Antineoplastic Agents Chapter 45 Antineoplastic Agents

Cancer When a normal cell reproduces, it forms a cell that is identical to itself Normal cell reproduction is controlled Cancer is a disease process that involves the development of abnormal cells Cancer cells do not follow the rules They reproduce and grow at uncontrolled rates As groups of cancer cells (malignant tumors) grow, they rob normal cells of vital nutrients Learning Outcome 45.1 Explain the terms chemotherapy, metastasis, remission, drug resistance, and myelosuppression. The original location of a tumor is referred to as the primary site. As the tumor enlarges, there is an increased likelihood that some of the tumor cells will detach and relocate in other body areas. These new sites of tumor development are referred to as secondary sites. This spread of cancer is referred to as metastasis. The route of metastases is usually through the lymphatic system or the circulatory system. The different forms of cancer can be broadly classified into solid tumors and diffuse tumors. Solid tumors (breast, prostate, and lung) are stationary and can usually be palpated if they are significantly large and accessible. The diffuse tumors (leukemias and Hodgkin’s disease) are not restricted to any one location. The successful treatment of any cancer depends mainly on the type of cancer present and its location.

Treatment of Cancer Surgery Radiation Chemotherapy Learning Outcome 45.1 Explain the terms chemotherapy, metastasis, remission, drug resistance, and myelosuppression. There are three main approaches to the treatment of cancer: surgery, radiation, and chemotherapy. Surgery is the best method for solid tumors that are surgically accessible. Radiation (X-ray treatment) is used after surgery in an attempt to kill any cancer cells located in the area around where the tumor was located. However, even after surgery and radiation, there is no guarantee that all cancerous cells have been eliminated. Chemotherapy is the use of drugs to kill cancer cells. This form of treatment is the primary therapy for diffuse tumors. Chemotherapy

Chemotherapy Use of drugs to kill cancer cells Administered in cycles to allow for recovery of normal cells Antineoplastic: Drugs that inhibit tumor growth or cell reproduction Cannot differentiate cancer cells from normal cells Therefore, they kill normal cells and are very toxic Cells that have the fastest rates of metabolism and reproduction are most affected Includes cells of bone marrow, GI tract, and skin Bone marrow suppression (myelosuppression) results in anemia (reduced red blood cells), leukopenia (reduced white blood cells), and thrombocytopenia (reduced platelets) Patients have increased risk of infection and bleeding, ulcerations of the mucus membranes, and hair loss Learning Outcome 45.1 Explain the terms chemotherapy, metastasis, remission, drug resistance, and myelosuppression. Chemotherapy is the use of drugs to kill cancer cells. This form of treatment is the primary therapy for diffuse tumors. In addition, chemotherapy is often used after surgery and irradiation of solid tumors in order to eliminate the possibility of any remaining cancer cells that may have metastasized. Chemotherapy is administered in cycles that usually vary between 1 and 6 weeks. The time between treatments allows recovery of normal cells. The term antineoplastic refers to drugs that inhibit tumor growth or cell reproduction. Unfortunately, most antineoplastic drugs cannot differentiate cancer cells from normal cells. Therefore, antineoplastic drugs usually kill some normal cells and are, in general, very toxic drugs. The goal of chemotherapy is to kill more cancer cells than normal cells and eventually rid the body of all cancer cells.

Chemotherapy Remission: Period when cancer cells are not actively reproducing Drug resistance: Lack of responsiveness of cancer cells to therapy Alternate drugs must be used Combination therapy is used in an attempt to prevent resistance Learning Outcome 45.1 Explain the terms chemotherapy, metastasis, remission, drug resistance, and myelosuppression. Disturbances and ulcerations of the skin and GI tract are also common. Many of the drugs cause temporary hair loss (alopecia). In order to limit toxicity, the antineoplastic drugs are usually administered in a series of treatments, which allows a drug-free period (1 to 6 weeks) between each treatment. Remission refers to an inactive period when cancer cells are not actively reproducing and increasing in number. This is one of the early goals of chemotherapy, which occurs when a drug treatment kills all of the actively dividing cancer cells. Other cancer cells that are dormant (resting) usually become active with time, but during remission the cancer is not growing.

Alkylating Drugs WW I introduced the world to chemical warfare Compounds were known as nitrogen mustard gases After the war they were studied and found to inhibit cell growth, including growth of cancerous cells They were the first cancer drugs developed Learning Outcome 45.2 Describe the mechanism of action of the alkylating drugs and the adverse effects associated with these drugs. The nitrogen mustards were the first cancer drugs developed and stimulated the search for additional drugs. Nitrogen mustards inhibit cell reproduction by binding irreversibly with the nucleic acids (DNA, RNA) and proteins. The specific type of chemical bonding involved is alkylation. Hence, the nitrogen mustards also are referred to as alkylating drugs. After alkylation, DNA is unable to replicate and therefore can no longer synthesize proteins and other essential cell metabolites. Consequently, cell reproduction is inhibited and the cell eventually dies from the inability to maintain its metabolic and reproductive functions. The nitrogen mustards and other alkylating drugs are considered cell-cycle nonspecific (CCNS) as they can cause cell death regardless of the cell cycle. However, they are more effective when cells are actively dividing.

Alkylating Drugs Adverse effects Nausea and vomiting Myelosuppression - Anemia, leukopenia, and thrombocytopenia Ulceration of the skin Hair loss (alopecia) Can cause teratogenic and carcinogenic effects Learning Outcome 45.2 Describe the mechanism of action of the alkylating drugs and the adverse effects associated with these drugs. Nausea and vomiting are characteristic adverse effects produced by the alkylating agents and most antineoplastic drugs. These effects occur shortly after drug administration and usually last for 1 or 2 days. Varying degrees of myelosuppression occur (anemia, leukopenia, and thrombocytopenia) in all patients. In addition, ulceration of the skin and GI tract and hair loss (alopecia) are common. Because of their growth-inhibiting properties, most antineoplastic drugs have the potential to cause teratogenic effects. These drugs should not be used during pregnancy if at all possible, but especially not during the first trimester. Alkylating drugs are also carcinogenic and can cause secondary malignancies, most commonly acute leukemias. Cyclophosphamide and ifosfamide are metabolized by the liver to a toxic metabolite, acrolein, that can cause hemorrhagic cystitis of the urinary bladder. Pre-drug hydration and administration of mesna disulfide, a chemical that inactivates acrolein, can reduce the incidence of cystitis.

Antimetabolites Inhibit enzymes that are essential to the synthesis of DNA and RNA Includes folic acid antagonists, purine antagonists, and pyrimidine antagonists Adverse effects include nausea, vomiting, diarrhea, myelosuppression, GI ulceration Learning Outcome 45.3 Explain how the different types of antimetabolite drugs inhibit the growth of cancer cells. The antimetabolites are a group of drugs whose chemical structures are similar to those of the purines, pyrimidines, and folic acid normally required for synthesis of DNA. The antimetabolite drug is taken up by both normal and cancerous cells and incorporated into the metabolic pathway for DNA synthesis as if it were the normal metabolite. However, when activated by the cell, the antimetabolites inhibit enzymes that are essential to the synthesis of DNA and RNA. The antimetabolites are considered cell-cycle specific (CCS) and are most effective when the cell is synthesizing DNA in the S phase.

Hormone Antagonists Used for tumors that are hormone dependent Indicated after surgery and radiation therapy Inhibit the growth of any remaining cancer cells Learning Outcome 45.5 Describe the mechanism of action of the different types of hormone antagonists. Tumors that involve the reproductive organs (prostate, testes, breast, uterus, and ovaries) are frequently hormone-dependent. These cancerous cells usually possess the same sex hormone receptors normally found on these organs. The hormones that normally develop and maintain these organs now act as growth factors and stimulate the growth of the cancer cells. Drugs that block or interfere with the actions of these hormones are classified as hormone antagonists. Hormone antagonists are not cytotoxic; they do not cause cell death. The function of the hormone antagonists is to inhibit the growth of any cancer cells that remain. These drugs are primarily indicated after surgery and radiation therapy.

Hormone Antagonists Tamoxifen - Estrogen receptor blocker Used in the treatment of breast cancer Toremifene and raloxifene - Similar to tamoxifen Common side effects are nausea, hot flashes, rash, and vaginal bleeding Can increase clotting factors which increases the risk of thromboembolism Aromatase inhibitors - Block estrogen synthesis More effective than Tamoxifen Similar side effects to Tamoxifen Learning Outcome 45.5 Describe the mechanism of action of the different types of hormone antagonists. Tamoxifen (Nolvadex) is an estrogen receptor blocker used in the treatment of breast cancer. Tamoxifen is usually administered orally, over a 5-year period following surgical removal of the primary tumor. This drug can also be taken prophylactically by women who have a family history or predisposition to developing breast cancer. The common side effects of tamoxifen are similar to the postmenopausal syndrome and include nausea, vasomotor hot flashes, rash, and vaginal bleeding. Tamoxifen can increase blood clotting factors and stimulate proliferation of the uterine lining. Toremifene (Fareston) and raloxifene (Evista) are additional estrogen antagonists similar to tamoxifen. Raloxifene is used to prevent postmenopausal osteoporosis and for prophylaxis of breast cancer in women with increased risk factors. An advantage of raloxifene is that it does not stimulate proliferation of the uterine lining. Aromatase is an enzyme involved in the synthesis of estrogens. Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are aromatase enzyme inhibitors indicated for the treatment of breast cancer following surgical removal of the tumor. By blocking the synthesis of estrogen, these drugs reduce the amount of estrogen available to stimulate estrogen receptors on cancer cells. These drugs are administered orally on a daily basis. The common adverse effects of aromatase inhibitors include nausea, vasomotor flushing or hot flashes, menstrual irregularities, and vaginal bleeding.

Hormone Antagonists Drugs affecting gonadotropin-releasing hormone (GnRH) Inhibit production of estrogen, progesterone, and testosterone Used in the treatment of prostate cancer and advanced breast and ovarian cancer Adverse effects include nausea, hot flashes, menstrual irregularities Androgen antagonists Used in the treatment of prostate cancer Adverse effects include GI disturbances, hot flashes, gynecomastia impotency, and changes in liver function Learning Outcome 45.5 Describe the mechanism of action of the different types of hormone antagonists. Gonadotropin-releasing hormone (GnRH) is released from the hypothalamus. It stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In females, FSH and LH are responsible for the development of the ovarian follicle and secretion of estrogen and progesterone. In males, FSH and LH stimulate the production of sperm and secretion of testosterone. Leuprolide (Lupron) and goserelin (Zoladex) are analogs of GnRH that, when administered as drugs in a continuous manner, inhibit the release of FSH and LH. Leuprolide is usually administered by subcutaneous or intramuscular injection. Additional gonadotropin inhibitors are nafarelin (Synarel), administered by nasal spray, and triptorelin (Trelstar), administered by IM injection. The main pharmacologic action of these drugs is to inhibit production of estrogen, progesterone, and testosterone. In males, these drugs are used to block the secretion of testosterone in the treatment of prostate cancer. In females, these drugs can be used in advanced breast and ovarian cancer to block secretion of both estrogen and progesterone. Adverse effects of these hormone antagonists include headache, nausea, vasomotor hot flashes, and other symptoms of hypogonadism.

New Approaches to Cancer Chemotherapy Biological agents that selectively bind to and inhibit the actions of specific cell antigens and receptors are available Monoclonal antibodies are administered in combination with other chemotherapeutic drugs Effective in inhibiting cancer cell proliferation Antineoplastic drugs can interfere with fetal development Used in circumstances where the benefits of treatment outweigh the risks of harm to the fetus Learning Outcome 45.6 Explain the use of monoclonal antibodies and related drugs in the treatment of cancer. One of the goals of cancer chemotherapy is to discover drugs that selectively target cancer cells and do not affect normal cells. Advances in molecular biology have identified specific cell antigens and membrane receptors involved in cellular proliferation and growth of certain cancer cells. Biological agents are now available that selectively bind to and inhibit the actions of these antigens and receptors. A number of monoclonal antibodies and other drug molecules have been approved for treatment of various cancers. These drugs are administered in combination with other chemotherapeutic drugs and have proven effective in inhibiting cancer cell proliferation. The drugs are usually well tolerated and do not cause myelosuppression. Nausea, vomiting, and rash are common to most drugs.