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Pharmacology of Oral Chemotherapy Agents
Ann Birner, PharmD
he past few years have
numerous (Borner, Scheithauer,
been witness to exciting
Twelves, Maroun, & Wilke,
The abundance of orally formulated chemotherapy
advances in the treat2001; Liu, Franssen, Fitch, &
agents reflects the expanding role of oral chemotherapy
ment of patients with cancer.
Warner, 1997). Oral drugs may
in the care of patients with cancer. Many oral chemoTwo trends in particular are of
be derivations of previously
therapy agents have been used for a number of years,
note: the use of chemotherapy
available injected agents or dethat is less generally cytotoxic
veloped as original concepts.
and several have been developed recently. Newer agents
and more specifically targeted to
During the oral drug developinclude the prodrugs capecitabine and temozolomide, the
cancer cells and the administrament process, challenges that
retinoid bexarotene, the immunomodulatory agent thalition of oral medications to cure
are specific to the route of ador control cancer.
ministration must be overcome
domide, the protein kinase inhibitor imatinib, and the
This article focuses on oral
(Bardelmeijer, van Tellingen,
epidermal growth factor receptor inhibitors gefitinib and
chemotherapy agents that have
Schellens, & Beijnen, 2000;
erlotinib. Each agent has unique pharmacologic properbeen approved recently for use
Birner, 2003; Lipinski, 2002;
ties, dosing, and side-effect profiles. This article reviews
in the United States and includes
Stenberg, Bergström, Luthman,
a discussion about what makes
& Artursson, 2002). Ideally, a
these agents from a pharmacology perspective.
them unique in their effects on
drug is stable in a formulation
cancer cells as opposed to
that is suitable for oral use, is
Key Words: antineoplastic agents, pharmacokinetics,
healthy cells. Their effects may
palatable, does not irritate the
prodrugs, retinoids
be a matter of preferential delivgastrointestinal tract, readily
ery to the anatomical site of the
dissolves after ingestion, and is
cancer, exploitation of molecular differences natural products such as plants or created adequately and reliably absorbed into the
between cancer cells and healthy cells, or anew in the laboratory. Many thousands of systemic circulation.
variation in enzymatic transformation of the molecular entities often are screened during
Many drugs are, in fact, prodrugs. A
drug that tends to spare healthy cells at the the search for a single promising agent for prodrug is a pharmacologically inert comexpense of cancer cells.
further investigation. Although sophisti- pound that is converted to an active agent
The earliest discoveries in cancer research cated techniques and instrumentation have by metabolic transformation in vivo (Maletfeatured chemotherapy agents. These drugs improved efficiency greatly, the process still Martino & Martino, 2002). A prodrug is dedisrupted the cell cycle in various ways, is an arduous and often lengthy one veloped with features that favor it over the
leading to cell death. Because cancer cell (Swinyard, 1990).
pharmacologically active component. For
growth is not as controlled as the growth of
Development of drugs may be based on example, an active cytotoxic agent may be
healthy cells, these therapies would, in astute observations of the effects on humans manipulated to produce a compound that is
theory, affect cancer cells to a greater de- of previously available chemicals. A classic relatively nontoxic and, therefore, easier to
gree than healthy cells. In reality, the effects example is the case of mechlorethamine. handle and produce. Prodrugs historically
on healthy cells were and often are quite During World War I, the remarkable effects have improved the in vivo delivery of a drug
toxic, particularly on cells with rapid growth of chemical warfare in the form of nitrogen when the active component faces obstacles
rates. Thus, the typical adverse effect pro- mustard gas on blood and bone marrow were such as poor oral absorption, insolubility,
file includes myelosuppression, alopecia, observed (Krumbhaar & Krumbhaar, 1919). and instability. Double prodrugs, or “proand mucositis. Recently, advancing knowl- Eventually, mechlorethamine was approved prodrugs,” require two metabolic transforedge regarding the genetic and molecular in- and made commercially available. To this mations before becoming chemically active
tricacies of human cells has allowed re- day, it is known as “nitrogen mustard” and
searchers to focus more specifically on the still is used to treat certain malignancies.
Mention of specific products and opinions redifferences between healthy and malignant Whatever the basis of discovery, staggering
lated to those products do not indicate or imcells and to exploit these differences to tar- amounts of data must be collected, from preply endorsement by the Clinical Journal of
get the latter.
clinical to human benefit and safety data,
Oncology Nursing or the Oncology Nursing
How do researchers develop drugs, and prior to submission to the U.S. Food and
Society.
what makes a suitable candidate for an oral Drug Administration (FDA) for approval.
agent? Substances may be derived from
The advantages of oral drug delivery are Digital Object Identifier: 10.1188/03.CJON.S6.11-19
T
CLINICAL JOURNAL OF ONCOLOGY NURSING • SUPPLEMENT TO VOLUME 7, NUMBER 6 • PHARMACOLOGY OF ORAL CHEMOTHERAPY AGENTS
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