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INTRODUCTION

BIOLOGY OF TUMOR GROWTH

Two essential features of cancer cells are uncontrolled growth and the ability to metastasize. The malignant phenotype of a cell is the end result of a series of genetic changes that remove safeguards restricting cell growth and induce new features that enable the cell to metastasize, including surface receptors for binding to basement membranes, enzymes to poke holes in anatomic barriers, cytokines to facilitate mobility, and angiogenic factors to develop a new vascular lifeline for nutrients and oxygen. These genetic changes usually involve increased or abnormal expression or activity of certain genes known as proto-oncogenes (often growth factors or their receptors, enzymes in growth pathways, or transcription factors), deletion or inactivation of tumor-suppressor genes, and defects in DNA repair enzymes. These genetic changes may occur by point mutation, gene amplification, gene rearrangement, or epigenetic changes such as altered gene methylation.

Once cells are malignant, their growth kinetics are similar to those of normal cells but lack regulation. For unclear reasons, tumor growth kinetics follow a Gompertzian curve: as the tumor mass increases, the fraction of dividing cells declines. Thus, by the time a cancer is large enough to be detected clinically, its growth fraction is often small. Unfortunately, tumor growth usually does not stop altogether before the tumor reaches a lethal tumor burden. Cancer cells proceed through the same cell-cycle stages as normal cycling cells: G1 (period of preparation for DNA synthesis), S (DNA synthesis), G2 (tetraploid phase preceding mitosis in which integrity of DNA replication is assessed), and M (mitosis). Some noncycling cells may remain in a G0, or resting, phase for long periods. Certain chemotherapeutic agents are specific for cells in certain phases of the cell cycle.

DEVELOPMENT OF DRUG RESISTANCE

Drug resistance can be divided into de novo resistance or acquired resistance. De novo resistance refers to the tendency of many of the most common solid tumors to be unresponsive to chemotherapeutic agents. In acquired resistance, tumors initially responsive to chemotherapy develop resistance during treatment, usually because resistant clones appear within tumor cell populations (Table 71-1).

TABLE 71-1CURABILITY OF CANCERS WITH CHEMOTHERAPY

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