Chemotherapy



Chemotherapy 3446
Photo by: Li Wa

Chemotherapy is the controlled use of chemicals for a medicinal purpose. The term was coined by the German bacteriologist Paul Ehrlich, around 1900, when he examined aniline dyes and arsenicals as possible treatments for diseases such as trypanosomiasis and syphilis. He envisioned "magic bullets" that could target invading organisms and leave the host unscathed. This goal of providing therapeutic benefits with minimal side effects continues in all areas of drug development. Remarkable successes have been obtained in compounds that modulate normal biochemistry within the human body. These include analgesics , antihistamines, cardiac rhythm regulators, blood pressure modifiers, anesthetics, anti-inflammatory agents, sedatives, diuretics, and vasodilators. In the battle against the unwanted growth of invading organisms and mutated cells (cancer), the greatest successes have occurred in the bacterial antibiotics; in the twentieth century they have increased human longevity more than any other medication. Similar successes for drugs treating viral infections and cancer have been elusive.

A young patient receiving a chemotherapy treatment.
A young patient receiving a chemotherapy treatment.

In recent years chemotherapy has become a popular form of anticancer treatment. The goal of a magic bullet endures, but it is often difficult to attain because most of chemotherapy's useful agents are poisonous. This results from the similarities between cancerous cells and normal cells. Drugs that kill tumors are not specific enough to leave normal cells unharmed. Therefore, virtually all cancer chemotherapy is a delicate compromise between effectiveness and toxicity, resulting in significant side effects. Patients and physicians accept this because the alternatives are limited and the progression of the often fatal disease usually occurs more quickly without some intervening form of chemotherapy treatment.

The pursuit of chemical agents that can more effectively treat cancer has led to many decades of research by a multitude of chemists, biochemists, microbiologists, biologists, and research physicians. Thousands of chemicals have been synthesized and tested in tissue cultures and animal models. Only a modest number have proved to be useful in treating humans, but they have become the mainstay of the chemotherapeutic attack on cancer. In combination with early detection, surgery, radiation, and newly developing immunotherapies and targeted therapies, the judicious use of chemotherapy can kill tumors and limit their recurrence.

Common Agents

The most active chemotherapeutic agents fall into a small number of broad categories depending on their mode of action: alkylating/cross-linking agents that interact with DNA ; antibiotics that can kill mammalian cells instead of bacteria; antimetabolites/inhibitors that interfere with normal biochemistry; hormones that interact with receptors on tumor cells; and cytokines that can alter the balance of the intercellular communication system. Some commonly used agents, and their classifications, are listed in Table 1.

All these drugs, more generally, can be classified as either reactive or interactive. In the first case, biological activity depends on the chemical reaction of the drug with a target molecule. The resulting adduct interferes with normal cellular processes and may enhance cell death. Such reactive molecules are often indiscriminant, however, and are prone to powerful side effects. In the second case, biological activity depends only on the drug's structure, allowing it to interfere with cellular pathways that depend on lock-and-key recognition processes. These interactions can often be very specific, but may be limited in efficacy due to the existence of parallel pathways for most critical processes.

Reactions with DNA are prototypical of reactive anticancer chemicals. Alkylating and cross-linking agents such as nitrogen mustards, platinum compounds, alkane sulfonates, nitrosoureas, and methylating agents are believed to achieve their therapeutic effect by irreversibly binding to DNA and blocking its replication. This class of drugs is used routinely to treat most forms of cancer: sarcoma, carcinoma, teratoma, and leukemia.

Naturally occurring antibiotics (i.e., produced by other organisms) are complicated, multipurpose compounds. They often contain unsaturated polycyclic rings that can squeeze between DNA bases (intercalation) and interrupt DNA replication; quinone redox sites that can create free radicals

Table 1. Names and properties of routinely prescribed chemotherapy agents.
Table 1. Names and properties of routinely prescribed chemotherapy agents.

NAMES AND PROPERTIES OF ROUTINELY PRESCRIBED CHEMOTHERAPY AGENTS
Common Name Primary Target Mechanism Similar Drugs
SOURCE: Compiled from data contained in Perry, Michael C., ed. (2001). The Chemotherapy Source Book , 3rd edition. Philadelphia: Lippincott Williams & Wilkins.
Alkylating Agents, Cross-linkers
cyclophosphamide DNA nitrogen mustard ( reactive ) ifosfamide melphalan
cisplatin DNA platinum coordination ( reactive ) carboplatin
Antibiotics
doxorubicin (adriamycin) DNA polycyclic rings allow intercalation ( interactive ), quinones allow redox reactions ( reactive ) bleomycin mitomycin C daunorubicin
Antimetabolites, Inhibitors
methotrexate dihydrofolate reductase mimics folate interactive ) trimetrexate
5-fluorouracil thymdylate synthase, also incorporated into RNA and DNA mimics deoxyuridine triphosphate ( reactive and interactive ) 5-azacytidine cytarabine 6-mercaptopurine
vincristine microtubules inhibits tubule assembly ( reactive ) vinblastine
paclitaxel (taxol) microtubules inhibits tubule depolymerization ( reactive ) docetaxel
etoposide topoisomerase II inhibits reconnection of DNA ( interactive ) teniposide
topotecan topoisomerase I inhibits reconnection of DNA ( interactive ) irinotecan
Hormones
dexamethasone glucocorticoid receptor modify DNA transcription ( interactive ) hydrocortisone prednisone cortisone
diethylstilbestrol estrogen receptors change hormonal balance ( interactive ) estradiol modified estrogens
tamoxifen estrogen receptors blocks receptors in receptor-positive breast cancer ( interactive ) torimenifene

in the cell; and electrophilic moieties that can alkylate the guanine of DNA. They are used routinely in the treatment of leukemia, germ cell tumors of the testis and ovary, lymphomas, and some childhood cancers.

Antimetabolites substitute for naturally occurring compounds in normal metabolism and biosynthesis reactions. They are designed to interfere with the normal biochemistry of a cell by deactivating or retarding enzyme action or by replacing normal nucleic acids in DNA and RNA with analogs that inhibit replication or repair. Special classes of inhibitory molecules include the microtubule-targeting drugs and topoisomerase inhibitors, which interfere with specific targets within a cell. They are used routinely in all forms of cancer, usually in combination with each other and with the alkylating/cross-linking agents.

Hormones and hormone receptor inhibitors can be administered because some tumors have hormone receptors. The response of the tumor to such therapy, however, is difficult to predict. It can be detrimental or beneficial depending on the hormone, the type of cancer, and even the individual. These drugs are used routinely to treat breast cancer patients with receptor-positive tumor types.

Cytokines, like hormones, are interactive molecules. They bind to receptors on either effector cells of the immune system or the tumor cells themselves. In doing so, they activate programs within the cells that may be useful at a particular time and location in killing the tumor or attracting immune killer cells. A special class of immune system cytokines, called interleukins, has been tested in melanoma and renal carcinoma with some encouraging results. Although cytokines are still largely experimental, their use is growing due to increased understanding of the complex signaling of the immune system.

Kinetics

To understand why chemical compounds are useful drugs in treating diseases like cancer, scientists study their complicated kinetics within the human body. The first concern is their rate of reaction or target binding affinities with other biological compounds. The second is their rate of distribution and excretion . Together, these are referred to as pharmacokinetics. This is part of a broader series of effects, referred to as pharmacodynamics, which include the positive and negative physiological changes induced by a drug. When a drug is administered (orally or by injection), it must reach the desired target in the organism before it is excreted or altered by detoxifying enzymes (usually located in the liver). Studies using radioactive forms of drugs have been used as tracers to follow both the chemical modifications and their distributions in various compartments of the body. Results have allowed the synthesis of new drugs with better chemistries, distributions, and toxicity profiles.

The most useful reactive drugs are those that have biologically relevant reaction rates. This means that they react slowly enough to reach their targets but fast enough to damage target cells before they are cleared. This appears to be a simple concept for drug design, but the immense number of reactions that can occur in a biological environment have made the discovery and development of such drugs a tedious procedure.

A successful strategy for achieving this kinetic balance is to use a compound that has a long-lived intermediate form which keeps it near its target. Two widely used drugs, cyclophosphamide and cisplatin, are good examples of this, but for different reasons.

In cyclophosphamide, the nitrogen mustard moiety of the parent compound is unreactive because the electron-withdrawing property of the ring reduces the reactivity of the lone pair of nitrogen electrons. The result is a drug that is both nontoxic and nontherapeutic. As the drug circulates in the bloodstream, liver enzymes (cytochrome P450) oxidize the 4th position of the ring (see Figure 1). The 4-OH form undergoes nonenzymatic cleavage of the acyclic tautomer, forming a phosphoramide mustard. This last step occurs slowly enough for the 4-OH form to leave the liver and enter other cells. Once the charged product forms, it cannot escape the cells that it enters. The chloro-ethyl side groups then cyclize sequentially into highly reactive aziridinium forms, which attack and cross-link DNA, leading to cell death.

In cisplatin, the +2 oxidation state of the platinum atom forms four coordination bonds in a square plane. Each ammine supplies two electrons

Figure 1. Activation reactions for the anticancer drugs cyclophosphamide and cisplatin.
Figure 1. Activation reactions for the anticancer drugs cyclophosphamide and cisplatin.

from the filled orbital of nitrogen, while each chloride anion supplies two electrons and one negative charge that neutralizes the molecule. The result is a molecule stable to nucleophilic attack and able to cross cell membranes due to its charge neutrality. In the presence of low chloride, such as inside a cell, the chlorides begin to leave the platinum at a slow rate (a half-life of 5–6 hours). They are replaced by water molecules forming first mono-aquo and then di-aquo species, which are singly and doubly charged, respectively. These forms cannot penetrate the cell membrane and are confined inside the cell. Water makes a much better leaving group than Cl , resulting in rapid reactions with intracellular nucleophiles. With two sites of attack, the cross-linking of protein and DNA occurs readily.

In the case of interactive drugs, the most useful are those that exhibit long-term biological stability which allows them to reach their targets before they are degraded. They also have very high affinities for their targets so they can block normal molecules from binding. Many of these have been extracted from fungi, bacteria, and plants. Years of evolution have fine-tuned these complex molecules into effective poisons that have been targeted against the predators of these organisms. In humans, many have shown remarkable antitumor properties with manageable toxicities. Others have been chemically modified to give them the necessary pharmacokinetic properties suitable for fighting cancer. It is believed that many more of these molecules remain to be discovered and that much will be learned by studying their mechanisms of action.

Specificity

Many successful drugs have shown specificity for certain tumors. The reason for this selectivity is usually not obvious, since the expected mechanisms of action often suggest that they would kill all cells equally well. In fact, many do harm normal cells, leading to the unpleasant side effects that most patients experience. Nonetheless, such drugs can be effective in reducing or eliminating large tumors while sparing the patient.

The specificity of a given drug for a particular tumor has largely been discovered by trial and error on patients enrolled in clinical trials. In many cases, the reasons for that specificity are still unknown but appear to result from the different biochemistries of tumor cells. In particular, the regulatory pathways in tumor cells are dramatically out of balance. This is often the result of several mutations in oncogenes and suppressor genes disabling the control elements of cell division and homeostasis. DNA replication accelerates and remains unwrapped longer, exposing it to more cross-linking. In some tumors, DNA repair enzymes are expressed at reduced levels, allowing damage to accumulate faster. There is also evidence that many active agents shift the unbalanced regulation of tumor cells into apoptosis (programmed cell death), causing the tumor to essentially commit suicide. These various lines of research show that although tumor cells are aggressive and uncontrolled, they are also vulnerable to the right kind of attack.

The continuing goal of mechanism-of-action and specificity research is to provide a better understanding of the interaction between drugs and tumor cells. This will allow the rational design of new drugs that are lower in toxicity and higher in effectiveness. As cellular targets are identified, as new proteins are characterized from the human genome project, as cell–cell communication pathways are elucidated, and as high-power computation is established, rational drug design will become more practical. Future chemotherapy will likely be targeted, individualized therapy, where patients will be fitted to therapies just as they would be to finely tailored clothes.

SEE ALSO Coordination Compounds ; Ehrlich, Paul .

David A. Juckett

Bibliography

Berkow, Robert, ed. (1997). The Merck Manual of Medical Information: Home Edition. Whitehouse Station, NJ: Merck Research Laboratories.

Drews, Jurgen (2000). "Drug Discovery: A Historical Perspective." Science 287:1960–1964.

Gibbs, J. B. (2000). "Mechanism-Based Target Identification and Drug Discovery in Cancer Research." Science 287:1969–1973.

Hardman, Joel; Limbird, Lee; and Gilman, Alfred, eds. (2002). Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill.

Perry, Michael C., ed. (2001). The Chemotherapy Source Book , 3rd edition. Philadelphia: Lippincott Williams & Wilkins.

Schreiber, Stuart L. (2000). "Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery." Science 287:1964–1969.

Workman, Paul, and Kaye, Stanley B. (2002). "Translating Basic Cancer Research into New Cancer Therapeutics." Trends in Molecular Medicine 8(4) (Suppl.): S1–S9.

Internet Resources

"Chemotherapy and You: A Guide to Self-Help During Cancer Treatment." National Cancer Institute. Available from http://www.nci.nih.gov/cancerinfo/chemotherapy-and-you .

"Specific Chemotherapy Drugs." Cancer Information and Support International. Available from http://www.cancer-info.com/chemotypes.htm .



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