The object of all chemotherapy drugs is to kill
the cancerous cells and not harm the adjacent healthy cells. To that end,
scientists tried to identify characteristics that are unique to cancer cells
and are not found on normal tissue. A distinct cancer trait could serve as a
potential target for a chemotherapy drugs and thereby fulfill the above goal.
One feature that is truly unique for most cancer cells is that they grow at a
rate faster than normal cells. Therefore targeting some aspect of the cell
growth cycle seems reasonable. Fast growing cells would be affected the most
and slow growing cells would be least disturbed. In fact, that is the basis for
many chemotherapeutics. This seems obvious when considering the side effect
profiles of most chemotherapy drugs. Hair follicles, skin, and the cells that
line the gastrointestinal tract are some of the fastest growing cells in the
human body, and therefore are most sensitive to the effects of chemotherapy. It
is for this reason that patients may experience hair loss, diarrhea, and
rashes.
The human body processes and excretes all drugs
through either the liver or the kidneys. Therefore, when a patient has kidney
or liver damage, giving chemotherapy becomes precarious. Administering the
recommended amount of drug may prove to be too toxic in a patient unable to
metabolize and excrete it. The pharmacokinetics for cancer patients are very
complex and chemotherapy pharmacology is a subspecialty on its own.
Unfortunately, kidney and liver damage often result due to cancer invasion,
limiting the patient's chemotherapy options.
Pharmacokinetics is further complicated in the
cancer patient, as they are often taking multiple medications, some of which
have overlapping metabolic pathways and side effect profiles. An example of
this difficult situation is in the brain cancer patient. Because brain tumors
often present as seizures, many of these patients take anti-seizure
medications. Anti-seizure medications are metabolized by the liver and affect
the metabolism of many chemotherapy drugs. Dose adjustments are an absolute
necessity to avoid toxicities or sub-therapeutic dosing.
The cell cycle is broken up into four phases the
G1, S, G2, and M phases. The G1 phase is the
phase most active in protein synthesis. The cellular DNA at this phase is
tightly coiled and is not actively being transcribed. Few chemotherapy agents
are active at this phase of the cell cycle. By contrast, the S phase is the
synthetic phase of the cell cycle. DNA replication is most active and many
chemotherapeutic agents are most active in this phase. G2 represent
a time when mostly RNA, but some protein, is actively produced. Mitosis, actual
cell division, occurs during the M phase. There are two major classes of
chemotherapy drugs that are most active during this phase of the cell cycle.
The remainder of this article includes a summary
of the major classes of chemotherapy drugs.
Alkylating agents are the oldest class of
anticancer drugs. Almost all of these drugs are active or latent nitrogen
mustards. Nitrogen mustards are various poisonous compounds originally
developed for military use. Alkylating agents all share a common mechanism of
action but differ in their clinical activity. They attack the negatively
charged sites on the DNA -- the oxygen, nitrogen, phosphorous and sulfur atoms.
By binding to the DNA, replication, transcription and even base pairing are
significantly altered. Alkylation of the DNA also leads to DNA strand breaks
and DNA strand cross- linking. By altering DNA in this manner, cellular
activity is effectively stopped and the cell will die. Chemotherapy drugs in
this class are active in every stage of the cell cycle. As a consequence, this
class of anticancer drugs is very powerful and is used in most every type of
cancer both solid tumors and leukemia.
In general, prolonged use of these drugs will
lead decreased sperm production, cessation of menstruation, and possibly cause
permanent infertility. This class of chemotherapeutics should never be used in
the first trimester of pregnancy as they are been shown to increase fetal
malformations. Use in the second or third trimester does not seem to carry the
same risk. All alkylating agents can cause secondary cancers although not all
agents are equal in their carcinogenic potential. The most common secondary
cancer is a leukemia (Acute Myeloid Leukemia) that can occur years after
therapy.
Some of the more common alkylating agents
include: Cyclophosphamide, Ifosphamide, Melphalan, Chlorambucil, BCNU, CCNU,
Decarbazine, Procarbazine, Busulfan, and Thiotepa.
In 1948, Dr. Sidney Farber showed that a folic
acid analog could induce remission in childhood leukemia. Approximately 10 out
of the 16 patients treated demonstrated evidence of hematologic improvement.
This experience provided the foundation for scientists to synthesize a number
of other agents that either target naturally occurring compounds or inhibit key
enzymatic reactions in their biochemical pathways. In general, all
antimetabolites interfere with normal metabolic pathways, including those
necessary for making new DNA. The most widely used antifolate in cancer therapy
with activity against leukemia, lymphoma, breast cancer, head and neck cancer,
sarcomas, colon cancer, bladder cancer and choriocarcinomas is Methotraxate.
Methotraxate inhibits a crucial enzyme required for DNA synthesis and therefore
exerts its effect on the S phase of the cell cycle.
Another widely used antimetabolite that thwarts
DNA synthesis by interfering with the nucleotide (DNA components) production is
5-Fluorouracil. It too has a wide range of activity including colon cancer,
breast cancer, head and neck cancer, pancreatic cancer, gastric cancer, anal
cancer, esophageal cancer and hepatomas. A unique and interesting aspect of
this drug is its toxicity profile. 5-Fluorouracil is metabolized by a naturally
occurring enzyme called dihydropyrimidine dehydrogenase, DPD. There is a small
population of people who may be deficient of this particular enzyme. Lacking
DPD does not interfere with normal body biochemistry and thus the phenotype is
silent. However, when these patients are challenged with this chemotherapy
drug, they are unable to metabolize it and therefore get acute and sever
toxicity. The most often seen toxicities include bone marrow suppression, severe
GI toxicities, and neurotoxicities which may include seizures and even coma.
It is important for the oncologist to recognize
this early and provide the patient with Thymidine as an antidote. A drug called
Capecitabine is an oral pro-5-Fluorouracil compound that has similar side
effect potentials.
Other antimetabolites that inhibit DNA synthesis
and DNA repair include: Cytarabine, Gemcitabine (Gemzar®),
6-mercaptopurine, 6-thioguanine, Fludarabine, and Cladribine.
Many of the currently effective anti-cancer
drugs are from natural sources. The drug, daunorubicin was isolated from
Streptomyces, a soil-dwelling fungus. Doxorubicin, another Anthracycline drug,
was isolated from a mutated strain of the same fungus. Both of these drugs have
a similar mechanism of action, but the latter is more effective in the
treatment of carcinomas. This class of chemotherapeutics works by the formation
of free oxygen radicals. These radicals result in DNA strand breaks and
subsequent inhibition of DNA synthesis and function. Anthracyclines also
inhibit the enzyme topoisomerase by forming a complex with the enzyme and DNA.
Topoisomerases are a class of enzymes that serve to unwind the DNA double
strand helix to allow for DNA repair, replication and transcription. This class
of chemotherapeutics is also not cell cycle specific. The most important side
effect of this group of drugs is cardiac toxicity. The same free radicals that
serve to damage the DNA of the cancer cell may damage the cells of the heart
muscle. Oncologists monitor heart function very carefully when patients are on
these medications. Other commonly used anthracyclines include Idarubicin,
Epirubicin and Mitoxantrone.
Another small peptide isolated form the fungus Streptomyces
verticullus is Bleomycin. Its mechanism of action is similar to that of the
anthracyclines, in that free oxygen radicals are formed that result in DNA
breaks leading to cancer cell death. This drug is rarely used by itself rather
in conjunction to other chemotherapies. Bleomycin is an active agent in the
regimen for testicular cancer as well as Hodgkin's lymphoma. The most
concerning side effect of this drug is lung toxicities due to oxygen free
radical formation.
The drugs in this class of chemotherapeutics act
by forming a complex with Topoisomerase and DNA resulting in the inhibition and
function of this enzyme. The presence of Topoisomerase is required for on-going
DNA synthesis. These drugs are used in many solid and liquid tumors and the
side effect profile of this class of drugs is agent specific. Camptothecins
include both irinotecan and topotecan. The parent compound, first identified in
the late 1950's, is a naturally occurring alkaloid found in the bark and wood
of the Chinese tree Camptotheca accuminata.
Etoposide, a chemotherapeutic that works by the
same mechanism, is a natural product isolated from the mandrake plant and is
not considered a camptothecin but rather an epipodophyllotoxin.
Vinca Alkaloids The leaves of a periwinkle
plant, Vinca rosea, were used to make tea that reportedly improved
diabetes. Early research showed that aqueous extract of this plant administered
by injection into rats resulted in their death within a week. Further
investigation showed that the rats die of sepsis due to bone marrow suppression
caused by this extract. Isolation and chemical characterization lead to the
currently used drugs: vincristine, vinblastine, and vinorelbine. These
chemotherapeutics bind to the tubulin and lead to the disruption of the mitotic
spindle apparatus. The disruption of mitosis implies that these drugs are
active specifically during the M phase of the cell cycle. They have a wide
application to many different malignancies and cause neurotoxicity as the most
prominent and dose limiting side effect.
Another class of chemotherapeutics that are
specific for the M phase of the cell cycle is the Taxanes. The taxanes include
paclitaxel and docetaxel. They bind with high affinity to the microtubules and
inhibit their normal function. This class of drugs has a broad range of
clinical activity including breast cancer, lung cancer, head and neck cancer,
ovarian cancer, bladder cancer, esophageal cancer, gastric cancer and prostate
cancer. The most common side effect of these drugs is the lowering of the blood
cells. These compounds were first isolated for the bark of the Pacific yew tree
Taxus brevifolia in 1963. It was not until 1971 that paclitaxel was
identified as the active component.
Natural metal derivatives were also shown to
have some activity in the fight against cancer. These agents work by
cross-linking DNA subunits. (The cross linking can happen either between two
strands or within one strand of DNA.) The resultant cross-link acts to inhibit DNA
synthesis, transcription and function. The platinum compounds can act in any
cell cycle. Cisplatin is used most often in lung cancer and testicular cancer.
The most significant toxicity of cisplatin is kidney damage. Second-generation
platinum, called carboplatin, has fewer kidney side effects, and at times may
be an appropriate substitute for regiments containing cisplatinum. Oxaliplatin
is a third-generation platinum that is active in colon cancer and has no renal
toxicities, however, its major side effect is neuropathies.
There are
other drugs now being used as effective therapies for malignancy. These include
hormones for breast, prostate and endometrial cancers, monoclonal antibodies,
immunotherapy with IL-2 and TNF alpha, and small molecule inhibitors. The
process of drug discovery involves much time, effort and resources. New
approaches are constantly being developed and modified. The process of testing
a new agent in clinical trials begins with the discovery of new compounds, new
ideas, new pathways, and new principles.