Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

can be tolerated when they are divided into multiple smaller, fractionated doses. Normal tissue is usually able to recover from radiation damage more readily than is cancerous tissue. Therapeutic radiation can be delivered in one of three ways: external beam or teletherapy, with beams gener- ated by a linear accelerator or cobalt-60 machine at a distance and aimed at the patient’s tumor; brachyther- apy, in which a sealed radioactive source is placed close to or directly in the tumor site; and systemic therapy, in which radioisotopes with a short half-life are given by mouth or injected into the tumor site. Chemotherapy Cancer chemotherapy has evolved as one of the major systemic treatment modalities. 58,59 Unlike surgery and radiation, cancer chemotherapy is a systemic treatment that enables drugs to reach the site of the tumor as well as distant sites. Chemotherapeutic drugs may be used as the primary form of treatment, or they may be used as part of a multimodal treatment plan. Chemotherapy is the primary treatment for most hematologic and some solid tumors, including choriocarcinoma, testicular can- cer, acute and chronic leukemia, Burkitt lymphoma, Hodgkin disease, and multiple myeloma. Most cancer drugs are more toxic to rapidly prolif- erating cells than to those incapable of replication or in phase G 0 of the cell cycle. Because of their mechanism of action, they are more effective against tumors with a high growth fraction. By the time many cancers reach a size that is clinically detectable, the growth fraction has decreased considerably. In this case, reduction in tumor size through the use of surgical debulking procedures or radiation therapy often causes tumor cells residing in G 0 to reenter the cell cycle. Thus, surgery or radiation ther- apy may be used to increase the effectiveness of chemo- therapy, or chemotherapy may be given to patients with no overt evidence of residual disease after local treat- ment (e.g., surgical resection of a primary breast cancer). For most chemotherapy drugs, the relationship between tumor cell survival and drug dose is exponen- tial, with the number of cells surviving being propor- tional to drug dose, and the number of cells at risk for exposure being proportional to the destructive action of the drug. Exponential killing implies that a propor- tion or percentage of tumor cells is killed, rather than an absolute number (Fig. 7-10). This proportion is a con- stant percentage of the total number of cells. For this reason, multiple courses of treatment are needed if the tumor is to be eradicated. A major problem in cancer chemotherapy is the development of cellular resistance. Acquired resistance develops in a number of drug-sensitive tumor types. 59 Experimentally, drug resistance can be highly specific to a single agent and is usually based on genetic changes in a given tumor cell type. In other instances, a multidrug- resistant phenomenon affecting anticancer drugs with differing structures occurs. This type of resistance often involves the increased expression of transmembrane transporter genes involved in drug efflux.

10 12

10 11

10 10

3 log cell kill

Clinically overt disease

10 9

Disease in clinical remission

10 8

1 log cell regrowth

10 7

10 6

10 5

Cell Number

Tumor regrowth following premature cessation of therapy

10 4

10 3

10 2

10 1

Cycles of chemotherapy 1 2 3 4 5

10 0

Time

Cancer chemotherapy drugs may be classified as either cell cycle specific or cell cycle nonspecific (see Understanding—The Cell Cycle, Chapter 4). 58 Drugs are cell cycle specific if they exert their action during a spe- cific phase of the cell cycle. For example, methotrexate, an antimetabolite, acts by interfering with DNA synthe- sis and thereby interrupts the S phase of the cell cycle. Cell cycle–nonspecific drugs exert their effects through- out all phases of the cell cycle. The alkylating agents, which are cell cycle nonspecific, act by disrupting DNA when cells are in the resting state as well as when they are dividing. The site of action of chemotherapeutic drugs varies. Chemotherapy drugs that have similar structures and effects on cell function usually are grouped together, and these drugs usually have similar side effect profiles. Because chemotherapy drugs differ in their mechanisms of action, cell cycle–specific and cell cycle–nonspecific agents are often combined to treat cancer. Combination chemotherapy has been found to be more effective than treatment with a single drug. With this method, several drugs with different mechanisms of action, metabolic pathways, times of onset of action and recovery, side effects, and onset of side effects are FIGURE 7-10. Relationship between tumor cell survival and administration of chemotherapy.The exponential relationship between drug dose and tumor cell survival dictates that a constant proportion, not number, of tumor cells is killed with each treatment cycle. In this example, each cycle of drug administration results in a 99.9% (3 log) cell kill, and 1 log of cell growth occurs between cycles.The broken line indicates what would occur if the last cycle of therapy were omitted: despite complete clinical remission of disease, the tumor ultimately would recur. (Reprinted by the permission from Raymond E. Lenhard Jr., et al. The American Cancer Society’s Clinical Oncology. Atlanta, GA: American Cancer Society; 2001: 181. © American Cancer Society.)