymerization is blocked. The result of blocking
the mid-1940s when Alfred Gilman and Louis Goodman showed either of these processes is the inhibition of microtubule function
the efficacy of nitrogen mustard in tumor-bearing mice, and these in the dividing cell. Microtubule function is critical to progression
results were quickly translated and verified in human patients. through mitosis via spindle fiber formation and the separation of
These results and the efforts of others such as Sydney Farber with chromosome pairs into daughter cells. Blockade of this process by
antifolates and George Hitchings and Gertrude Elion with purine antitubulin agents has proved to be an effective strategy because
analogs rapidly advanced the growing interest of treating cancer cells blocked in this part of the cell cycle (M phase) can undergo
with drugs. The beginning of a systematic screening program for apoptosis, other mechanisms of cell death and loss of viability.
anticancer drugs at the National Cancer Institute (NCI) in 1955
set the framework for cancer chemotherapy development in both Terminology and Concepts
the public and private sectors and led to the characterization of
many of the agents still in clinical use today. 1,2 Terms that are related to the efficacy and toxicity of cancer che-
The basis of anticancer drug activity is the targeting of dividing motherapy are important concepts for understanding their
cells through interference with processes involved in progression pharmacologic activity. The therapeutic index for a given chemo-
through the cell cycle. As shown in Fig. 12.1, the major classes therapeutic agent is the ratio between the toxic dose and the thera-
of drugs used to treat cancer work at various steps in the pro- peutic dose for that drug. For most cytotoxic drugs used to treat
cesses of DNA replication (S phase) and subsequent cell division cancer, the therapeutic index is an abstract parameter because the
(M phase). Another set of therapeutic agents, the signal transduc- administered dose is based on the maximum tolerated dose (MTD)
tion inhibitors, work by interfering with the signaling processes rather than dose response. The MTD is an empirically derived
that trigger entry into the cell cycle and continuing cellular pro- value that represents the highest dose of a given drug that can
liferation. This newer class of agents is discussed in Chapter 15, be administered with few patients experiencing unacceptable or
Section B. DNA synthesis is a complicated process involving irreversible adverse effects (AEs). MTD is initially derived from
anabolic processes to create the purine and pyrimidine nucleo- a limited population sample and then refined with additional
tide triphosphates required for replication, unwinding of the tem- clinical experience. This is an important concept in cancer drug
plate DNA to provide access to the replication machinery, and administration in that drug doses are generally based on this value
the high-fidelity process of creating complementary strands. Anti- rather than assessments of efficacy. A newer concept for drugs used
cancer drugs may work at any of these steps, including the antime- to treat cancer is the biologically effective dose (BED), based on a
tabolites that inhibit anabolic processes required for providing the measured response at a putative target or surrogate that is related
nucleotide building blocks, topoisomerase inhibitors that interfere to the mechanism of action of the agent. Determination of the
with the enzymatic process of DNA unwinding, and alkylating/ BED is currently more related to the use of signal transduction
DNA binding agents that can either act in a bifunctional man- inhibitors and molecularly targeted agents; however, the concept
ner to cross-link DNA through either interstrand or intrastrand is not exclusive to these agents and this approach may be useful
interactions blocking strand separation and template processing, when applied to cytotoxic chemotherapy using dosing protocols
or in a monofunctional manner interfering with the replication not based on the MTD. Dose intensity (DI) is a measure of dose
machinery through multiple mechanisms of altered binding and per unit of time and thus allows comparisons between protracted
base recognition. The resulting effects of interacting at these levels and compacted dosing schedules. Comparisons of DI between,
of DNA replication can include the generation of DNA strand for example, every 3 weeks and every week dosing allows for deter-
breaks, incomplete replication, and triggering of apoptotic signal- mining whether the total dose of the drug or the DI relates to
ing such that cell death is the ultimate result. toxicity or therapeutic outcome and the effect that altering dosing

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