Although our understanding of the basic molecular nature of the neoplastic transformation is still relatively primitive, significant advances have been made during the past three decades in the successful treatment of neoplasms that were not curable by surgery and/or radiation alone prior to 1970. The principal modality (used alone or in combination) that has resulted in signifi- cant improvement in treating a number of neoplasms, many of which are in persons less than 30 years of age (Chapter 1), is chemotherapy, by use of an increased spectrum of drugs, hormones, and other natural products.
Chemotherapy may be defined as the treatment of disease through the use of chemicals. This includes infectious as well as neoplastic disease. Cancer chemotherapy specifically is the treatment of cancer by chemicals that maximize the killing of neoplastic cells while minimizing the killing of most or all other cells of the host. With most malignant neoplasms, the greatest danger to the host results from dissemination of the disease throughout the organism. By defini- tion, a malignant neoplasm is capable of metastatic growth, making successful surgery an im- possibility unless carried out prior to successful metastatic dissemination of the neoplasm. Similarly, for radiotherapy, control of localized disease is quite reasonable, but anything less than whole-body irradiation would be unsatisfactory for the treatment of metastatic disease. The complications of whole-body radiation make this in most cases an untenable mode of therapy. As with infectious diseases, systemic treatment is absolutely necessary if one is to have any hope of eradicating disseminated disease. Such an ideal state has not been achieved for most neo- plasms in the human. However, cancer chemotherapy, by eliminating small foci of metastatic disease, has been instrumental in increasing the survival of many patients with a variety of neo- plasms. This curative effect of cancer chemotherapy has been most common in children; it has also been successful with a few selected neoplasms in adults (Table 20.1). Chemotherapy has also been combined with other therapeutic modalities to achieve both cures and dramatic, life- prolonging responses (see below).
HISTORY AND RATIONALES OF CANCER CHEMOTHERAPY
The term chemotherapy as well as a significant number of its basic concepts originated in the work of Paul Ehrlich, who coined the term in referring to the systemic treatment of both infec- tious disease and neoplasia. Ehrlich developed a system that allowed the transplantation of neo- plasms in rodents, on which he could test the effectiveness of drugs in slowing or eliminating neoplastic development. Many of Ehrlich’s concepts have formed the basis for modern chemo-
therapy. Although the concept of treating cancers with drugs may be traced back several centu- ries, there were no examples of truly successful cancer chemotherapy in the whole organism until the 1940s (Donehower et al., 1995). During World War II, an explosion on a ship contain- ing mustard gas resulted in the exposure of a number of people to this agent. It was noted at that time that exposed individuals exhibited a significant degree of bone marrow and lymphoid hypo- plasia (Infield, 1971). As a result of this serendipitous finding, Gilman and Philips (1946) stud- ied and reported the first clinical trial of nitrogen mustard in patients with malignant lymphomas at Yale University. Their results, which demonstrated dramatic although somewhat transient re- gression of lymphomas, may be considered as the beginning of modern chemotherapy.
Prior to 1960, the rationale for the therapy of neoplasia by drugs was derived largely from the successful treatment of a number of different neoplasms. Since that time, there has been not only an increasing number of drugs used for chemotherapy of cancer but also an increased un- derstanding of their mechanism of action. Figure 20.1 gives a historical indication of the time of introduction of a variety of drugs in the chemotherapy of human cancer. The mechanism of ac- tion of many of these chemicals is considered further on, but it is important to point out that most of them exert their cytotoxic and/or cytostatic effects during one or more phases of the cell cycle (see below).
Most neoplasms for which chemotherapy has been most successful exhibit the similar bio- logical characteristic of rapid growth. Neoplasms that are less susceptible or nonsusceptible to chemotherapy include many slowly growing malignant tumors such as colorectal cancer, renal cancer, melanoma, and carcinoma of the liver (see below). In many instances, drug responsive- ness is related to the growth fraction—i.e., the percentage of cells in the neoplasm undergoing division at any one time. Where the growth fraction is large, rapid growth results, but the greater proportion of the cell population is susceptible to the effects of cytocidal and cytostatic drugs. Conversely, neoplasms having a small growth fraction are not affected significantly by most drugs used in cancer treatment. Some examples of growth fractions, labeling indices, and cell loss are given in Table 20.2.
More recently, considerable evidence has indicated that many chemotherapeutic agents— in addition to or as part of their primary mechanism of cell killing—induce apoptosis (cf. Schmitt and Lowe, 1999; Hannun, 1997; Martin et al., 1997). The mechanisms of programmed cell death or apoptosis (Figure 7.11) have previously been considered, and are not treated here. In addition to inhibiting cell replication through alteration in DNA synthesis or damaging the DNA template, drugs may also alter the intracellular levels of adenosine triphosphate (cf. Berger, 1986; Martin et al., 1997) and alter or disrupt a variety of signal transduction pathways, as exemplified by the responsiveness of a number of neoplasms to hormonal therapy (cf. Gulli- ford and Epstein, 1996). A number of chemotherapeutic agents whose action is associated with
Year of Acquisition
Figure 20.1 Acquisition of new anti-cancer drugs, 1940–90. (Adapted from Krakoff, 1991, with permis- sion of the author and publisher.)
the induction of apoptosis in neoplastic cells are listed in Table 20.3. The table also indicates those neoplasms susceptible to the induction of apoptosis by one or more of the agents listed.
Chemical Agents Utilized in Human Cancer Chemotherapy
On the basis of the rationales for cancer chemotherapy given above, as well as by a certain amount of serendipity, a variety of different chemicals have been developed and found to be effective in the treatment of human cancer. The listing in Figure 20.1 gives a relatively complete picture of most of the drugs utilized today for the treatment of cancer as well as a number that
Table 20.3 Chemotherapeutic Agents Associated with the Induction of Apoptosis in Specific Types of Neoplasms
have been found successful in the past but have been superseded by other, more effective agents. Some of these agents, listed by their classification on a functional and descriptive basis, are shown in Table 20.4. In many but not all instances, the mechanism of action of these drugs on cellular pathways and components is known. Alkylating agents are highly reactive chemicals capable of alkylating DNA and other macromolecules directly, just as the ultimate forms of chemical carcinogens alkylate DNA (Chapter 3). Some alkylating agents are bifunctional, e.g., bisulfan, and are thus capable of crosslinking the two strands of the DNA double helix. Another group of highly effective crosslinking agents are the platinum complexes based on the original structure cis-Pt(II)(NH3)2Cl2, which is now known as the drug cisplatin. A more recently devel-
oped derivative is carboplatin, having a dicarboxylcyclobutane complex to two of the four coor-
dinate covalent sites of the platinum complex (Figure 20.2). Such crosslinking prevents the replication of these alkylated molecules by preventing their separation during DNA synthesis. Melphalan similarly induces interstrand, intrastrand, or DNA protein crosslinks, as does cyclo- phosphamide (Donehower et al., 1995). Nitrosoureas directly alkylate DNA with the formation of specific adducts. The antibiotics listed are complex natural products acting by several differ- ent mechanisms. Actinomycin D (dactinomycin) and plicamycin form complexes with DNA, effectively inhibiting transcription of most genetic information, while daunorubicin binds to DNA by intercalation between base pairs, thus inhibiting both DNA and RNA synthesis (cf. Donehower et al., 1995). Bleomycin is a mixture of polypeptides, some or all of which bind to DNA, causing strand scission (cf. Black and Livingston, 1990). Antimetabolites effectively used in chemotherapy generally prevent the formation or the utilization of normal cellular metabolites essential for the synthesis of nucleic acids, either directly or indirectly. In addition, 5-azacytidine inhibits the methylation of DNA cytosines as well (Glover and Leyland-Jones, 1987).
Although the ability to induce differentiation of neoplastic cells in vitro has been known for a number of years (Friend et al., 1971; Sachs, 1978), only relatively recently have such ther-
Table 20.4 Classification and Examples of Drugs Useful in Clinical Cancer Chemotherapy
Alkylating agents: Bi- or monofunctional, chemically highly reactive: Melphalan, nitrosoureas, bisulfan, cyclophosphamide, carboplatin Antibiotics: Complex natural products, acting by various mechanisms:
Actinomycin D, duanorubicin, bleomycin, plicamycin
Antimetabolites: Slow-acting. Resemble normal metabolites in structure and compete with them for an en- zyme, thus preventing further utilization of the normal metabolites:
Antipurines: 6-Mercaptopurine, 6-thioguanine
Antipyrimidines: 5-Fluorouracil, FUdR, cytosine arabinoside, 5-azacytidine
Differentiating agents: Induce differentiation of neoplastic cells
All-trans retinoic acid
Hormones: Estrogens, androgens, progestins, corticosteroids, antiestrogens, antiandrogens, gonadotropin- releasing hormone/agonists
Miscellaneous: Procarbazine, hydroxyurea, o,p′-dichlorodiphenyldichloroethane Plant alkaloids: Colchicine, vinblastine, vincristine, maytansine, taxol Topoisomerase inhibitors:
Topoisomerase I (catalyzes DNA unwinding) Camptothecin, innotecan (CPF-11), topotecan
Topoisomerase II (regulates 3D structure of DNA by binding to DNA, cleaving both strands and subse- quent religation)
Teniposide, etoposide, amsacrine
Fig. 20.2 Chemical structures of representative chemotherapeutic agents useful in clinical cancer chemotherapy.
apies been shown effective in the treatment of neoplastic disease. The principal effective agent is all-trans-retinoic acid (ATRA), which has been found especially effective in the treatment of acute promyelocytic leukemia (Fenaux et al., 1997). Unfortunately, this differentiation therapy with retinoids has not been very effective in other types of neoplasms, but it has shown some degree of efficacy as one of a number of retinoids effective in chemoprevention. In addition to specific chemicals, both synthetic and natural, several different enzymes have also been utilized in the chemotherapy of neoplasia, based at least in part on their ability to metabolize and elimi- nate specific metabolites, usually amino acids, essential for the growth of specific neoplastic cells (Chapter 8). Primary among these agents is the enzyme produced by Escherichia coli, L-asparaginase, which catalyzes the conversion of the amino acid L-asparagine to aspartic acid. By its catalytic action, the enzyme rapidly and completely depletes circulating pools of L-aspar- agine in the organism, thus compromising any cells that are unable or ineffective in synthesizing
L-asparagine. By a similar rationale, bacterial glutaminase and methioninase have been utilized both experimentally and in the clinic (Spiers and Wade, 1976; Tan et al., 1996). The efficacy of these other agents has not yet been suitably tested.
The usefulness of hormonal and antihormonal therapy in cancer dates back to the century- old observation by Beatson (1896) of the regression of metastatic breast cancer after oophorec- tomy. Nearly 50 years later, Huggins and Hodges (1941) demonstrated the effects of castration and of estrogens in inducing regression of prostatic neoplasia (cf. Figure 20.1). Since that time, a number of natural and synthetic hormones as well as antihormones have found use in the therapy of specific histogenetic types of neoplasms, predominantly those of endocrine origin or those from tissues exhibiting a relatively high degree of sensitivity to endocrine hormones. As noted in Chapter 18, for sex hormones to be effective in the treatment of specific neoplastic disease, the receptor for the therapeutic hormone or antihormone as a target must be present in the neoplastic cells. Mutations in steroid receptors have been associated causally with resistance of some neo- plasms to the effects of hormones and antihormones (Sluyser, 1994), but in most instances the presence of substantial amounts of receptor is indicative of a potential favorable response to its hormonal ligand. The exact mechanism of tumor regression by such agents, since they do not directly affect DNA synthesis or structure, is not clear. Because these agents exert their effects through signal transduction pathways (Chapters 3 and 7), it is likely that one of the mechanisms for inducing tumor regression is the induction of apoptosis in the hormonally responsive neo- plastic cell (Gulliford and Epstein, 1996). Apoptosis is induced in normal endocrine responsive tissues by removal of the appropriate trophic hormone (cf. Walker et al., 1989).
Several drugs effective in cancer chemotherapy are not easily classified in the listing of Table 20.4. An example is hydroxyurea, which has a relatively specific action in inhibiting one of the subunits of ribonucleotide reductase, thereby inactivating the enzyme (Yarbro, 1992). This eliminates the production of deoxyribonucleotides, thus indirectly inhibiting DNA synthesis and producing cell death in the S phase of the cell cycle and some synchronization of surviving cells that are also at risk for the development of gene amplification and chromosomal abnormalities owing to the dramatic alteration in the deoxyribonucleotide pool sizes (D’Anna et al., 1986). A number of plant alkaloids have also been found to be effective in cancer chemotherapy. Several of these, including colchicine (the first of many such compounds), vinblastine, vincristine, and most recently the taxanes (paclitaxel and docetaxel), are effective in the chemotherapy of a vari- ety of different neoplasms. These agents have in common a mechanism involving binding to microtubules and interruption of a variety of cellular functions, especially mitosis, cell migra- tion, and polarization. The topoisomerase inhibitors also represent a large class of naturally oc- curring compounds that have been found effective in the therapy of a variety of neoplasms. Topoisomerases are enzymes involved in the replication and stabilization of DNA by catalyzing breakage and reannealing of DNA strands to allow replication to occur as well as in relaxation and alteration of the structure of the DNA molecule (Rothenberg, 1997). Topoisomerase inhibi- tors prevent the religation of DNA after cleavage by the normal enzyme (Rothenberg, 1997; Pommier et al., 1996). In so doing, they disrupt DNA synthesis dramatically, leading to cell death or in many cases clastogenic effects. Figure 20.2 shows representative examples of chemo- therapeutic agents from each of the representative classes listed in Table 20.4.