It is estimated that over 25% of the population of the United States will face a diagnosis of cancer during their lifetime, with more than 1.6 million new cancer patients diagnosed each year. Less than a quarter of these patients will be cured solely by surgery and/or local radiation. Most of the remainder will receive systemic chemotherapy at some time during their illness. In a small fraction (approximately 10%) of patients with cancer representing selected neoplasms, the chemotherapy will result in a cure or a prolonged remission. However, in most cases, the drug therapy will produce only a regression of the disease, and complications and/or relapse may eventually lead to death. Thus, the overall 5-year survival rate for cancer patients is about 68%, ranking cancer second only to cardiovascular disease as a cause of mortality.
Anticancer Drugs: PRINCIPLES OF CANCER CHEMOTHERAPY
Focus topic: Anticancer Drugs
Cancer chemotherapy strives to cause a lethal cytotoxic event or apoptosis in the cancer cells that can arrest a tumor’s progression. The attack is generally directed toward DNA or against metabolic sites essential to cell replication, for example, the availability of purines and pyrimidines, which are the building blocks for DNA or RNA synthesis. Ideally, these anticancer drugs should interfere only with cellular processes that are unique to malignant cells. Unfortunately, most currently available anticancer drugs do not specifically recognize neoplastic cells but, rather, affect all kinds of proliferating cells, both normal and abnormal. Therefore, almost all antitumor agents have a steep dose–response curve for both therapeutic and toxic effects.
A. Treatment strategies
1. Goals of treatment: The ultimate goal of chemotherapy is a cure (that is, long-term, disease-free survival). A true cure requires the eradication of every neoplastic cell. If a cure is not attainable, then the goal becomes control of the disease (stop the cancer from enlarging and spreading) to extend survival and maintain the best quality of life. Thus, the individual maintains a “near-normal” existence, with the cancer being treated as a chronic disease. In either case, the neoplastic cell burden is initially reduced (debulked), either by surgery and/or by radiation, followed by chemotherapy, immunotherapy, therapy using biological modifiers, or a combination of these treatment modalities. In advanced stages of cancer, the likelihood of controlling the cancer is far from reality and the goal is palliation (alleviation of symptoms and avoidance of life-threatening toxicity). This means that chemotherapeutic drugs may be used to relieve symptoms caused by the cancer and improve the quality of life, even though the drugs may not extend survival. The goal of treatment should always be kept in mind, as it often influences treatment decisions.
2. Indications for treatment: Chemotherapy is sometimes used when neoplasms are disseminated and are not amenable to surgery. Chemotherapy may also be used as a supplemental treatment to attack micrometastases following surgery and radiation treatment, in which case it is called adjuvant chemotherapy. Chemotherapy given prior to the surgical procedure in an attempt to shrink the cancer is referred to as neoadjuvant chemotherapy, and chemotherapy given in lower doses to assist in prolonging a remission is known as maintenance chemotherapy.
3. Tumor susceptibility and the growth cycle: The fraction of tumor cells that are in the replicative cycle (“growth fraction”) influences their susceptibility to most cancer chemotherapeutic agents. Rapidly dividing cells are generally more sensitive to chemotherapy, whereas slowly proliferating cells are less sensitive to chemotherapy. In general, non-dividing cells (those in the G0 phase;
- Cell cycle specificity of drugs: Both normal cells and tumor cells go through growth cycles. However, the number of cells that are in various stages of the cycle may differ in normal and neoplastic tissues. Chemotherapeutic agents that are effective only against replicating cells (that is, those cells that are dividing) are said to be cell cycle specific, whereas other agents are said to be cell cycle nonspecific. The nonspecific drugs, although having generally more toxicity in cycling cells, are also useful against tumors that have a low percentage of replicating cells.
- Tumor growth rate: The growth rate of most solid tumors in vivo is initially rapid, but growth rate usually decreases as the tumor size increases. This is due to the unavailability of nutrients and oxygen caused by inadequate vascularization and lack of blood circulation. Tumor burden can be reduced through surgery, radiation, or by using cell cycle–nonspecific drugs to promote the remaining cells into active proliferation, thus increasing their susceptibility to cell cycle– specific chemotherapeutic agents.
B. Treatment regimens and scheduling
Drug dosages are usually calculated on the basis of body surface area, in an effort to tailor the medications to each patient.
1. Log kill phenomenon: Destruction of cancer cells by chemotherapeutic agents follows first-order kinetics (that is, a given dose of drug destroys a constant fraction of cells). The term “log kill” is used to describe this phenomenon. For example, a diagnosis of leukemia is generally made when there are about 109 (total) leukemic cells. Consequently, if treatment leads to a 99.999-percent kill, then 0.001% of 109 cells (or 104 cells) would remain. This is defined as a 5-log kill (reduction of 105 cells). At this point, the patient will become asymptomatic, and the patient is in remission. For most bacterial infections, a 5-log (100,000- fold) reduction in the number of microorganisms results in a cure, because the immune system can destroy the remaining bacterial cells. However, tumor cells are not as readily eliminated, and additional treatment is required to totally eradicate the leukemic cell population.
2. Pharmacologic sanctuaries: Leukemic or other tumor cells find sanctuary in tissues such as the central nervous system (CNS), where transport constraints prevent certain chemotherapeutic agents from entering. Therefore, a patient may require irradiation of the craniospinal axis or intrathecal administration of drugs to eliminate the leukemic cells at that site. Similarly, drugs may be unable to penetrate certain areas of solid tumors.
3. Treatment protocols: Combination drug chemotherapy is more successful than single-drug treatment in most of the cancers for which chemotherapy is effective.
- Combinations of drugs: Cytotoxic agents with qualitatively different toxicities, and with different molecular sites and mechanisms of action, are usually combined at full doses. This results in higher response rates, due to additive and/or potentiated cytotoxic effects, and nonoverlapping host toxicities. In contrast, agents with similar dose-limiting toxicities, such as myelosuppression, nephrotoxicity, or cardiotoxicity, can be combined safely only by reducing the doses of each.
- Advantages of drug combinations: The advantages of such drug combinations are that they 1) provide maximal cell killing within the range of tolerated toxicity, 2) are effective against a broader range of cell lines in the heterogeneous tumor population, and 3) may delay or prevent the development of resistant cell lines.
- Treatment protocols: Many cancer treatment protocols have been developed, and each one is applicable to a particular neoplastic state. They are usually identified by an acronym. For example, a common regimen called R-CHOP, used for the treatment of non-Hodgkin lymphoma, consists of rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and prednisone or prednisolone. Therapy is scheduled intermittently (approximately 21 days apart) to allow recovery or rescue of the patient’s immune system, which is also affected by the chemotherapeutic agents, thus reducing the risk of serious infection.
C. Problems associated with chemotherapy
Cancer drugs are toxins that present a lethal threat to the cells. It is, therefore, not surprising that cells have evolved elaborate defense mechanisms to protect themselves from chemical toxins, including chemotherapeutic agents.
1. Resistance: Some neoplastic cells (for example, melanoma) are inherently resistant to most anticancer drugs. Other tumor types may acquire resistance to the cytotoxic effects of a medication by mutating, particularly after prolonged administration of suboptimal drug doses. The development of drug resistance is minimized by short-term, intensive, intermittent therapy with combinations of drugs. Drug combinations are also effective against a broader range of resistant cells in the tumor population.
2. Multidrug resistance: Stepwise selection of an amplified gene that codes for a transmembrane protein (P-glycoprotein for “permeability” glycoprotein;This resistance is due to adenosine triphosphate–dependent pumping of drugs out of the cell in the presence of P-glycoprotein. Cross-resistance following the use of structurally unrelated agents also occurs. For example, cells that are resistant to the cytotoxic effects of the Vinca alkaloids are also resistant to dactinomycin and to the anthracycline antibiotics, as well as to colchicine, and vice versa. These drugs are all naturally occurring substances, each of which has a hydrophobic aromatic ring and a positive charge at neutral pH. [Note: P-glycoprotein is normally expressed at low levels in most cell types, but higher levels are found in the kidney, liver, pancreas, small intestine, colon, and adrenal gland. It has been suggested that the presence of P-glycoprotein may account for the intrinsic resistance to chemotherapy observed with adenocarcinomas.] Certain drugs at high concentrations (for example, verapamil) can inhibit the pump and, thus, interfere with the efflux of the anticancer agent. However, these drugs are undesirable because of adverse pharmacologic actions of their own. Pharmacologically inert pump blockers are being sought.
3. Toxicity: Therapy aimed at killing rapidly dividing cancer cells also affects normal cells undergoing rapid proliferation (for example, cells of the buccal mucosa, bone marrow, gastrointestinal [GI] mucosa, and hair follicles), contributing to the toxic manifestations of chemotherapy.
- Common adverse effects: Most chemotherapeutic agents have a narrow therapeutic index. Severe vomiting, stomatitis, bone marrow suppression, and alopecia occur to a lesser or greater extent during therapy with all antineoplastic agents. Vomiting is often controlled by administration of antiemetic drugs. Some toxicities, such as myelosuppression that predisposes to infection, are common to many chemotherapeutic agents, whereas other adverse reactions are confined to specific agents, such as bladder toxicity with cyclophosphamide, cardiotoxicity with doxorubicin, and pulmonary fibrosis with bleomycin. The duration of the side effects varies.widely. For example, alopecia is transient, but the cardiac, pulmonary, and bladder toxicities can be irreversible.
- Minimizing adverse effects: Some toxic reactions may be ameliorated by interventions, such as the use of cytoprotectant drugs, perfusing the tumor locally (for example, a sarcoma of the arm), removing some of the patient’s marrow prior to intensive treatment and then reimplanting it, or promoting intensive diuresis to prevent bladder toxicities. The megaloblastic anemia that occurs with methotrexate can be effectively counteracted by administering folinic acid (leucovorin). With the availability of human granulocyte colony–stimulating factor (filgrastim), the neutropenia associated with treatment of cancer by many drugs can be partially reversed.
4. Treatment-induced tumors: Because most antineoplastic agents are mutagens, neoplasms (for example, acute nonlymphocytic leukemia) may arise 10 or more years after the original cancer was cured. [Note: Treatment-induced neoplasms are especially a problem after therapy with alkylating agents.] Most tumors that develop from cancer chemotherapeutic agents respond well to treatment strategies.
Anticancer Drugs: ANTIMETABOLITES
Focus topic: Anticancer Drugs
Antimetabolites are structurally related to normal compounds that exist within the cell. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are in S-phase and are, therefore, cell cycle specific.
A. Methotrexate, pemetrexed, and pralatrexate
The vitamin folic acid plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units and is essential for cell replication. Folic acid is obtained mainly from dietary sources and from that produced by intestinal flora. Methotrexate [meth-oh-TREK-sate] (MTX), pemetrexed [pem-e-TREX-ed], and pralatrexate [pral-a-TREX-ate] are antifolate agents.
1. Mechanism of action: MTX is structurally related to folic acid and acts as an antagonist of the vitamin by inhibiting mammalian dihydrofolate reductase (DHFR), the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4). The inhibition of DHFR can only be reversed by a 1000-fold excess of the natural substrate, dihydrofolate (FH2), or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the folate pool. [Note: Leucovorin, or folinic acid, is the N5-formyl group–carrying form of FH4.] MTX is specific for the S-phase of the cell cycle. Pemetrexed is an antimetabolite similar in mechanism to methotrexate. However, in addition to inhibiting DHFR, it also inhibits thymidylate synthase and other enzymes involved in folate metabolism and DNA synthesis. Pralatrexate is a newer antimetabolite that also inhibits DHFR.
2. Therapeutic uses: MTX, usually in combination with other drugs, is effective against acute lymphocytic leukemia, Burkitt lymphoma in children, breast cancer, bladder cancer, and head and neck carcinomas. In addition, low-dose MTX is effective as a single agent against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis, as well as Crohn disease. All patients receiving MTX require close monitoring for possible toxic effects. Pemetrexed is primarily used in non–small cell lung cancer. Pralatrexate is used in relapsed or refractory T-cell lymphoma.
3. Resistance: Nonproliferating cells are resistant to MTX, probably because of a relative lack of DHFR, thymidylate synthase, and/ or the glutamylating enzyme. Decreased levels of the MTX polyglutamate have been reported in resistant cells and may be due to its decreased formation or increased breakdown. Resistance in neoplastic cells can be due to amplification (production of additional copies) of the gene that codes for DHFR, resulting in increased levels of this enzyme. The enzyme affinity for MTX may also be diminished. Resistance can also occur from a reduced influx of MTX, apparently caused by a change in the carrier-mediated transport responsible for pumping the drug into the cell.
4. Pharmacokinetics: MTX is variably absorbed at low doses from the GI tract, but it can also be administered by intramuscular, intravenous (IV), and intrathecal routes. Because MTX does not easily penetrate the blood–brain barrier, it can be administered intrathecally to destroy neoplastic cells that are thriving in the sanctuary of the CNS. High concentrations of the drug are found in the intestinal epithelium, liver, and kidney, as well as in ascites and pleural effusions. MTX is also distributed to the skin. High doses of MTX undergo hydroxylation at the 7 position and become 7-hydroxymethotrexate. This derivative is much less active as an antimetabolite. It is less water soluble than MTX and may lead to crystalluria. Therefore, it is important to keep the urine alkaline and the patient well hydrated to avoid renal toxicity. Excretion of the parent drug and the 7-OH metabolite occurs primarily via urine, although some of the drug and its metabolite appear in feces due to enterohepatic excretion.
5. Adverse effects: Pemetrexed should be given with folic acid and vitamin B12 supplements to reduce hematologic and GI toxicities. It is also recommended to pretreat with corticosteroids to prevent cutaneous reactions. One of the more common side effects of pralatrexate is mucositis. Doses must be adjusted or withheld based on the severity of mucositis. Pralatrexate also requires supplementation with folic acid and vitamin B12.
6-Mercaptopurine [mer-kap-toe-PYOOR-een] (6-MP) is the thiol analog of hypoxanthine. 6-MP and 6-thioguanine were the first purine analogs to prove beneficial for treating neoplastic disease. [Note: Azathioprine, an immunosuppressant, exerts its cytotoxic effects after conversion to 6-MP.] 6-MP is used principally in the maintenance of remission in acute lymphoblastic leukemia. 6-MP and its analog, azathioprine, are also beneficial in the treatment of Crohn disease.
1. Mechanism of action:
- Nucleotide formation: To exert its antileukemic effect, 6-MP must penetrate target cells and be converted to the nucleotide analog, 6-MP-ribose phosphate (better known as 6-thioinosinic acid or TIMP; The addition of the ribose phosphate is catalyzed by the salvage pathway enzyme, hypoxanthine– guanine phosphoribosyltransferase (HGPRT).
- Inhibition of purine synthesis: A number of metabolic processes involving purine biosynthesis and interconversions are affected by the nucleotide analog, TIMP. Similar to nucleotide monophosphates, TIMP can inhibit the first step of de novo purine ring biosynthesis (catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase). TIMP also blocks the formation of adenosine monophosphate and xanthinuric acid from inosinic acid.
- Incorporation into nucleic acids: TIMP is converted to thioguanine monophosphate, which after phosphorylation to di- and triphosphates can be incorporated into RNA. The deoxyribonucleotide analogs that are also formed are incorporated into DNA. This results in nonfunctional RNA and DNA.
2. Resistance: Resistance is associated with 1) an inability to biotransform 6-MP to the corresponding nucleotide because of decreased levels of HGPRT, 2) increased dephosphorylation, or 3) increased metabolism of the drug to thiouric acid or other metabolites.
3. Pharmacokinetics: Oral absorption is erratic and incomplete. Once it enters the blood circulation, the drug is widely distributed throughout the body, except for the cerebrospinal fluid (CSF). The bioavailability of 6-MP can be reduced by first-pass metabolism in the liver. 6-MP is converted in the liver to the 6-methylmercaptopurine derivative or to thiouric acid (an inactive metabolite). [Note: The latter reaction is catalyzed by xanthine oxidase.] The parent drug and its metabolites are excreted by the kidney.
Fludarabine [floo-DARE-a-been] is the 5′-phosphate of 2-fluoroadenine arabinoside, a purine nucleotide analog. It is useful in the treatment of chronic lymphocytic leukemia, hairy cell leukemia, and indolent non-Hodgkin lymphoma. Fludarabine is a prodrug, the phosphate being removed in the plasma to form 2-F-araA, which is taken up into cells and again phosphorylated (initially by deoxycytidine kinase). Although the exact cytotoxic mechanism is uncertain, the triphosphate is incorporated into both DNA and RNA. This decreases their synthesis in the S-phase and affects their function. Resistance is associated with reduced uptake into cells, lack of deoxycytidine kinase, and decreased affinity for DNA polymerase, as well as other mechanisms. Fludarabine is administered IV rather than orally, because intestinal bacteria split off the sugar to yield the very toxic metabolite, fluoroadenine. Urinary excretion accounts for partial elimination.
Another purine analog, 2-chlorodeoxyadenosine or cladribine [KLAdri-been], undergoes reactions similar to those of fludarabine, and it must be phosphorylated to a nucleotide to be cytotoxic. It becomes incorporated at the 3′-terminus of DNA and, thus, hinders elongation. It also affects DNA repair and is a potent inhibitor of ribonucleotide reductase. Resistance may be due to mechanisms analogous to those that affect fludarabine, although cross-resistance is not observed. Cladribine is effective against hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The drug is given as a single, continuous infusion. Cladribine distributes throughout the body, including into the CSF.
5-Fluorouracil [flure-oh-YOOR-ah-sil] (5-FU ), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of thymidine, one of the essential precursors for DNA synthesis. 5-FU is employed primarily in the treatment of slowly growing solid tumors (for example, colorectal, breast, ovarian, pancreatic, and gastric carcinomas). When applied topically, 5-FU is also effective for the treatment of superficial basal cell carcinomas.
1. Mechanism of action: 5-FU itself is devoid of antineoplastic activity. It enters the cell through a carrier-mediated transport system and is converted to the corresponding deoxynucleotide (5-fluorodeoxyuridine monophosphate [5-FdUMP]; DNA synthesis decreases due to lack of thymidine, leading to imbalanced cell growth and “thymidine-less death” of rapidly dividing cells. [Note: Leucovorin is administered with 5-FU, because the reduced folate coenzyme is required in the thymidylate synthase inhibition. For example, a standard regimen for advanced colorectal cancer is irinotecan plus 5-FU/leucovorin.] 5-FU is also incorporated into RNA, and low levels have been detected in DNA. In the latter case, a glycosylase excises the 5-FU, damaging the DNA. 5-FU produces the anticancer effect in the S-phase of the cell cycle.
2. Resistance: Resistance is encountered when the cells have lost their ability to convert 5-FU into its active form (5-FdUMP) or when they have altered or increased thymidylate synthase levels.
3. Pharmacokinetics: Because of its severe toxicity to the GI tract, 5-FU is given IV or, in the case of skin cancer, topically. The drug penetrates well into all tissues, including the CNS. 5-FU is rapidly metabolized in the liver, lung, and kidney. It is eventually converted to fluoro-β-alanine, which is removed in the urine. The dose of 5-FU must be adjusted in impaired hepatic function. Elevated levels of dihydropyrimidine dehydrogenase (DPD) can increase the rate of 5-FU catabolism and decrease its bioavailability. The DPD level varies from individual to individual and may differ by as much as sixfold in the general population. Patients with DPD deficiency may experience severe toxicity manifested by pancytopenia, mucositis, and life-threatening diarrhea. Knowledge of an individual’s DPD activity should allow more appropriate dosing of 5-FU.
Capecitabine [cape-SITE-a-been] is a novel, oral fluoropyrimidine carbamate. It is used in the treatment of colorectal and metastatic breast cancer. After being absorbed, capecitabine, which is itself nontoxic, undergoes a series of enzymatic reactions, the last of which is hydrolysis to 5-FU. This step is catalyzed by thymidine phosphorylase, an enzyme that is concentrated primarily in tumors. Thus, the cytotoxic activity of capecitabine is the same as that of 5-FU and is tumor specific. The most important enzyme inhibited by 5-FU (and, thus, capecitabine) is thymidylate synthase. Capecitabine is well absorbed following oral administration. It is extensively metabolized to 5-FU and is eventually biotransformed into fluoro-β-alanine. Metabolites are primarily eliminated in the urine.
Cytarabine [sye-TARE-ah-been] (cytosine arabinoside or ara-C) is an analog of 2′-deoxycytidine in which the natural ribose residue is replaced by d-arabinose. Cytarabine acts as a pyrimidine antagonist. The major clinical use of cytarabine is in acute nonlymphocytic (myelogenous) leukemia (AML). Cytarabine enters the cell by a carrier-mediated process and, like the other purine and pyrimidine antagonists, must be sequentially phosphorylated by deoxycytidine kinase and other nucleotide kinases to the nucleotide form (cytosine arabinoside triphosphate or ara-CTP) to be cytotoxic. Ara-CTP is an effective inhibitor of DNA polymerase. The nucleotide is also incorporated into nuclear DNA and can terminate chain elongation. It is, therefore, S-phase (and, hence, cell cycle) specific.
1. Resistance: Resistance to cytarabine may result from a defect in the transport process, a change in activity of phosphorylating enzymes (especially deoxycytidine kinase), or an increased pool of the natural dCTP nucleotide. Increased deamination of the drug to uracil arabinoside (ara-U) can also cause resistance.
2. Pharmacokinetics: Cytarabine is not effective when given orally, because of its deamination to the noncytotoxic ara-U by cytidine deaminase in the intestinal mucosa and liver. Given IV, it distributes throughout the body but does not penetrate the CNS in sufficient amounts. Therefore, it may also be injected intrathecally. A liposomal preparation that provides slow release into the CSF is also available. Cytarabine undergoes extensive oxidative deamination in the body to ara-U, a pharmacologically inactive metabolite. Both cytarabine and ara-U are excreted in urine.
Azacitidine [A-zuh-SITE-i-dine] is a pyrimidine nucleoside analog of cytidine. It is used for the treatment of myelodysplastic syndromes and AML. Azacitidine undergoes activation to the nucleotide metabolite azacitidine triphosphate and gets incorporated into RNA to inhibit RNA processing and function. It is S-phase cell cycle specific. The mechanism of resistance is not well described.
Gemcitabine [jem-SITE-ah-been] is an analog of the nucleoside deoxycytidine.
It is used most commonly for pancreatic cancer and non–
small cell lung cancer. Gemcitabine is a substrate for deoxycytidine
kinase, which phosphorylates the drug to 2′,2′-difluorodeoxycytidine
triphosphate (Figure 46.14). Resistance to the drug is probably due
to its inability to be converted to a nucleotide, caused by an alteration
in deoxycytidine kinase. In addition, the tumor cell can produce
increased levels of endogenous deoxycytidine that compete for the
kinase, thus overcoming the inhibition. Gemcitabine is infused IV.
It is deaminated to difluorodeoxyuridine, which is not cytotoxic, and
is excreted in urine.