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Cancer Chemotherapy

Cancer is a disease characterized by a shift in the control mechanisms that govern cell survival, proliferation, and differentiation. Cells that have undergone neoplastic transformation usually express cell surface antigens that may be of normal fetal type, may display other signs of apparent immaturity, and may exhibit qualitative or quantitative chromosomal abnormalities, including various translocations and the appearance of amplified gene sequences. Such cells proliferate excessively and form local tumors that can compress or invade adjacent normal structures. A small subpopulation of cells within the tumor can be described as tumor stem cells. They retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonize various organs in the process called metastasis. Such tumor stem cells thus can express clonogenic or colony-forming capability. Tumor stem cells are characterized by chromosome abnormalities reflecting their genetic instability, which leads to progressive selection of subclones that can survive more readily in the multicellular environment of the host. Quantitative abnormalities in various metabolic pathways and cellular components accompany this neoplastic progression. The invasive and metastatic processes as well as a series of metabolic abnormalities resulting from the cancer cause illness and eventual death of the patient unless the neoplasm can be eradicated with treatment.

CAUSES OF CANCER

The incidence, geographic distribution, and behavior of specific types of cancer are related to multiple factors, including sex, age, race, genetic predisposition, and exposure to environmental carcinogens. Of these factors, environmental exposure is probably most important. Exposure to ionizing radiation has been well established to be a significant risk factor for a number of cancers, including acute leukemias, thyroid cancer, breast cancer, lung cancer, soft tissue sarcoma, and basal cell skin cancers. Chemical carcinogens (particularly those in tobacco smoke) as well as azo dyes, aflatoxins, asbestos, benzene, and radon have been clearly implicated in cancer induction in humans and animals. Identification of potential carcinogens in the environment has been greatly simplified by the widespread use of the Ames test for mutagenic agents. Ninety percent of carcinogens can be shown to be mutagenic with this assay. Ultimate identification of potential human carcinogens, however, requires testing in at least two animal species.

Viruses have been implicated as the etiologic agents of several human cancers. Expression of virus-induced neoplasia probably also depends on additional host and environmental factors that modulate the transformation process. Cellular genes are known that are homologous to the transforming genes of the retroviruses, a family of RNA viruses, and induce oncogenic transformation. These mammalian cellular genes, known as oncogenes, have been shown to code for specific growth factors and their receptors and may be amplified (increased number of gene copies) or modified by a single nucleotide in malignant cells. The bcl-2 oncogene may be a generalized cell death suppressor gene that directly regulates apoptosis, a pathway of programmed cell death.

Another class of genes, tumor suppressor genes, may be deleted or damaged, with resulting neoplastic change. The p53 gene has been shown to be mutated in up to 50% of all human solid tumors, including liver, breast, colon, lung, cervix, bladder, prostate, and skin. The normal wild form of this gene appears to play an important role in suppressing neoplastic transformation; mutations in this gene place the cell at high risk.

CANCER THERAPEUTIC MODALITIES

In 2005, cancer was the most common cause of death from disease in the USA, causing over 500,000 fatalities. With present methods of treatment, one third of patients are cured with local modalities (surgery or radiation therapy), which are quite effective if the tumor has not metastasized by the time of treatment. Earlier diagnosis might lead to increased cure rates with such local treatment; however, in the remaining cases, early micrometastasis is a characteristic feature of the neoplasm, indicating that a systemic approach such as chemotherapy is required (often along with surgery or radiation) for effective cancer management. At present, about 50% of patients who initially are diagnosed with cancer can be cured. However, chemotherapy is able to cure only about 10-15% of all cancer patients.

Cancer chemotherapy, as currently employed, can be curative in certain disseminated neoplasms that have undergone either gross or microscopic spread by the time of diagnosis. These cancers include germ cell cancer, non-Hodgkin’s lymphoma, Hodgkin’s disease, and choriocarcinoma as well as childhood cancers such as acute lymphoblastic leukemia, Burkitt’s lymphoma, Wilms’ tumor, and embryonal rhabdomyosarcoma. In an increasing number of cancers, the use of chemotherapy combined with radiation therapy followed by surgery can increase the cure rate; these include locally advanced bladder cancer, breast cancer, esophageal cancer, head and neck cancer, rectal cancer, and osteogenic sarcoma.

In patients with widespread disseminated disease, chemotherapy provides only palliative rather than curative therapy at present. Effective palliation results in temporary improvement of the symptoms and signs of cancer and enhancement in the overall quality of life. In the past decade, advances in cancer chemotherapy have also begun to provide evidence that chemical control of neoplasia may become a reality for many forms of cancer. This will probably be achieved through a combined-modality approach in which optimal combinations of surgery, radiotherapy, and chemotherapy are used to eradicate both the primary neoplasm and its occult micrometastases before gross spread can be detected on physical or x-ray examination. Use of hormonal agents to modulate tumor growth is playing an increasing role in hormone-responsive tumors thanks to the development of hormone antagonists and partial agonists. Several recombinant biologic agents have been identified as being active for cancer therapy, including certain cytokines.

ANTICANCER DRUG DEVELOPMENT

A major effort to develop anticancer drugs through both empiric screening and rational design of new compounds has been under way for over 3 decades. The drug development program has employed testing in a few well-characterized transplantable animal tumor systems. Simple in vitro assays for measuring drug sensitivity of a battery of human tumor cells augment and shorten the testing program and are used currently as the primary screening tests for new agents. New drugs with potential anticancer activity are subjected to preclinical toxicologic and limited pharmacologic studies in animals. Promising agents that do not have excessive toxicity are then advanced to phase I clinical trials, wherein their pharmacologic and toxic effects are usually tested in patients with advanced cancer. Other features of clinical testing are similar to the procedure for other drugs but may be accelerated.

Under ideal circumstances, anticancer drugs would eradicate cancer cells without harming normal tissues. Unfortunately, no agents currently available are completely devoid of toxicity, and clinical use of these drugs involves a weighing of benefits against toxicity in a search for a favorable therapeutic index.

Classes of drugs that have recently entered clinical development include signal transduction inhibitors, focused on critical signaling pathways essential for cell growth and proliferation; microtubule inhibitors, directed against the mitotic spindle apparatus; differentiation agents, intended to force neoplastic cells past a maturation block to form end-stage cells with little or no proliferative potential; antimetastatic drugs, designed to perturb surface properties of malignant cells and thus reduce their invasive and metastatic potential; antiangiogenic agents, designed to inhibit the formation of tumor vasculature; hypoxic tumor stem cell-specific agents, designed to exploit the greater capacity for reductive reactions in these often therapeutically resistant cells; tumor radiosensitizing and normal tissue radioprotecting drugs, aimed at increased therapeutic effectiveness of radiation therapy; cytoprotective agents, focused on protecting certain normal tissues against the toxic effects of chemotherapy; and biologic response modifiers, which alter tumor-host metabolic and immunologic relationships.

IMPORTANCE OF NEOPLASTIC CELL BURDEN

Patients with widespread cancer may have up to 1012 tumor cells throughout the body at the time of diagnosis. If tolerable dosing of an effective drug is capable of killing 99.99% (ie, 104) of clonogenic tumor cells, treatment would induce a clinical remission of the neoplasm associated with symptomatic improvement. However, there would still be up to 8 “logs” of tumor cells (108) remaining in the body, including those that might be inherently resistant to the drug because of tumor heterogeneity. There may also be other tumor cells that reside in pharmacologic sanctuary sites (eg, the central nervous system, testes), where effective drug concentrations may be difficult to achieve. When cell cycle-specific drugs are used, the tumor stem cells must also be in the sensitive phase of the cell cycle (not in G0). For this reason, scheduling of these agents is particularly important. In common bacterial infections, a three-log reduction in microorganisms might be curative because host resistance factors can eliminate residual bacteria through immunologic and microbicidal mechanisms; however, host mechanisms for eliminating even moderate numbers of cancer cells appear to be generally ineffective.

Combinations of agents with differing toxicities and mechanisms of action are often employed to overcome the limited log kill of individual anticancer drugs. If drugs display nonoverlapping toxicities, they can be used at almost full dosage, and at least additive cytotoxic effects can be achieved with combination chemotherapy; furthermore, subclones resistant to only one of the agents can potentially be eradicated. Some combinations of anticancer drugs also appear to exert true synergism, wherein the effect of the two drugs is greater than additive. The efficacy of combination chemotherapy has now been validated in many human cancers, and combination chemotherapy is now the standard approach to curative treatment of testicular cancer and lymphomas and to palliative treatment of many other tumor types. This important therapeutic approach was first formulated by Skipper and Schabel and described as the log-kill hypothesis.

The growth of acute leukemias and aggressive high-grade lymphomas closely follows exponential cell kinetics. In contrast, most human solid tumors do not grow in such a manner; instead, they follow a Gompertzian model of tumor growth and regression. Under Gompertzian kinetics, the growth fraction of the tumor is not constant and peaks when the tumor is about one third of its maximum size.

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