Chemotherapy Drugs

Although phase-nonspecific drugs can inflict biochemical lesions at any time during the cell cycle, they usually are more toxic to proliferating cells than to cells in G0 because

(1) G0 cells often have time to repair drug-induced damage before it can result in significant harm, and (2) toxicity may not become manifest until the cells attempt to divide.

Agents used for drug therapy fall into two main groups:

(1) cytotoxic agents and (2) noncytotoxic agents, such as hormones, immunomodulators, and targeted drugs.

Ideally, the drugs used in combination therapy should have

(1) different mechanisms of action, (2) minimally overlapping toxicities, and (3) good efficacy when used alone.

Renal injury from hyperuricemia can be minimized by giving

(1) fluids, (2) prophylactic allopurinol (a drug that blocks uric acid formation) and, (3) if hyperuricemia develops despite these measures, rasburicase (an enzyme that catalyzes uric acid degradation).

Flutamide, an androgen receptor blocker, is used in combination with a GnRH agonist to treat prostate cancer. Benefits derive from

(1) preventing cancer cells from undergoing increased stimulation during the initial phase of GnRH therapy, and (2) blocking the effects of adrenal androgens on prostate cells.

Antiestrogens fall into two major categories:

(1) pure estrogen receptor antagonists and (2) SERMs, which block estrogen receptors in some tissues, and activate estrogen receptors in others.

Anticancer drugs can cause irreversible male sterility:

Accordingly, men undergoing chemotherapy should be counseled about possible sperm banking.

Anticancer drugs can cause fetal malformation and death:

Accordingly, women undergoing chemotherapy should be warned against becoming pregnant.

Bifunctional alkylating agents form cross-links in DNA, and thereby prevent DNA replication:

Bifunctional agents are more effective than monofunctional agents.

Methotrexate, a folic acid analog, prevents conversion of folic acid to its active form:

Cell kill results primarily from disruption of DNA synthesis.

Asparaginase converts asparagine into aspartic acid, and thereby deprives cells of asparagine needed to make proteins:

Cytotoxicity is limited primarily to leukemic lymphoblasts because these cells are unable to manufacture their own asparagine, whereas normal cells can.

Chemotherapy can cause hyperuricemia as a result of

DNA degradation secondary to massive cell death.

Doxorubicin is a planar molecule that intercalates DNA, thereby distorting DNA structure. As a result,

DNA polymerase and RNA polymerase are unable to use DNA as a template, and hence synthesis of DNA, RNA, and proteins is disrupted.

Antiestrogens block estrogen receptors (ERs), whereas aromatase inhibitors block estrogen synthesis. :

For either group to work, the cancer must be ER positive.

The cell cycle has four major phases:

G1, in which cells prepare to synthesize deoxyribonucleic acid (DNA); S, in which cells synthesize DNA; G2, in which cells prepare for mitosis (division); and M, in which cells actually divide. Following mitosis, the resulting daughter cells may either enter G1 and repeat the cycle, or enter G0 and become mitotically dormant.

Most antimetabolites are

S-phase specific.

. Nausea and vomiting can be reduced by premedication with antiemetics

The combination of aprepitant, dexamethasone, and ondansetron is especially effective.

The purpose of intermittent chemotherapy is to allow normal cells to repopulate between rounds of treatment:

Unfortunately if the cancer cells repopulate as fast as (or faster than) normal cells, there will be no reduction in tumor burden with each round of treatment, and hence treatment will fail.

When a neutropenic patient develops an infection, immediate and vigorous intervention is required:

Until lab reports on the identity and drug sensitivity of the infecting organism are available, empiric therapy with IV antibiotics should be instituted.

Epidermal growth factor receptor linked with tyrosine kinase (EGFR-TK),

a regulatory molecule found in certain normal cells and many cancer cells, plays an important role in regulating cell proliferation.

Because alkylation reactions can take place at any time during the cell cycle,

alkylating agents are considered cell-cycle phase- nonspecific.

Cetuximab is monoclonal antibody that blocks the receptor portion of EGFR-TK,

and thereby suppresses cell growth and promotes apoptosis

Advanced prostate cancer is treated with

androgen deprivation, which can be achieved with castration or drug therapy.

Antitumor antibiotics fall into two major groups:

anthracyclines (which damage the heart) and nonanthracyclines (which don't).

By injuring the epithelial lining of the GI tract,

anticancer drugs often cause stomatitis and diarrhea.

Cell-cycle phase-nonspecific drugs can affect cells during

any phase of the cell cycle, including G0.

Rituximab is a monoclonal antibody that binds with CD20, and thereby initiates

apoptosis plus a lethal immune attack on B cells. The drug is indicated only for B-cell non-Hodgkin's lymphoma.

Also, glucocorticoids can improve

appetite, promote weight gain, and may impart a generalized sense of well-being.

Antimetabolites are analogs of important natural metabolites, and hence

are able to disrupt critical metabolic processes, especially DNA replication.

Targeted anticancer drugs are designed to bind with specific molecules (targets) that drive tumor growth. If the target molecules are found only (or mainly) on cancer cells, targeted drugs should be able to

arrest tumor growth while causing little or no injury to normal cells. The current reality, however, is that most targeted drugs cause serious adverse effects.

Killing of cancer cells follows first-order kinetics:

at any given dose, drugs kill a constant percentage of malignant cells, regardless of how many cells are present.

Neutropenia can be minimized by treatment with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor:

both of which act on the bone marrow to increase neutrophil production.

Cytotoxic anticancer drugs act directly on

cancer cells and healthy cells to produce cell death.

Over the course of chemotherapy

cancer cells often become drug resistant, thereby decreasing the chance of success.

Tamoxifen, a SERM, is approved for prevention and treatment of breast cancer. Benefits derive from blocking estrogen receptors on tumor cells. The drug is not active against

cancers that are ER negative.

The major adverse effect of trastuzumab is

cardiac injury, manifesting as ventricular dysfunction and heart failure.

Anticancer drugs often injure hair follicles, thereby

causing alopecia (hair loss).

Cell-cycle phase-specific drugs are effective only during a specific phase of the

cell cycle (eg, S phase, M phase). Accordingly, they are only active against cells that are participating in the cell cycle. Cells in G0 are spared.

. In addition to their use against lymphoid-derived cancers, glucocorticoids are used to manage complications of cancer and cancer therapy. Specific benefits include suppression of

chemotherapy-induced nausea and vomiting, reduction of cerebral edema secondary to irradiation of the cranium, reduction of pain secondary to nerve compression or edema, and suppression of hypercalcemia in steroid-responsive tumors.

Multidrug chemotherapy is generally much more effective than single-drug therapy because

combination therapy can (1) suppress drug resistance, (2) increase cell kill, and (3) reduce injury to normal cells (at any given level of anticancer effect).

Cancer chemotherapy has three possible benefits:

cure, palliation, and prolongation of useful life. For treatment to be justified, at least one of these benefits should be forthcoming.

Cytotoxic anticancer drugs are more toxic to cancers that have a high growth fraction than to cancers that have a low growth fraction because

cytotoxic anticancer drugs are more active against proliferating cells than against cells in G0.

Fluorouracil, a uracil analog, undergoes intracellular activation, after which it inhibits thymidylate synthetase, thereby

depriving cells of thymidylate needed to make DNA.

By activating certain estrogen receptors, tamoxifen increases the risk of

endometrial cancer and thromboembolism

In contrast to tamoxifen and other SERMs, fulvestrant poses no risk of

endometrial cancer, and only a slight risk of thromboembolism.

Interferon alfa, a biologic response modifier, benefits cancer patients by

enhancing immune responses and suppressing cancer cell proliferation.

Alkylating agents injure cells primarily by

forming covalent bonds with DNA.

Androgen deprivation can be achieved with two types of drugs:

gonadotropin-releasing hormone (GnRH) agonists and androgen receptor blockers.

Angiogenesis inhibitors block

growth of new blood vessels needed to supply solid tumors with oxygen and nutrients.

As a rule, serious toxicity occurs to normal tissues that have a

high growth fraction (ie, bone marrow, gastrointestinal [GI] epithelium, hair follicles, sperm-forming cells).

Tissues with a large percentage of proliferating cells and few cells in G0 have a

high growth fraction.

Nearly all of the anticancer drugs discussed in this chapter—hormonal agents, biologic response modifiers, and targeted drugs—are cell-cycle phase-nonspecific,

in contrast to many cytotoxic anticancer drugs, which are phase-specific.

Many anticancer drugs cause moderate to severe nausea and vomiting,

in part by stimulating the chemoreceptor trigger zone.

Nearly all of the drugs discussed in this chapter lack the characteristic toxicities of the cytotoxic anticancer drugs,

including bone marrow suppression, stomatitis, and severe nausea and vomiting. Nonetheless, most can cause severe toxicities of their own.

Cyclophosphamide, the most widely used alkylating agent,

is active against a broad spectrum of neoplastic diseases.

Anastrozole is more effective than tamoxifen and poses no risk of endometrial cancer. However,

it can cause osteoporosis and fractures, and (rarely) thromboembolism.

Vincristine is toxic to peripheral nerves, but does not significantly suppress bone marrow function because

it spares bone marrow, vincristine can be safely combined with drugs that suppress bone marrow.

Drugs are the treatment of choice for disseminated cancers which are:

leukemias, disseminated lymphomas, widespread metastases

Tissues composed mostly of G0 cells have a

low growth fraction

Glucocorticoids are toxic to cancers of

lymphoid origin, including acute and chronic lymphocytic leukemias, Hodgkin's disease, and non-Hodgkin's lymphomas.

Drugs are also used as adjuvants to surgery and irradiation to kill

malignant cells that surgery and irradiation leave behind

Surgery and/or irradiation are the treatments of choice for

most solid tumors.

In patients taking myelosuppressive drugs,

neutrophil counts must be monitored.

The CD20 antigen is a molecule present in the cell membrane of

normal and malignant B lymphocytes (B cells).

Cancer cells are characterized by

persistent proliferation, invasive growth, and the ability to form metastases.

To be effective, phase-specific drugs must be present as neoplastic cells cycle through the phase in which the drugs act:

phase-specific drugs must be in the blood continuously over a long time.

Myelosuppression (toxicity to bone marrow) can reduce the number of neutrophils, platelets, and erythrocytes, thereby

posing a risk of infection (from loss of neutrophils), bleeding (from loss of platelets), and anemia (from loss of erythrocytes).

Anastrozole, an aromatase inhibitor, is used to treat ER-positive breast cancer in postmenopausal women only. Benefits derive from

preventing production of estrogen from adrenal androgens.

Bevacizumab is a monoclonal antibody that binds with vascular endothelial growth factor (VEGF), and thereby

prevents VEGF from promoting blood vessel formation. By suppressing angiogenesis, bevacizumab can inhibit further tumor growth, but cannot directly kill existing tumor cells.

The growth fraction of a tissue is defined as the ratio of

proliferating cells to cells in G0.

Patients who want to wear a hairpiece should

select one before hair loss occurs.

For drugs that act during a specific phase of the cell cycle:

selecting the right dosing schedule is critical to success

Cetuximab can cause

severe infusion reactions and severe acne-like rash.

Rituximab can cause

severe infusion-related hypersensitivity reactions.

In contrast to vincristine, vinblastine causes

significant bone marrow suppression but is relatively harmless to peripheral nerves.

Loss of neutrophils and platelets during chemotherapy is common;

significant loss of erythrocytes is relatively rare, but can happen with certain drugs (eg, cisplatin).

Like cetuximab, gefitinib inhibits EGFR-TK. However, in contrast to cetuximab, gefitinib is a

small molecule (rather than an antibody) that works inside the cell to directly inhibit TK (rather than outside the cell to block EGFR).

Many targeted drugs are monoclonal antibodies directed at antigens found primarily on cancer cells. Most other targeted drugs are

small molecules that inhibit specific tyrosine kinases that regulate cell proliferation.

The most common cancers are

solid tumors of the breast, lung, prostate, colon, and rectum have a low growth fraction, and hence respond poorly to drugs.

Toxicity to normal tissues is the major obstacle to

successful therapy with cytotoxic anticancer drugs.

rarer cancers

such as acute lymphocytic leukemia, Hodgkin's disease, and certain testicular cancers—have a high growth fraction, and hence tend to respond well.

Early (localized) prostate cancer is treated with

surgery or radiation, sometimes followed by androgen deprivation.

Cancer can be treated with three basic modalities:

surgery, radiation therapy, and drug therapy

Breast cancer is treated with

surgery, radiation, cytotoxic drugs, and hormonal agents, of which there are two major groups: antiestrogens and aromatase inhibitors.

Anticancer drugs with vesicant properties can cause severe local injury if

the IV line through which they are being administered becomes extravasated.

Doxorubicin is an anthracycline-type antitumor antibiotic. To reduce the risk of heart failure,

the cumulative lifetime dose should be kept below 550 mg/m2. The risk can be further reduced with dexrazoxane, a drug that helps protect the heart from doxorubicin.

Vincristine and vinblastine block assembly of the microtubules that move chromosomes during cell division. Accordingly,

the drugs are M-phase specific.

If neutropenia is substantial (absolute neutrophil count below 500/mm3):

the next round of chemotherapy should be delayed.

About 50% of the cytotoxic anticancer drugs are phase specific;

the rest are phase nonspecific.

Leuprolide, a GnRH agonist, has a biphasic mechanism of action. During the initial phase the drug stimulates release of interstitial cell-stimulating hormone (ICSH) from the pituitary, and thereby increases production of testosterone by the testes. As a result,

there may be a transient "flare" in prostate cancer symptoms. With continuous use, the drug suppresses ICSH release, and thereby causes testosterone production to fall. It is important to note that leuprolide does not decrease production of adrenal androgens.

Cytotoxic anticancer drugs injure normal tissue because

these drugs lack selective toxicity

Because angiogenesis inhibitors affect blood vessels rather than specific cancer cells,

they should be active against a wide variety of tumors.

High doses of methotrexate coupled with leucovorin rescue can be used to treat methotrexate-resistant tumors:

this technique can be dangerous in that failure to give sufficient leucovorin at the right time can be lethal.

Doxorubicin also disrupts the function of

topoisomerase II, thereby causing strand breakage. This may be the primary mechanism of cell kill.

In addition to antiestrogens and aromatase inhibitors, breast cancer can be treated with

trastuzumab, a monoclonal antibody that binds with HER2, and thereby inhibits cell proliferation and promotes immune-mediated cell death.

Antitumor antibiotics are used to

treat cancer, not infections.

Like tamoxifen, raloxifene (a SERM) decreases the risk of breast cancer. Compared with tamoxifen, raloxifene carries a lower risk of

uterine cancer, and hence appears safer than tamoxifen for breast cancer prevention.

To cure a patient of cancer

we must produce 100% cell kill, which is rare with chemotherapy alone.

When glucocorticoids are used acutely, their toxicities are both mild and manageable. However,

when used long term, these drugs can cause many serious toxicities, including osteoporosis, adrenal insufficiency, increased susceptibility to infection, and peptic ulcers.

Cytarabine, a pyrimidine analog, undergoes intracellular activation followed by incorporation into DNA,

where it acts to inhibit DNA synthesis.