This chapter is a continuation of Chapter 45 and focuses on additional classes of antineoplastic drugs. Chapter 45 describes the various antineoplastic drugs that are effective against cancer cells during specific phases in the cell growth cycle. In contrast, this chapter focuses on drugs that have antineoplastic activity regardless of the phase of the cell cycle. Also discussed in this chapter are drugs that are classified as miscellaneous antineoplastics, either because of their lack of clear cell cycle specificity or their unique or novel (new) mechanisms of action. For a description of the cell growth cycle, see Chapter 45.

Pharmacology Overview

Cell Cycle–Nonspecific Antineoplastic Drugs

There are currently two broad classes of cell cycle–nonspecific cancer drugs: alkylating drugs and cytotoxic antibiotics.

Alkylating Drugs

Records of the use of drugs to treat cancer date back several centuries. However, truly successful systemic cancer chemotherapy treatments are not documented until the 1940s. At this time, the first alkylating drugs were developed from mustard gas agents that were used for chemical warfare before and during World War I. The first drug to be developed was mechlorethamine, which is also known as nitrogen mustard. It is the prototypical drug of this class and is still used today for cancer treatment. Since its antineoplastic activity was discovered in the mid-twentieth century, many analogues have been synthesized for use in the treatment of cancer, and they are collectively referred to as nitrogen mustards also.

The alkylating drugs commonly used in clinical practice in the United States today fall into three categories: classic alkylators (the nitrogen mustards); nitrosoureas, which have a different chemical structure than the nitrogen mustards but also work by alkylation; and miscellaneous alkylators, which also have a different chemical structure than the nitrogen mustards but are known to work at least partially by alkylation. These drugs are used to treat a wide spectrum of malignancies. The drugs in each category are as follows:

Classic alkylators (nitrogen mustards)

Miscellaneous alkylators

Mechanism of Action and Drug Effects

The alkylating drugs work by preventing cancer cells from reproducing. Specifically, they alter the chemical structure of the cells’ deoxyribonucleic acid (DNA), which is essential to the reproduction of any cell. DNA molecules consist of two adjacent strands, each consisting of alternating sequences of phosphate and sugar molecules (Figure 46-1). These components make up what is called the “backbone” of the DNA strands. These two strands are chemically linked to each other by the third DNA structural element: nitrogen-containing bases (adenine, guanine, thymine, and cytosine, abbreviated A, G, T, and C, respectively). These bases are bound to the sugar molecules of the DNA backbone, and two bases, linked to each other by hydrogen bonds, form the molecular bridges between the two DNA strands that bring them into the double helix structure. A nucleotide, which consists of one molecule each of base, sugar, and phosphate that are bound together, is the structural unit of the molecules of both DNA and ribonucleic acid (RNA), another nucleic acid that is important in cellular reproduction. Messenger RNA (mRNA) molecules are produced by DNA molecules during the complex process of transcription. These mRNA molecules differ from DNA molecules in at least three ways: they are single stranded (instead of double stranded), the thymine base is replaced by another base known as uracil (U), and the sugar molecule is ribose, which has a slightly different structure from that of the deoxyribose molecules of DNA.

FIGURE 46-1 Deoxyribonucleic acid (DNA) double helix. A, Diagrammatic model of the helical structure, showing its dimensions, the major and minor grooves, the periodicity of the bases, and the antiparallel orientation of the backbone chains (represented by ribbons). The base pairs (represented by rods) are perpendicular to the axis and lie stacked one on another. B, The chemical structure of the backbone and bases of DNA, showing the sugar-phosphate linkages of the backbone and the hydrogen bonding between the base pairs. There are two hydrogen bonds between adenine and thymine, and three between cytosine and guanine. (From *Dorland’s illustrated medical dictionary,* ed 31, Philadelphia, 2007, Saunders.)

During the normal process of reproduction, the double helix uncoils, and its two strands separate. A strand of RNA is then assembled next to each single DNA strand in a process known as transcription. RNA strands, in turn, are involved in both protein synthesis (translation) and replication of the original DNA structure before cell division, or mitosis. These processes ultimately result in the creation of a new cell with the same DNA sequence, and thus the same characteristics, as its parent cell.

Alkyl groups that are part of the structure of antineoplastic alkylating drugs attach to DNA molecules by forming covalent bonds with the bases described earlier. As a result, abnormal chemical bonds form between the adjacent DNA strands, which leads to the formation of defective nucleic acids that are then unable to perform the normal cellular reproductive functions mentioned previously. This leads to cell death.

Alkylating drugs can be characterized by the number of alkylation reactions in which they can participate. Bifunctional alkylating drugs have two reactive alkyl groups that are able to alkylate two sites on the DNA molecule. Polyfunctional alkylating drugs can participate in several alkylation reactions. Figure 46-2 shows the location along the DNA double helix where the alkylating drugs work.

FIGURE 46-2 Organization of deoxyribonucleic acid (DNA) and site of action (∗) of alkylating drugs.

Indications

The most commonly used alkylating drugs today are effective against a wide spectrum of malignancies, including both solid and hematologic tumors. Common examples of the various types of cancer that different alkylating drugs are used to treat are listed in the Dosages table on p. 752.

Adverse Effects

Alkylating drugs are capable of causing all of the dose-limiting adverse effects described in Chapter 45. Other adverse effects are described in Table 46-1. The relative emetic potential of the various alkylating drugs is given in Box 45-1. The adverse effects of these drugs are important because of their severity, but they can often be prevented or minimized by prophylactic measures. For instance, nephrotoxicity from cisplatin can often be prevented by adequately hydrating the patient with intravenous fluids.

TABLE 46-1

COMMONLY USED ALKYLATING DRUGS: SEVERE ADVERSE EFFECTS

DRUG	ADVERSE EFFECTS
busulfan	Pulmonary fibrosis
carboplatin^∗	Nephrotoxicity, neurotoxicity, bone marrow suppression
cisplatin	Nephrotoxicity, peripheral neuropathy, ototoxicity
cyclophosphamide	Hemorrhagic cystitis

^∗Carboplatin has less nephrotoxicity and neurotoxicity but more bone marrow suppression than cisplatin.

Drug extravasation (Box 46-1) occurs when an intravenous catheter punctures the vein and medication leaks (infiltrates) into the surrounding tissues. With cancer chemotherapeutic drugs, in particular doxorubicin (a cytotoxic antibiotic), extravasation can cause severe tissue damage and necrosis (tissue death). Extravasation antidotes for selected drugs are listed in Table 46-2.

BOX 46-1

EXTRAVASATION OF ANTINEOPLASTICS

Extravasation is one of the more devastating complications of antineoplastic therapy and may lead to extensive tissue damage, the need for skin grafting, other problems in the surrounding areas, and even loss of limb. Because many cell cycle–specific and cell cycle–nonspecific drugs are given intravenously, there is a constant danger of extravasation of vesicants and subsequent injury, including permanent damage to nerves, tendons, and muscles. Skillful and perceptive nursing care helps to prevent extravasation or to identify it early if it does occur, which may reduce the severity of tissue damage. There are important reasons for the placement of central venous intravenous catheters rather than peripheral catheters when long-term treatment is anticipated. Infiltration may occur with any intravenous catheter; it is the specific drug and its characteristics, such as irritant (irritating the IV site or vein) or vesicant (causing cell death with extravasation and necrosis with ulcerative properties, that poses the concern. Because peripheral veins are small and offer minimal dilution of the intravenous drug with blood, there is a greater risk of severe and irreversible damage if a substance infiltrates and spreads to surrounding areas. If the drug is a vesicant, extravasation may lead to massive tissue injury, whereas extravasation of an irritant results in significantly less damage. Central venous access is needed for administration of vesicants to avoid the problems associated with extravasation. However, extravasation may occur with central lines and PICC lines due to dislodging of the access catheter, venous thrombosis, and catheter breakage. Blood needs to be aspirated prior to administration to check for patency. Extravasation may be suspected if the following occurs at either a central line site, PICC line site, or peripheral IV site: complaints of burning, stinging pain, or any other acute change of sensation at the site or along the chest wall, neck, or shoulder (central line); or leakage, swelling, or induration at the site. If extravasation of a vesicant is suspected, immediate action must be taken and the antidote, if known, must be given following strict guidelines and procedures. Steps to help manage extravasation of an irritant and/or a vesicant include the following: (1) Stop the infusion immediately and contact the prescriber, leaving the intravenous catheter in place. (2) Next, it is usually recommended to aspirate any residual drug and/or blood from the catheter. (3) Consult institutional policy or guidelines or the pharmacist regarding the use of antidotes, application of hot or cold packs and/or sterile occlusive dressings, and elevation and rest of the affected limb. Document the extravasation incident with attention to all phases of the nursing process related to the problem. Remember to always consult facility protocol and guidelines.

Data from National Cancer Institute website, http://www.nci.nih.gov; United States Pharmacopeial Convention: USP DI volume 1: drug information for the health care professional, Greenwood Village, CO, 2005, Micromedex. Internet resources for additional information: www.cancer.org, www.oncolink.org/index.cfm, www.hospicenet.org, http://www.acponline.org.

TABLE 46-2

ALKYLATING DRUG EXTRAVASATION: SPECIFIC ANTIDOTES

DRUG	ANTIDOTE PREPARATION	METHOD
carmustine	Mix equal parts 1 mEq/mL sodium bicarbonate (premixed) with sterile NS (1:1 solution); resulting solution is 0.5 mEq/mL.	1. Inject 2 to 6 mL IV through the existing line along with multiple subcut injections into the extravasated site. 2. Apply cold compresses. 3. Total dose is not to exceed 10 mL of 0.5-mEq/mL solution.
mechlorethamine	Mix 4 mL 10% sodium thiosulfate with 6 mL sterile water for injection.	1. Inject 5 to 6 mL IV through the existing line with multiple subcut injections into the extravasated site.
		2. Repeat subcut injections over the next few hours.
		3. Apply cold compresses.
		4. No total dose has been established.

IV, Intravenous; NS, normal saline; subcut, subcutaneous.

Interactions

Only a few alkylating drugs are capable of causing significant drug interactions. The most important rule for preventing such drug interactions is to avoid administering an alkylating drug with any other drug capable of causing similar toxicities. For example, a major adverse effect of cisplatin is nephrotoxicity. Therefore, if possible, do not administer it with a drug such as an aminoglycoside antibiotic (gentamicin, tobramycin, or amikacin) because of the resulting additive nephrotoxic effects and hence the increased likelihood of renal failure. Mechlorethamine and cyclophosphamide, both of which have significant bone marrow–suppressing effects, are not to be administered with radiation therapy or with other drugs that suppress the bone marrow. In general, you need to work with available pharmacy and oncology staff to proactively anticipate (and avoid, if possible) undesirable drug and treatment interactions.

Dosages

For dosage information on selected alkylating drugs, see the table on p. 752. It is important to note that dosages are highly

DOSAGES
Selected Alkylating Drugs

DRUG (PREGNANCY CATEGORY)	PHARMACOLOGIC SUBCLASS	USUAL DOSAGE RANGE^∗	INDICATIONS
♦ cisplatin (Platinol-AQ) (D)	Platinum coordination complex	IV: 50-100 mg/m² q4wk	Metastatic testicular, ovarian, and bladder cancer; brain tumors; esophageal, head, neck, lung, and cervical cancer
♦ cyclophosphamide (Cytoxan) (D)	Classic alkylator	IV: 3-5 mg/kg 2 × wk (many other regimens as well)	HL, NHL, leukemia; breast, ovarian, and testicular cancer; retinoblastoma; almost every solid tumor
♦ mechlorethamine (Mustargen) (D)	Classic alkylator	IV: 6 mg/m² day 1 and day 28 q4wk	HL, NHL, leukemia, bronchogenic carcinoma, others

HL, Hodgkin’s lymphoma; IV, intravenous; NHL, non-Hodgkin’s lymphoma.

^∗NOTE: Dosages are highly variable.

variable based on type of cancer, previous drugs used, and concurrent drug administration.

Drug Profiles

The most widely used alkylating drugs, based on standard treatment protocols, are profiled here. Information for these drugs also appears in the Dosages table on this page.

♦ cisplatin

Cisplatin (Platinol) is an antineoplastic drug that contains platinum in its chemical structure. It is classified as a probable alkylating drug because it is believed to destroy cancer cells in the same way as the classic alkylating drugs—by forming cross-links with DNA and thereby preventing its replication. It is also considered a bifunctional alkylating drug.

Cisplatin is used for the treatment of many solid tumors, such as bladder, lung, testicular, and ovarian tumors. It is available only in injectable form. Medication errors, resulting in deaths, have occurred when cisplatin was confused for carboplatin. The best practice is to use both trade name and generic name when dealing with chemotherapy drugs.

♦ cyclophosphamide

Cyclophosphamide (Cytoxan) is a nitrogen mustard derivative that was discovered during the course of research to improve mechlorethamine. It is a polyfunctional alkylating drug and is a prodrug requiring in vivo activation. It is used in the treatment of cancers of the bone and lymph, as well as other solid tumors. Cyclophosphamide is also used in the treatment of leukemias and multiple myeloma, as well as for non-cancer related illnesses such as prophylaxis for rejection of kidney, heart, liver, and bone marrow transplants and severe rheumatoid disorders. It is available in both oral and injectable dosage forms.

♦ mechlorethamine

Mechlorethamine (nitrogen mustard) (Mustargen) is the prototypical alkylating drug. It is a nitrogen analogue of sulfur mustard (mustard gas) that was used for chemical warfare in World War I. Mechlorethamine was the first alkylating antineoplastic drug discovered, and its beneficial effects in the treatment of various cancers were identified after the war. Although its use has declined with the development of newer and better drugs, it continues to be administered in the treatment of Hodgkin’s and Non-Hodgkin’s lymphoma.

Mechlorethamine is a bifunctional alkylating drug capable of forming cross-links between two DNA nucleotides, which interferes with RNA transcription and prevents cell division and protein synthesis. It is available in parenteral form only, for administration intravenously or by an intracavitary route, such as intrapleurally or intraperitoneally. It can also be used topically for treatment of cutaneous T-cell lymphoma.