Anticancer drugs I: cytotoxic agents

CHAPTER 102


Anticancer drugs I: cytotoxic agents




Introduction to the cytotoxic anticancer drugs


The cytotoxic agents constitute the largest class of anticancer drugs. As their name implies, these agents act directly on cancer cells to cause their death. The cytotoxic drugs can be subdivided into eight major groups: (1) alkylating agents, (2) platinum compounds, (3) antimetabolites, (4) hypomethylating agents, (5) antitumor antibiotics, (6) mitotic inhibitors, (7) topoisomerase inhibitors, and (8) miscellaneous cytotoxic drugs. I don’t discuss each drug in detail. Rather, I focus on selected representative agents. Individual cytotoxic agents are listed in Table 102–1.



TABLE 102–1 


Cytotoxic Anticancer Drugs



















































































































































































































































































































































































































Generic Name Trade Name Cell-Cycle Phase Specificity Route Dose-Limiting Toxicity
Alkylating Agents
Nitrogen Mustards
Bendamustine Treanda Phase nonspecific IV Bone marrow suppression, infusion reactions
Chlorambucil Leukeran Phase nonspecific PO Bone marrow suppression
Cyclophosphamide generic only Phase nonspecific PO, IV Bone marrow suppression
Ifosfamide Ifex Phase nonspecific IV Bone marrow suppression and hemorrhagic cystitis
Mechlorethamine Mustargen Phase nonspecific IV, IC, IP Bone marrow suppression
Melphalan Alkeran Phase nonspecific PO, IV Bone marrow suppression
Nitrosoureas
Carmustine BiCNU, Gliadel Phase nonspecific IV, CNS implant Bone marrow suppression
Lomustine CeeNU Phase nonspecific PO Bone marrow suppression
Streptozocin Zanosar Phase nonspecific IV Nephrotoxicity
Others
Busulfan Myleran, Busulfex Phase nonspecific PO, IV Bone marrow suppression, pulmonary fibrosis
Temozolomide Temodar, Temodalimage Phase nonspecific PO Bone marrow suppression
Platinum Compounds
Carboplatin generic only Phase nonspecific IV Bone marrow suppression
Cisplatin generic only Phase nonspecific IV Nephrotoxicity
Oxaliplatin Eloxatin Phase nonspecific IV Peripheral neuropathy
Antimetabolites
Folic Acid Analogs
Methotrexate Rheumatrex, Trexall S-phase specific IV, IM, PO, IT Bone marrow suppression, mucositis
Pemetrexed Alimta S-phase specific IV Bone marrow suppression
Pralatrexate Folotyn S-phase specific IV Bone marrow suppression, mucositis
Pyrimidine Analogs
Capecitabine Xeloda Kills dividing cells only, mainly in S phase PO Bone marrow suppression, diarrhea, hand-and-foot syndrome
Cytarabine DepoCyt, Tarabine PFS S-phase specific IV, subQ, IT Bone marrow suppression
Floxuridine FUDR Kills dividing cells only, mainly in S phase IA Bone marrow suppression, oral and GI ulceration
Fluorouracil Adrucil Kills dividing cells only, mainly in S phase IV Bone marrow suppression, oral and GI ulceration
Gemcitabine Gemzar S-phase specific IV Bone marrow suppression
Purine Analogs
Cladribine Leustatin Kills dividing cells only, mainly in S phase IV Bone marrow suppression
Clofarabine Clolar S-phase specific IV Bone marrow suppression
Fludarabine Fludara, Oforta S-phase specific PO, IV Bone marrow suppression
Mercaptopurine Purinethol S-phase specific PO Bone marrow suppression
Nelarabine Arranon, Atrianceimage S-phase specific IV Neurotoxicity
Pentostatin Nipent S-phase specific IV Bone marrow suppression
Thioguanine Tabloid, Lanvisimage S-phase specific PO, IV Bone marrow suppression
Hypomethylating Agents
Azacitidine Vidaza S-phase specific subQ Bone marrow suppression
Decitabine Dacogen S-phase specific IV Bone marrow suppression
Antitumor Antibiotics
Anthracyclines
Daunorubicin (liposomal) DaunoXome Phase nonspecific IV Bone marrow suppression, cardiotoxicity
Doxorubicin Adriamycin, Doxil, Caelyximage Phase nonspecific IV Bone marrow suppression, cardiotoxicity
Epirubicin Ellence Phase nonspecific, but S and G2 most sensitive IV Bone marrow suppression, cardiotoxicity
Idarubicin Idamycin Phase nonspecific, but S most sensitive IV Bone marrow suppression, cardiotoxicity
Mitoxantrone* Novantrone Phase nonspecific IV Bone marrow suppression, cardiotoxicity
Nonanthracyclines
Bleomycin generic only G2-phase specific IV, IM, subQ, IP Pneumonitis and pulmonary fibrosis
Dactinomycin Cosmegen Phase nonspecific IV Bone marrow suppression, mucositis
Mitomycin generic only Phase nonspecific, but G1 and S most sensitive IV Bone marrow suppression
Mitotic Inhibitors
Vinca Alkaloids
Vinblastine Velban M-phase specific IV Bone marrow suppression
Vincristine Oncovin, Vincasar PFS M-phase specific IV Peripheral neuropathy
Vinorelbine Navelbine M-phase specific IV Bone marrow suppression
Taxanes
Cabazitaxel Jevtana G2/M-phase specific IV Bone marrow suppression, diarrhea
Docetaxel Taxotere G2/M-phase specific IV Bone marrow suppression
Paclitaxel Abraxane, Onxol, Taxolimage G2/M-phase specific IV Bone marrow suppression
Others
Eribulin Halaven G2/M-phase specific IV Bone marrow suppression, peripheral neuropathy
Estramustine Emcyt M-phase specific PO Nausea and vomiting
Ixabepilone Ixempra G2/M-phase specific IV Bone marrow suppression, neurotoxicity
Topoisomerase Inhibitors
Etoposide Etopophos, Toposar S and G2 most sensitive IV, PO Bone marrow suppression
Irinotecan Camptosar S-phase specific IV Bone marrow suppression and late diarrhea
Teniposide Vumon S and G2 most sensitive IV Bone marrow suppression
Topotecan Hycamtin S-phase specific IV Bone marrow suppression
Miscellaneous
Altretamine Hexalen Specificity unknown PO Bone marrow suppression
Asparaginase Elspar, Erwinaseimage, Kidrolaseimage G1-phase specific IV, IM None
Dacarbazine DTIC-Dome Phase nonspecific IV Bone marrow suppression
Hydroxyurea Hydrea, Droxia S-phase specific PO Bone marrow suppression
Mitotane Lysodren Phase nonspecific PO CNS depression
Pegaspargase Oncaspar G1-phase specific IV, IM None
Procarbazine Matulane Phase nonspecific PO Bone marrow suppression


image


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IA = intra-arterial, IC = intracavitary, IM = intramuscular, IP = intrapleural, IT = intrathecal, IV = intravenous, PO = oral, subQ = subcutaneous.


*Mitoxantrone is classified chemically as an anthracenedione, which is very similar to an anthracycline.



Mechanisms of cytotoxic action


Table 102–2 summarizes the principal mechanisms by which the cytotoxic anticancer drugs act. As the table shows, most cytotoxic agents disrupt processes related to synthesis of DNA or its precursors. In addition, some agents (eg, vinblastine, vincristine) act specifically to block mitosis, and one drug—asparaginase—disrupts synthesis of proteins. Note that, with the exception of asparaginase, all of the cytotoxic drugs disrupt processes carried out exclusively by cells that are undergoing replication. As a result, these drugs are most toxic to tissues that have a high growth fraction (ie, a high proportion of proliferating cells).




Cell-cycle phase specificity


As discussed in Chapter 101, the cell cycle is the sequence of events that a cell goes through from one mitotic division to the next. Some anticancer agents, known as cell-cycle phase–specific drugs, are effective only during a specific phase of the cell cycle. Other anticancer agents, known as cell-cycle phase–nonspecific drugs, can affect cells during any phase of the cell cycle. About half of the cytotoxic anticancer drugs are phase specific, and the other half are phase nonspecific. The phase specificity of individual cytotoxic agents is summarized in Table 102–1.




Cell-cycle phase–specific drugs.

Phase-specific agents are toxic only to cells that are passing through a particular phase of the cell cycle. Vincristine, for example, acts by causing mitotic arrest, and hence is effective only during M phase. Other agents act by disrupting DNA synthesis, and hence are effective only during S phase. Because of their phase specificity, these drugs are toxic only to cells that are active participants in the cell cycle; cells that are “resting” in G0 will not be harmed. Obviously, if these drugs are to be effective, they must be present as neoplastic cells cycle through the specific phase in which they act. Accordingly, these drugs must be present for an extended time. To accomplish this, phase-specific drugs are often administered by prolonged infusion. Alternatively, they can be given in multiple doses at short intervals over an extended time. Because the dosing schedule is so critical to therapeutic response, phase-specific drugs are also known as schedule-dependent drugs.



Cell-cycle phase–nonspecific drugs.

The phase-nonspecific drugs can act during any phase of the cell cycle, including G0. Among the phase-nonspecific drugs are the alkylating agents and most antitumor antibiotics. Because phase-nonspecific drugs can injure cells throughout the cell cycle, whereas phase-specific drugs cannot, phase-nonspecific drugs can increase cell kill when combined with phase-specific drugs.


Although the phase-nonspecific drugs can cause biochemical lesions at any time during the cell cycle, as a rule these drugs are more toxic to proliferating cells than to cells in G0. There are two reasons why this is so. First, cells in G0 have time to repair drug-induced damage before it can result in significant harm. In contrast, proliferating cells often lack time for repair. Second, toxicity may not become manifest until the cells attempt to proliferate. For example, many alkylating agents act by producing cross-links between DNA strands. Although these biochemical lesions can be made at any time, they are largely without effect until cells attempt to replicate DNA. This is much like inflicting a flat tire on an automobile: The tire can be deflated at any time; however, loss of air is consequential only if the car is moving. Carrying the analogy further, if the flat occurs while the car is stopped, and is repaired before travel is attempted, the flat will have no functional impact at all.


It should be noted that some dividing cells are more vulnerable than others. Specifically, cells that divide quickly are harmed more readily than cells that divide slowly. Why? Because quickly dividing cells have less time for repair.



Toxicity


As discussed in Chapter 101, many anticancer drugs are toxic to normal tissues—especially tissues that have a high percentage of proliferating cells (bone marrow, hair follicles, GI epithelium, germinal epithelium). The common major toxicities of the cytotoxic anticancer drugs, together with management procedures, are discussed at length in Chapter 101. Therefore, as we consider individual anticancer agents in this chapter, discussion of most toxicities is brief.



Dosage, handling, and administration


Cancer chemotherapy is a highly specialized field. Accordingly, in a general text such as this, presentation of detailed information on dosage and administration of specific agents seems inappropriate. However, be aware that dosages for anticancer agents must be individualized and that timing of administration may vary with the particular protocol being followed. Also, because of the complex and hazardous nature of cancer chemotherapy, anticancer drugs should be administered under the direct supervision of a clinican experienced in their use.





Administering vesicants.

As discussed in Chapter 101, extravasation of vesicants can cause severe local injury, sometimes requiring surgical débridement and skin grafting. Drugs with strong vesicant properties include carmustine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, mechlorethamine, mitomycin, plicamycin, streptozocin, vinblastine, and vincristine. To minimize the risk of injury, IV administration should be performed only into a vein with good flow. Sites of previous irradiation should be avoided. If extravasation occurs, the infusion should be discontinued immediately.



Alkylating agents


The family of alkylating agents consists of nitrogen mustards, nitrosoureas, and other compounds. Before considering the properties of individual alkylating agents, we discuss the characteristics of the group as a whole. The alkylating agents are listed in Table 102–1.



Shared properties




Mechanism of action.

The alkylating agents are highly reactive compounds that can transfer an alkyl group to various cell constituents. Cell kill results primarily from alkylation of DNA. As a rule, alkylating agents interact with DNA by forming a covalent bond with a specific nitrogen atom in guanine (Fig. 102–1).


image
Figure 102–1  Cross-linking of DNA by an alkylating agent.
A, Reactions leading to cross-linkage between guanine moieties in DNA. B, Schematic representation of interstrand cross-linking within the DNA double helix. (A = adenine, C = cytosine, G = guanine, T = thymine.)

Some alkylating agents have two reactive sites, whereas others have only one. Alkylating agents with two reactive sites (bifunctional agents) are able to bind DNA in two places to form cross-links. These bridges may be formed within a single DNA strand or between parallel DNA strands. Figure 102–1 illustrates the production of interstrand cross-links by nitrogen mustard. Alkylating agents with only one reactive site (monofunctional agents) lack the ability to form cross-links, but can still bind to a single guanine in DNA.


The consequences of guanine alkylation are miscoding, scission of DNA strands, and, if cross-links have been formed, inhibition of DNA replication. Because cross-linking of DNA is especially injurious, cell death is more likely with bifunctional agents than with monofunctional agents.


Because alkylation reactions can take place at any time during the cell cycle, alkylating agents are considered cell-cycle phase nonspecific. However, most of these drugs are more toxic to dividing cells—especially cells that divide rapidly—than they are to cells in G0. Why? Because (1) alkylation of DNA produces its most detrimental effects when cells attempt to replicate DNA, and (2) quiescent cells are often able to repair damage to DNA before it can affect cell function. Because alkylating agents are phase nonspecific, they needn’t be present over an extended time. Accordingly, they can be administered by bolus dosing, rather than by prolonged infusion.





Properties of individual alkylating agents



Nitrogen mustards


Cyclophosphamide.

Cyclophosphamide, formerly available as Cytoxan and Neosar, is a bifunctional alkylating agent active against a broad spectrum of neoplastic diseases. Indications include Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma, and solid tumors of the head, neck, ovary, and breast. Of all the alkylating agents, cyclophosphamide is employed most widely.


Cyclophosphamide is a prodrug that undergoes conversion to its active form in the liver. Because activation is required, onset of effects is delayed. Cyclophosphamide is not a vesicant, and hence can be administered PO as well as IV. Oral doses should be administered with food.


The major dose-limiting toxicity is bone marrow suppression. Severe nausea, vomiting, and alopecia are also common, especially at high doses. In addition, the drug can cause acute hemorrhagic cystitis; bladder injury and associated bleeding can be minimized by (1) maintaining adequate hydration, and (2) giving a protective agent called mesna [Mesnex] when high-dose cyclophosphamide is employed. Other adverse effects include sterility, immunosuppression, and hypersensitivity reactions.









Bendamustine.


Bendamustine [Treanda], approved in 2008, is a derivative of mechlorethamine, and may be better tolerated. The drug has two indications: chronic lymphocytic leukemia and non-Hodgkin’s lymphoma. Administration is IV. As with mechlorethamine, the dose-limiting toxicity is bone marrow suppression. Nausea and vomiting are common. Some patients experience an infusion reaction, characterized by fever, hypotension, chills, rigors, and myalgias. There have been postmarketing reports of serious skin reactions, including bullous exanthema and toxic epidermal necrolysis. However, a causal relationship has not been established. Nonetheless, if a severe skin reaction occurs, bendamustine should be withheld or discontinued. Fluvoxamine [Luvox] and other drugs that inhibit CYP1A2 (the 1A2 isozyme of cytochrome P450) may raise bendamustine levels, whereas carbamazepine [Tegretol] and other drugs that induce CYP1A2 may reduce bendamustine levels.





Ifosfamide.


Ifosfamide [Ifex], a derivative of cyclophosphamide, is approved for refractory germ cell testicular cancer, and is used off-label against many other tumors, including Hodgkin’s and non-Hodgkin’s lymphomas, non–small cell and small cell lung cancer, and head and neck cancer. Dose-limiting toxicities are bone marrow suppression and hemorrhagic cystitis. The risk of cystitis is minimized by concurrent therapy with mesna [Mesnex] and by extensive hydration (at least 2 L of oral or IV fluid daily). Owing to the risk of cystitis, urinalysis should be performed before each dose. If the analysis reveals microscopic hematuria, dosing should be postponed until hematuria resolves. Additional adverse effects include nausea, vomiting, metabolic acidosis, and central nervous system (CNS) toxicity (confusion, hallucinations, blurred vision, coma). Severe adverse effects are most likely in patients receiving high-dose therapy and in those with renal failure. Administration is IV.




Nitrosoureas

The nitrosoureas are bifunctional alkylating agents, and are active against a broad spectrum of neoplastic diseases. Cell kill results from cross-linking DNA. Unlike many anticancer drugs, the nitrosoureas are highly lipophilic, and hence can readily penetrate the blood-brain barrier. As a result, these drugs are especially useful against cancers of the CNS. The major dose-limiting toxicity is delayed bone marrow suppression.



Carmustine (BCNU).

Carmustine [BiCNU, Gliadel] was the first nitrosourea to undergo extensive clinical testing and can be considered the prototype for the group. Owing to its ability to cross the blood-brain barrier, carmustine is especially useful against primary and metastatic tumors of the brain. Other indications include Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma, malignant melanoma, hepatoma, and adenocarcinoma of the stomach, colon, and rectum. The principal dose-limiting toxicity is delayed bone marrow suppression; leukocyte and platelet nadirs occur 4 to 6 weeks after treatment. Nausea and vomiting can be severe. Injury to the liver and kidneys has been reported. High cumulative doses may cause pulmonary fibrosis. Accordingly, if pulmonary function begins to decline, corticosteroids should be given to prevent fibrosis.


Administration may be topical or IV. Topical administration is done by implanting a biodegradable, carmustine-impregnated wafer [Gliadel] into the cavity created by surgical removal of a brain tumor. This technique has the obvious benefit of concentrating the drug where it is most needed. When administered IV, carmustine can cause local phlebitis and extravasation injury, even though it is not a vesicant.










Other alkylating agents




Temozolomide. 







Platinum compounds


The platinum-containing anticancer drugs—cisplatin, carboplatin, and oxaliplatin—are similar to the alkylating agents, and often classified as such. Like the bifunctional alkylating agents, the platinum compounds produce cross-links in DNA, and hence are cell-cycle phase nonspecific.




Cisplatin

Cisplatin, formerly available as Platinol-AQ, kills cells primarily by forming cross-links between and within strands of DNA. The drug is approved only for metastatic testicular and ovarian cancers and advanced bladder cancer. Nonetheless, it is used off-label as a component in standard-of-care regimens for lung cancer and head and neck cancer. The major dose-limiting toxicity is kidney damage, which can be minimized by extensive hydration coupled with diuretic therapy and amifostine [Ethyol]. Cisplatin is highly emetogenic; nausea and vomiting begin about 1 hour after dosing and can persist for several days. Other adverse effects include clinically important peripheral neuropathy, mild to moderate bone marrow suppression, kidney damage, and ototoxicity, which manifests as tinnitus and high-frequency hearing loss. The drug is given by IV infusion.






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Jul 24, 2016 | Posted by in NURSING | Comments Off on Anticancer drugs I: cytotoxic agents

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