Anticancer Drugs: ANTIBIOTICS
Focus topic: Anticancer Drugs
The antitumor antibiotics owe their cytotoxic action primarily to their interactions with DNA, leading to disruption of DNA function. In addition to intercalation, their abilities to inhibit topoisomerases (I and II) and produce free radicals also play a major role in their cytotoxic effect. They are cell cycle nonspecific with bleomycin as an exception.
A. Anthracyclines: Doxorubicin, daunorubicin, idarubicin, epirubicin, and mitoxantrone
Doxorubicin [dox-oh-ROO-bi-sin] and daunorubicin [daw-noe-ROObi-sin] are classified as anthracycline antibiotics. Doxorubicin is the Nhydroxylated analog of daunorubicin. Idarubicin [eye-da-ROO-bi-sin], the 4-demethoxy analog of daunorubicin, epirubicin [eh-pee-ROObih-sin], and mitoxantrone [mye-toe-ZAN-trone] are also available. Applications for these agents differ despite their structural similarity and their apparently similar mechanisms of action. Doxorubicin is one of the most important and widely used anticancer drugs. It is used in combination with other agents for treatment of sarcomas and a variety of carcinomas, including breast and lung, as well as for treatment of acute lymphocytic leukemia and lymphomas. Daunorubicin and idarubicin are used in the treatment of acute leukemias, and mitoxantrone is used in prostate cancer.
1. Mechanism of action: Doxorubicin and other anthracyclines induce cytotoxicity through several different mechanisms. For example, doxorubicin-derived free radicals can induce membrane lipid peroxidation, DNA strand scission, and direct oxidation of purine or pyrimidine bases, thiols, and amines.
2. Pharmacokinetics: All these drugs must be administered IV, because they are inactivated in the GI tract. Extravasation is a serious problem that can lead to tissue necrosis. The anthracycline antibiotics bind to plasma proteins as well as to other tissue components, where they are widely distributed. They do not penetrate the blood–brain barrier or the testes. These agents undergo extensive hepatic metabolism, and dosage adjustments are needed in patients with impaired hepatic function. Biliary excretion is the major route of elimination. Some renal excretion also occurs, but dosage adjustments are generally not needed in renal dysfunction. Because of the dark red color of the anthracycline drugs, the veins may become visible surrounding the site of infusion, and red discoloration of urine may occur.
3. Adverse effects: Irreversible, dose-dependent cardiotoxicity, apparently a result of the generation of free radicals and lipid peroxidation, is the most serious adverse reaction and is more common with daunorubicin and doxorubicin than with idarubicin and epirubicin. Addition of trastuzumab to protocols with doxorubicin or epirubicin increases congestive heart failure. There has been some success with the iron chelator dexrazoxane in protecting against the cardiotoxicity of doxorubicin. The liposomal-encapsulated doxorubicin is reported to be less cardiotoxic than the usual formulation.
Bleomycin [blee-oh-MYE-sin] is a mixture of different copper-chelating glycopeptides that, like the anthracycline antibiotics, cause scission of DNA by an oxidative process. Bleomycin is cell cycle specific and causes cells to accumulate in the G2 phase. It is primarily used in the treatment of testicular cancers and Hodgkin lymphoma.
- Mechanism of action: A DNA–bleomycin–Fe2+ complex appears to undergo oxidation to bleomycin–Fe3+. The liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which, in turn, attack the phosphodiester bonds of DNA, resulting in strand breakage and chromosomal aberrations.
- Resistance: Although the mechanisms of resistance have not been elucidated, increased levels of bleomycin hydrolase (or deaminase), glutathione S-transferase, and possibly, increased efflux of the drug have been implicated. DNA repair also may contribute.
- Pharmacokinetics: Bleomycin is administered by a number of routes. The bleomycin-inactivating enzyme (a hydrolase) is high in a number of tissues (for example, liver and spleen) but is low in the lung and is absent in skin (accounting for the drug’s toxicity in those tissues). Most of the parent drug is excreted unchanged in the urine, necessitating dose adjustment in patients with renal failure.
- Adverse effects: Mucocutaneous reactions and alopecia are common. Hypertrophic skin changes and hyperpigmentation of the hands are prevalent. There is a high incidence of fever and chills and a low incidence of serious anaphylactoid reactions. Pulmonary toxicity is the most serious adverse effect, progressing from rales, cough, and infiltrate to potentially fatal fibrosis. The pulmonary fibrosis that is caused by bleomycin is often referred as “bleomycin lung.” Bleomycin is unusual in that myelosuppression is rare.
Anticancer Drugs: ALKYLATING AGENTS
Focus topic: Anticancer Drugs
Alkylating agents exert their cytotoxic effects by covalently binding to nucleophilic groups on various cell constituents. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cells. Alkylating agents do not discriminate between cycling and resting cells, even though they are most toxic for rapidly dividing cells. They are used in combination with other agents to treat a wide variety of lymphatic and solid cancers. In addition to being cytotoxic, all are mutagenic and carcinogenic and can lead to secondary malignancies such as acute leukemia.
A. Cyclophosphamide and ifosfamide
These drugs are very closely related mustard agents that share most of the same primary mechanisms and toxicities. They are cytotoxic only after generation of their alkylating species, which are produced through hydroxylation by cytochrome P450 (CYP450). These agents have a broad clinical spectrum, being used either singly or as part of a regimen in the treatment of a wide variety of neoplastic diseases, such as non-Hodgkin lymphoma, sarcoma, and breast cancer.
- Mechanism of action: Cyclophosphamide [sye-kloe-FOSS-fah-mide] is the most commonly used alkylating agent. Both cyclophosphamide and ifosfamide [eye-FOSS-fah-mide] are first biotransformed to hydroxylated intermediates primarily in the liver by the CYP450 system.The hydroxylated intermediates then undergo breakdown to form the active compounds, phosphoramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. The parent drug and its metabolites are primarily excreted in urine.
- Pharmacokinetics: Cyclophosphamide is available in oral or IV preparations, whereas ifosfamide is IV only. Cyclophosphamide is metabolized in the liver to active and inactive metabolites, and minimal amounts are excreted in the urine as unchanged drug. Ifosfamide is metabolized primarily by CYP450 3A4 and 2B6 isoenzymes. It is mainly renally excreted.
- Resistance: Resistance results from increased DNA repair, decreased drug permeability, and reaction of the drug with thiols (for example, glutathione). Cross-resistance does not always occur.
- Adverse effects: A unique toxicity of both drugs is hemorrhagic cystitis, which can lead to fibrosis of the bladder. Bladder toxicity has been attributed to acrolein in the urine in the case of cyclophosphamide and to toxic metabolites of ifosfamide. Adequate hydration as well as IV injection of mesna (sodium 2-mercaptoethane sulfonate), which neutralizes the toxic metabolites, can minimize this problem. A fairly high incidence of neurotoxicity has been reported in patients on high-dose ifosfamide, probably due to the metabolite, chloroacetaldehyde.
Carmustine [KAR-mus-teen, BCNU] and lomustine [LOE-mus-teen, CCNU] are closely related nitrosoureas. Because of their ability to penetrate the CNS, the nitrosoureas are primarily employed in the treatment of brain tumors.
- Mechanism of action: The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and, eventually, RNA and protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed primarily on cells that are actively dividing. Therefore, nondividing cells can escape death if DNA repair occurs. Nitrosoureas also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins in the targeted cells.
- Pharmacokinetics: In spite of the similarities in their structures, carmustine is administered IV and as chemotherapy wafer implants, whereas lomustine is given orally. Because of their lipophilicity, they distribute widely in the body, but their most striking property is their ability to readily penetrate the CNS. The drugs undergo extensive metabolism. Lomustine is metabolized to active products. The kidney is the major excretory route for the nitrosoureas.
Dacarbazine [dah-KAR-bah-zeen] is an alkylating agent that must undergo biotransformation to an active metabolite, methyltriazenoimidazole carboxamide (MTIC). This metabolite is responsible for the drug’s activity as an alkylating agent by forming methylcarbonium ions that can attack the nucleophilic groups in the DNA molecule. Thus, similar to other alkylating agents, the cytotoxic action of dacarbazine has been attributed to the ability of its metabolite to methylate DNA on the O6 position of guanine. Dacarbazine has found use in the treatment of melanoma and Hodgkin lymphoma.
The treatment of tumors in the brain is particularly difficult. Temozolomide [te-moe-ZOE-loe-mide], a triazene agent, has been approved for use against glioblastomas and anaplastic astrocytomas. It is also used in metastatic melanoma. Temozolomide is related to dacarbazine, because both must undergo biotransformation to an active metabolite, MTIC, which probably is responsible for the methylation of DNA on the 6 position of guanine. Unlike dacarbazine, temozolomide does not require the CYP450 system for metabolic transformation, and it undergoes chemical transformation at normal physiological pH. Temozolomide also has the property of inhibiting the repair enzyme, O6-guanine-DNA alkyltransferase. Temozolomide differs from dacarbazine in that it crosses the blood–brain barrier. Temozolomide is administered intravenously or orally and has excellent bioavailability after oral administration. The parent drug and metabolites are excreted in urine.
E. Other alkylating agents
Mechlorethamine [mek-lor-ETH-ah-meen] was developed as a vesicant (nitrogen mustard) during World War I. Its ability to cause lymphocytopenia led to its use in lymphatic cancers. Melphalan [MELfah-lan], a phenylalanine derivative of nitrogen mustard, is used in the treatment of multiple myeloma. This is a bifunctional alkylating agent that can be given orally. Although melphalan can be given orally, the plasma concentration differs from patient to patient due to variation in intestinal absorption and metabolism. The dose of melphalan is carefully adjusted by monitoring the platelet and white blood cell counts. Chlorambucil [clor-AM-byoo-sil] is another bifunctional alkylating agent that is used in the treatment of chronic lymphocytic leukemia. Both melphalan and chlorambucil have moderate hematologic toxicities and upset the GI tract. Busulfan [byoo-SUL-fan] is another oral agent that is effective against chronic granulocytic leukemia. In aged patients, busulfan can cause pulmonary fibrosis (“busulfan lung”). Like other alkylating agents, all of these agents are leukemogenic.
Anticancer Drugs: MICROTUBULE INHIBITORS
Focus topic: Anticancer Drugs
The mitotic spindle is part of a larger, intracellular skeleton (cytoskeleton) that is essential for the movements of structures occurring in the cytoplasm of all eukaryotic cells. The mitotic spindle consists of chromatin plus a system of microtubules composed of the protein tubulin. The mitotic spindle is essential for the equal partitioning of DNA into the two daughter cells that are formed when a eukaryotic cell divides. Several plant-derived substances used as anticancer drugs disrupt this process by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules, thereby causing cytotoxicity.
A. Vincristine and vinblastine
Vincristine [vin-KRIS-teen] (VX) and vinblastine [vin-BLAS-teen] (VBL) are structurally related compounds derived from the periwinkle plant, Vinca rosea. They are, therefore, referred to as the Vinca alkaloids. A less neurotoxic agent is vinorelbine [vye-NOR-el-been] (VRB). Although the Vinca alkaloids are structurally similar to one another, their therapeutic indications are different. They are generally administered in combination with other drugs. VX is used in the treatment of acute lymphoblastic leukemia in children, Wilms tumor, Ewing soft tissue sarcoma, and Hodgkin and non-Hodgkin lymphomas, as well as some other rapidly proliferating neoplasms. [Note: VX (former trade name, Oncovin) is the “O” in the R-CHOP regimen for lymphoma. Due to relatively mild myelosuppressive activity, VX is used in a number of other protocols.] VBL is administered with bleomycin and cisplatin for the treatment of metastatic testicular carcinoma. It is also used in the treatment of systemic Hodgkin and non-Hodgkin lymphomas. VRB is beneficial in the treatment of advanced non–small cell lung cancer, either as a single agent or with cisplatin.
- Mechanism of action: VX, VRB, and VBL are all cell cycle specific and phase specific, because they block mitosis in metaphase (M-phase). Their binding to the microtubular protein, tubulin, blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation.
- Pharmacokinetics: IV injection of these agents leads to rapid cytotoxic effects and cell destruction. This, in turn, can cause hyperuricemia due to the oxidation of purines that are released from fragmenting DNA molecules. The Vinca alkaloids are concentrated and metabolized in the liver by the CYP450 pathway and eliminated in bile and feces. Doses must be modified in patients with impaired hepatic function or biliary obstruction.
- Adverse effects: VX and VBL have certain toxicities in common. These include phlebitis or cellulitis, if the drugs extravasate during injection, as well as nausea, vomiting, diarrhea, and alopecia. However, the adverse effects of VX and VBL are not identical. VBL is a more potent myelosuppressant than VX, whereas peripheral neuropathy (paresthesias, loss of reflexes, foot drop, and ataxia) is associated with VX. Constipation is more frequently encountered with VX. These agents should not be administered intrathecally. This potential drug error can result in death, and special precautions should be in place for administration.
B. Paclitaxel and docetaxel
Paclitaxel [PAK-li-tax-el] was the first member of the taxane family to be used in cancer chemotherapy. A semisynthetic paclitaxel is now available through chemical modification of a precursor found in the needles of Pacific yew species. An albumin-bound form is also available. Substitution of a side chain has resulted in docetaxel [doe-see-TAX-el], which is the more potent of the two drugs. Paclitaxel has shown good activity against advanced ovarian cancer and metastatic breast cancer. Favorable results have been obtained in non–small cell lung cancer when administered with cisplatin. Docetaxel is commonly used in prostate, breast, GI, and non–small cell lung cancers.
- Mechanism of action: Both drugs are active in the G2/M-phase of the cell cycle, but unlike the Vinca alkaloids, they promote polymerization and stabilization of the polymer rather than disassembly, leading to the accumulation of microtubules. The overly stable microtubules formed are nonfunctional, and chromosome desegregation does not occur. This results in death of the cell.
- Pharmacokinetics: These agents undergo hepatic metabolism by the CYP450 system and are excreted via the biliary system. Dose modification is not required in patients with renal impairment, but doses should be reduced in patients with hepatic dysfunction.
- Adverse effects: The dose-limiting toxicities of paclitaxel and docetaxel are neutropenia and leukopenia. Alopecia occurs, but vomiting and diarrhea are uncommon. [Note: Because of serious hypersensitivity reactions (including dyspnea, urticaria, and hypotension), patients who are treated with paclitaxel should be premedicated with dexamethasone and diphenhydramine, as well as with an H2 blocker.]
Anticancer Drugs: STEROID HORMONES AND THEIR ANTAGONISTS
Focus topic: Anticancer Drugs
Tumors that are steroid hormone sensitive may be either 1) hormone responsive, in which the tumor regresses following treatment with a specific hormone; or 2) hormone dependent, in which removal of a hormonal stimulus causes tumor regression; or 3) both. Removal of hormonal stimuli from hormone-dependent tumors can be accomplished by surgery (for example, in the case of orchiectomy—surgical removal of one or both testes—for patients with advanced prostate cancer) or by drugs (for example, in breast cancer, for which treatment with the antiestrogen tamoxifen is used to prevent estrogen stimulation of breast cancer cells; For a steroid hormone to influence a cell, that cell must have intracellular (cytosolic) receptors that are specific for that hormone.
Prednisone [PRED-ni-sone] is a potent, synthetic, anti-inflammatory corticosteroid with less mineralocorticoid activity than cortisol. [Note: At high doses,cortisol is lymphocytolytic and leads to hyperuricemia due to the breakdown of lymphocytes.] Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin and non-Hodgkin lymphomas. Prednisone is readily absorbed orally. Like other glucocorticoids, it is bound to plasma albumin and transcortin. Prednisone itself is inactive and must first undergo 11-β-hydroxylation to prednisolone in the liver. Prednisolone is the active drug. This steroid then binds to a receptor that triggers the production of specific proteins. The latter is glucuronidated and excreted in urine along with the parent compound.
Tamoxifen [tah-MOX-ih-fen] is an estrogen antagonist with some estrogenic activity, and it is classified as a selective estrogen receptor modulator (SERM). It is used for first-line therapy in the treatment of estrogen receptor–positive breast cancer. It also finds use prophylactically in reducing breast cancer occurrence in women who are at high risk. However, because of possible stimulation of premalignant lesions due to its estrogenic properties, patients should be closely monitored during therapy.
- Mechanism of action: Tamoxifen binds to estrogen receptors in the breast tissue, but the complex is unable to translocate into the nucleus for its action of initiating transcriptions. That is, the complex fails to induce estrogen-responsive genes, and RNA synthesis does not ensue. The result is a depletion (down-regulation) of estrogen receptors, and the growth-promoting effects of the natural hormone and other growth factors are suppressed. [Note: Estrogen competes with tamoxifen. Therefore, in premenopausal women, the drug is used with a gonadotropin-releasing hormone (GnRH) analog such as leuprolide, which lowers estrogen levels.]
- Pharmacokinetics: Tamoxifen is effective after oral administration. It is partially metabolized by the liver. Some metabolites possess antagonist activity, whereas others have agonist activity. Unchanged drug and metabolites are excreted predominantly through the bile into the feces. Tamoxifen is an inhibitor of CYP3A4 and P-glycoprotein.
- Adverse effects: Side effects caused by tamoxifen include hot flashes, nausea, vomiting, skin rash, and vaginal bleeding and discharge (due to estrogenic activity of the drug and some of its metabolites). Hypercalcemia may occur, requiring cessation of the drug. Tamoxifen can also lead to increased pain if the tumor has metastasized to bone. Tamoxifen has the potential to cause endometrial cancer. Other toxicities include thromboembolism and effects on vision. [Note: Because of a more favorable adverse effect profile, aromatase inhibitors are making an impact in the treatment of breast cancer.]
C. Fulvestrant and raloxifene
Fulvestrant [fool-VES-trant] and raloxifene [ral-OKS-i-feen] are two agents that interact with the estrogen receptor to prevent some of the downstream effects. Fulvestrant is an estrogen receptor antagonist that is given via intramuscular injection to patients with hormone receptor–positive metastatic breast cancer. This agent binds to and causes estrogen receptor down-regulation on tumors and other targets. Raloxifene is a SERM given orally that acts to block estrogen effects in the uterine and breast tissues, while promoting effects in the bone to inhibit resorption. This agent has been shown to reduce the risk of estrogen receptor–positive invasive breast cancer in postmenopausal women. These agents are known to cause hot flashes, arthralgias, and myalgias.
D. Aromatase inhibitors
The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from androstenedione, which takes place in liver, fat, muscle, skin, and breast tissues, including breast malignancies. Peripheral aromatization is an important source of estrogen in postmenopausal women. Aromatase inhibitors decrease the production of estrogen in these women.
- Anastrozole and letrozole: The imidazole aromatase inhibitors, such as anastrozole [an-AS-troe-zole] and letrozole [LE-troe-zole], are nonsteroidal aromatase inhibitors. They do not predispose patients to endometrial cancer and are devoid of the androgenic side effects that occur with the steroidal aromatase inhibitors such as aminoglutethimide. Although anastrozole and letrozole are considered second-line therapy after tamoxifen for hormone dependent
breast cancer in the United States, they have become first-line drugs in other countries for the treatment of breast cancer in postmenopausal women. They are orally active and cause almost a total suppression of estrogen synthesis. Both drugs are extensively metabolized in the liver, and metabolites and parent drug are excreted primarily in the urine.
- Exemestane: A steroidal, irreversible inhibitor of aromatase, exemestane [ex-uh-MES-tane], is orally well absorbed and widely distributed. Hepatic metabolism is by the CYP3A4 isoenzyme. Because the metabolites are excreted in urine, doses of the drug must be adjusted in patients with renal failure. Its major toxicities are nausea, fatigue, and hot flashes. Alopecia and dermatitis have also been noted.
Megestrol [me-JESS-trole] acetate is a progestin that was widely used in treating metastatic hormone-responsive breast and endometrial neoplasms. It is orally effective. Other agents are usually compared to it in clinical trials; however, the aromatase inhibitors are replacing it in therapy.
F. Leuprolide, goserelin, and triptorelin
GnRH is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones: 1) luteinizing hormone (LH), the primary stimulus for the secretion of testosterone by the testes, and 2) follicle-stimulating hormone (FSH), which stimulates the secretion of estrogen. Leuprolide [loo-PROE-lide], goserelin [GOE-se-rel-in], and triptorelin [TRIP-to-rel-in] are synthetic analogs of GnRH. As GnRH analogs, they occupy the GnRH receptor in the pituitary, which leads to its desensitization and, consequently, inhibition of release of FSH and LH. Thus, both androgen and estrogen syntheses are reduced. Response to leuprolide in prostatic cancer is equivalent to that of orchiectomy with regression of tumor and relief of bone pain. These drugs have some benefit in premenopausal women with advanced breast cancer and have largely replaced estrogens in therapy for prostate cancer. Leuprolide is available as 1) a sustained-release intradermal implant, 2) a subcutaneous depot injection, or 3) an intramuscular depot injection to treat metastatic carcinoma of the prostate. Goserelin acetate is a subcutaneous implant, and triptorelin pamoate is injected intramuscularly. Levels of androgen may initially rise but then fall to castration levels. The adverse effects of these drugs, including impotence, hot flashes, and tumor flare, are minimal compared to those experienced with estrogen treatment.
Estrogens, such as ethinyl estradiol, had been used in the treatment of prostatic cancer. However, they have been largely replaced by the GnRH analogs because of fewer adverse effects. Estrogens inhibit the growth of prostatic tissue by blocking the production of LH, thereby decreasing the synthesis of androgens in the testis. Thus, tumors that are dependent on androgens are affected. Estrogen treatment can cause serious complications, such as thromboemboli, myocardial infarction, strokes, and hypercalcemia. Men who are taking estrogens may experience gynecomastia and impotence.
H. Flutamide, nilutamide, and bicalutamide
Flutamide [FLOO-tah-mide], nilutamide [nye-LOO-ta-mide], and bicalutamide [bye-ka-LOO-ta-mide] are synthetic, nonsteroidal antiandrogens used in the treatment of prostate cancer. They compete with the natural hormone for binding to the androgen receptor and prevent its translocation into the nucleus. These antiandrogens are taken orally and are cleared through the kidney. [Note: Flutamide requires dosing three times a day and the others once a day.] Side effects include gynecomastia and GI distress. Rarely, liver failure has occurred with flutamide. Nilutamide can cause visual problems.