Principles of Antineoplastic Drug Use

Chapter 53 Principles of Antineoplastic Drug Use

One of the fundamental advances made in oncology in the last few decades is the recognition that cancer is a genetic disease. This does not mean that all cancers are inherited (although numerous genetic diseases are associated with a predisposition to cancer), but rather that neoplastic cells have an altered genetic content. This was first recognized in leukemias, which were all found to be associated with an abnormal karyotype. Eventually it was noted that most malignant cells have chromosomal rearrangements, and even cells with apparently normal karyotypes can almost always be found to have definable abnormalities (e.g., translocations, deletions).

By definition, neoplastic cells and tissues are characterized by uncontrolled growth, usually accompanied by a loss of cellular differentiation (anaplasia). The diseased cells and tissues are described as tumors, neoplasms, or cancers and occur in benign (nonvirulent) or malignant (virulent) states. Malignant neoplastic cells typically invade surrounding tissues, violating the basement membrane of the tissue of origin and eventually undergoing metastasis. More than 100 types of malignant neoplasms affect humans and are classified primarily according to their anatomical location and the type of cell involved. The advent of molecular diagnostic methods will almost certainly modify this number.

In the United States, malignant neoplasms are responsible for causing approximately 500,000 deaths per year (20% to 25% of total mortality), with approximately 1,000,000 new cases developing each year. Lung, large intestine, breast, and prostate neoplasms account for approximately 55% of both new cases and cancer deaths in the United States. Solid tumors arising from epithelial cells are termed carcinomas, whereas those originating from connective or mesenchymal tissue are termed sarcomas. Malignancies that arise from the hematopoietic system include the leukemias and lymphomas.

The mechanisms by which malignant neoplasms originate in humans are still not clear. Carcinogenesis (i.e., the creation of malignant neoplastic cells) appears to result from the activation of specific dominant growth genes, called oncogenes, or a loss of functional negative effectors, called tumor suppressor genes. On the basis of the findings in the best-studied tumors, it is now believed that both kinds of genetic changes are essential for development of a full malignant phenotype. Protooncogenes, when activated, become oncogenes, which encode modified proteins that cause cellular dedifferentiation and proliferation characteristics of the neoplastic state. Activation of protooncogenes can occur by means of several pathways that often involve exposure of cells to chemicals, radiation, or viruses. Activation can result from a single point mutation. The most common oncogenes found thus far in human tumors belong to the RAS gene family, which codes for guanosine triphosphate-binding proteins. When RAS is converted to the activated form, it fails to dephosphorylate guanosine triphosphate and cells are transformed to a neoplastic phenotype. More than 100 protooncogenes are known to exist. Clearly, most if not all products of these variously dominantly acting oncogenes are components of cellular signaling pathways. Other genes, known as tumor-suppressing genes, also are present in human cells and function to suppress excessive cellular growth. Retinoblastoma (tumor of the eye) is a prototype of a malignancy caused by a genetic loss of the tumor-suppressor gene RB. A second common tumor suppressor gene is P53, which has recently been shown to possess the important function of protecting genomic stability. Because cancer can be defined by a loss of genomic stability, it is not surprising that mutations in P53 are the single most prevalent lesion in human cancer.

Tumor growth represents a balance between cell division and cell death. Recently it has become clear that, in addition to cells dying from necrosis, cells can exit the cell cycle by way of apoptosis, which is a form of programmed cell death. Apoptosis is not only important developmentally (e.g., thymic involution), but the apoptotic pathway is also an important pathway in the cellular response to DNA-damaging agents such as chemotherapy. It is now believed that all chemotherapeutic agents act via apoptosis. Indeed, the apoptotic pathway is now being targeted in the development of drugs. Interestingly, some oncogenes, namely BCL2, act by blocking apoptosis.

From the clinical standpoint, the primary difficulty in the successful control and treatment of malignant neoplasms is that by the time cancers are detected, they are relatively large (a 1-cm³ volume of tumor usually contains 10⁹ cells) and frequently have metastasized. The chances of curing metastatic disease are small, because effective local treatments such as surgery and radiotherapy cannot remove or destroy all the malignant cells.

The generally accepted approach in the therapy of neoplastic diseases (Fig. 53-1) remains the removal or destruction of the neoplastic cells while minimizing toxic effects on non-neoplastic cells. It has been a long-standing question whether drugs effective against one type of neoplasm should be effective against all types. Clinical experience, however, has shown a wide range of drug activities among different types of tumors (sarcoma, carcinoma, leukemia, and lymphoma) and among tumors in different anatomical locations (breast, colon, and lung). Therefore interest has focused on treating each of the more than 100 clinically important forms of cancer as distinct diseases. Some of the therapeutic approaches listed in Figure 53-1 are not available for clinical use but represent experimental approaches that are under study. For example, drugs that function specifically to return neoplastic cells to normal differentiating cells and drugs that prevent metastases are not available or are highly experimental.

FIGURE 53–1 Major approaches to therapy of cancers. Tumor cells are shown in red and non-tumor cells in green. *In clinical use. Others are experimental.

These chapters on antineoplastic agents address the principles in using chemotherapy and the mechanisms of action and the problems associated with the clinical use of antineoplastic drugs in humans.

A growing number of tumor types now respond to treatment with antineoplastic drugs. The types of clinical response to chemotherapy in patients of various ages with advanced-stage tumors are listed in the Therapeutic Overview Box.

Chemotherapy has been very effective in the management of leukemias and lymphomas, both in children and adults, such that most cases of leukemia in children are now curable. The success of treatment for adult leukemias is somewhat less, but complete remission in response to induction therapy is often achievable. On the other hand, only a small number of solid tumors respond completely to chemotherapy. Choriocarcinoma, Ewing’s sarcoma, and testicular carcinoma are examples of solid tumors that can be cured with chemotherapy, even if they have metastasized.

It is of interest to compare the tumor types in which therapy has been aided greatly by antineoplastic drugs with the leading causes of cancer mortality (Fig. 53-2). Unfortunately, chemotherapy is only minimally effective in management of the most common forms of neoplastic diseases. Overall, carcinoma of the lung accounts for the greatest number of cancer deaths in men and women, and although chemotherapy can produce objective responses, it is not curative in this setting. Thus, despite progress, there is still a great need for more effective chemotherapy for the major neoplastic diseases.

FIGURE 53–2 Estimated cancer deaths in the United States in 2004—percentage distribution of sites by sex. (Excludes basal and squamous cell skin cancers and carcinoma in situ, except bladder).

Modified from American Cancer Society: Cancer statistics, 2004. CA Cancer J Clin 2004; 54:1.

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