187-2017

the anthracyclines, vinca alkaloids, taxanes, camptothecins, epipodophyllotoxins, and even small molecule inhibitors, such as imatinib.

■ BASIC PHARMACOLOGY OF CANCER CHEMOTHERAPEUTIC DRUGS

ALKYLATING AGENTS

The major clinically useful alkylating agents (Figure 54–3) have a structure containing a bis(chloroethyl)amine, ethyleneimine, or nitrosourea moiety, and they are classified in several different groups. Among the bis(chloroethyl)amines, cyclophosphamide, mechlorethamine, melphalan, and chlorambucil are the most useful. Ifosfamide is closely related to cyclophosphamide but has a somewhat different spectrum of activity and toxicity. Thiotepa and busulfan are used to treat breast and ovarian cancer, and chronic myeloid leukemia, respectively. The major nitrosoureas are carmustine (BCNU) and lomustine (CCNU).

Mechanism of Action

As a class, the alkylating agents exert their cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylation of DNA within the nucleus probably represents the major interaction leading to cell death. However, these drugs react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups of other cellular nucleophiles as well. The general mechanism of action of these drugs involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent. In addition to alkylation, a secondary mechanism that occurs with nitrosoureas involves carbamoylation of lysine residues of proteins through formation of isocyanates.

The major site of alkylation within DNA is the N7 position of guanine; however, other bases are also alkylated albeit to lesser degrees, including N1 and N3 of adenine, N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA. These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups. Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues.

The latter effect leads to DNA strand breakage through scission of the sugar-phosphate backbone of DNA. Cross-linking of DNA appears to be of major importance to the cytotoxic action of alkylating agents, and replicating cells are most susceptible to these drugs. Thus, although alkylating agents are not cell cycle-specific, cancer cells are most susceptible to this class of drugs in late G1 and S phases of the cell cycle.

Resistance

The mechanism of acquired resistance to alkylating agents may involve increased capability to repair DNA lesions through increased expression and activity of DNA repair enzymes, decreased cellular transport of the alkylating drug, and increased expression or activity of glutathione and glutathione-associated proteins, which are needed to conjugate the alkylating agent, or increased glutathione S-transferase activity, which catalyzes the conjugation.

Cyclophosphamide is one of the most widely used alkylating agents. One significant advantage of this compound relates to its high oral bioavailability. As a result, it can be administered via the oral and intravenous routes with equal clinical efficacy. It is inactive in its parent form and must be activated to cytotoxic metabolites by liver microsomal enzymes (Figure 54–4). The cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclo- phosphamide and carboxyphosphamide.

The major toxicities of the individual alkylating agents are outlined in Table 54–2 and discussed below.

Adverse Effects

The adverse effects associated with alkylating agents are generally dose-related and occur primarily in rapidly growing tissues such as bone marrow (myelosuppression), gastrointestinal tract (diarrhea), and reproductive system. Nausea and vomiting also can be a serious issue with a number of these agents. In addition, they are potent vesicants and can damage tissues at the site of administration as well as produce systemic toxicity. As a class, alkylating agents are carcinogenic in nature, and there is an increased risk of secondary malignancies, especially acute myelogenous leukemia.

NITROSOUREAS

These drugs appear to be non-cross-resistant with other alkylating agents; all require biotransformation, which occurs by nonenzymatic decomposition, to metabolites with both alkylating and carbamoylating activities. The nitrosoureas are highly lipid-soluble and are able to readily cross the blood-brain barrier, making them effective in the treatment of brain tumors. Although the majority of alkylations by the nitrosoureas are on the N7 position of guanine in DNA, the critical alkylation responsible for cytotoxicity appears to be on the O6 position of guanine, which leads to

G-C crosslinks in DNA. After oral administration of lomustine, peak plasma levels of metabolites appear within 1–4 hours; central nervous system concentrations reach 30–40% of the activity present in the plasma. Urinary excretion appears to be the major route of elimination from the body. One naturally occurring sugar-containing nitrosourea, streptozocin, is interesting because it has minimal bone marrow toxicity. This agent has activity in the treatment of insulin-secreting islet cell carcinoma of the pancreas.

NONCLASSIC ALKYLATING AGENTS

Several other compounds have mechanisms of action that involve DNA alkylation as their cytotoxic mechanism of action. These agents include procarbazine, dacarbazine, and bendamustine. Their clinical activities and toxicities are listed in Table 54–2.

Procarbazine

Procarbazine is an orally active methylhydrazine derivative, and in the clinical setting, it is used in combination regimens for Hodgkin’s and non-Hodgkin’s lymphoma as well as for brain tumors.

The precise mechanism of action of procarbazine is uncertain; however, it inhibits DNA, RNA, and protein biosynthesis; prolongs interphase; and produces chromosome breaks. Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and H2O2, which may be responsible for DNA strand scission. A variety of other drug metabolites are formed that may be cytotoxic. One metabolite is a weak monoamine oxidase (MAO) inhibitor, and adverse events can occur when procarbazine is given with other MAO inhibitors as well as with sympathomimetic agents, tricyclic antidepressants, antihistamines, central nervous system depressants, antidiabetic agents, alcohol, and tyramine-containing foods.

There is an increased risk of secondary cancers in the form of acute leukemia, and its carcinogenic potential is thought to be higher than that of other alkylating agents.

Dacarbazine

Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation in the liver by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to diazomethane, which generates a methyl carbonium ion that is believed to be the key cytotoxic species. Dacarbazine is administered parenterally and is used in the treatment of malignant melanoma, Hodgkin’s lymphoma, soft tissue sarcomas, and neuroblastoma. The main dose-limiting toxicity is myelosuppression, but nausea and vomiting can be severe in some cases. This agent is a potent vesicant, and care must be taken to avoid extravasation during drug administration.

Bendamustine

Bendamustine is a bifunctional alkylating agent consisting of a purine benzimidazole ring and a nitrogen mustard moiety. As with other alkylating agents, it forms cross-links with DNA resulting in

singleand double-stranded breaks, leading to inhibition of DNA synthesis and function. This molecule also inhibits mitotic checkpoints and induces mitotic catastrophe, which leads to cell death. Of note, the cross-resistance between bendamustine and other alkylating agents is only partial, thereby providing a rationale for its clinical activity despite the development of resistance to other alkylating agents. This agent is approved for use in chronic lymphocytic leukemia, with activity also observed in Hodgkin’s and non-Hodgkin’s lymphoma, multiple myeloma, and breast cancer. The main dose-limiting toxicities include myelosuppression and mild nausea and vomiting. Hypersensitivity infusion reactions, skin rash, and other skin reactions occur rarely.

PLATINUM ANALOGS

Three platinum analogs are currently used in clinical practice: cisplatin, carboplatin, and oxaliplatin. Cisplatin (cis-diamminedi- chloroplatinum [II]) is an inorganic metal complex that was initially discovered through a serendipitous observation that neutral platinum complexes inhibited division and filamentous growth of Escherichia coli. Several platinum analogs were subsequently synthesized. Although the precise mechanism of action of the platinum analogs is unclear, they exert their cytotoxic effects in the same manner as alkylating agents. As such, they kill tumor cells in all stages of the cell cycle and bind DNA through the formation of intrastrand and interstrand cross-links, thereby leading to inhibition of DNA synthesis and function. The primary binding site is the N7 position of guanine, but covalent interaction with the N3 position of adenine and O6 position of cytosine also can occur. In addition to targeting DNA, the platinum analogs have been shown to bind to both cytoplasmic and nuclear proteins, which may also contribute to their cytotoxic and antitumor effects. The platinum complexes appear to synergize with certain other anticancer drugs, including alkylating agents, fluoropyrimidines, and taxanes. The major toxicities of the individual platinum analogs are outlined in Table 54–2.

H3N Cl

Pt

H3N Cl

Cisplatin

Cisplatin has major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, cholangiocarcinoma, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer. When used in combination regimens, cisplatin-based therapy has led to the cure of nonseminomatous testicular cancer. Cisplatin and the other platinum analogs are cleared by the kidneys and excreted in the urine. As a result, dose modification is required in patients with renal dysfunction.

Carboplatin is a second-generation platinum analog whose mechanisms of cytotoxic action, mechanisms of resistance, and clinical pharmacology are identical to those described for cisplatin. As with cisplatin, carboplatin has broad-spectrum activity against

a wide range of solid tumors. However, in contrast to cisplatin, it exhibits significantly less renal and gastrointestinal toxicity. Its main dose-limiting toxicity is myelosuppression. It has, therefore, been widely used in transplant regimens to treat refractory hematologic malignancies. Moreover, since vigorous intravenous hydration is not required for carboplatin therapy, carboplatin is viewed as an easier agent to administer to patients, and as such, it has replaced cisplatin in various combination chemotherapy regimens.

Oxaliplatin is a third-generation diaminocyclohexane platinum analog. Its mechanism of action and clinical pharmacology are identical to those of cisplatin and carboplatin. However, tumors that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects are not cross-resistant to oxaliplatin, and this finding may explain the clinical activity of this platinum compound in colorectal cancer. Oxaliplatin was initially approved for use as second-line therapy in combination with the fluoropyrimidine 5-fluorouracil (5-FU) and leucovorin, termed the FOLFOX regimen, for metastatic colorectal cancer. There are various iterations of the FOLFOX regimen, which have now become the most widely used combinations in the first-line treatment of advanced colorectal cancer. This regimen also plays a major role in the adjuvant therapy of stage III colon cancer and high-risk stage II colon cancer. Clinical activity has also been observed in other gastrointestinal cancers, such as pancreatic, gastroesophageal, and hepatocellular cancer. Neurotoxicity is the main dose-limiting toxicity, and it is manifested by a peripheral sensory neuropathy. There are two forms of neurotoxicity, an acute form that is often triggered and worsened by exposure to cold, and a chronic form that is dose-dependent. Although the chronic form of oxaliplatin toxicity is dependent on the cumulative dose of drug administered, it tends to be more readily reversible than that observed with cisplatin-induced neurotoxicity.

ANTIMETABOLITES

The antimetabolites represent an important class of agents that have been rationally designed and synthesized based on knowledge of critical cellular processes involved in DNA biosynthesis. The individual antimetabolites and their respective clinical spectrum and toxicities are presented in Table 54–3 and are discussed below.

ANTIFOLATES

Methotrexate

Methotrexate (MTX) is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR). This results in inhibition of synthesis of tetrahydrofolate (THF), the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Inhibition of these metabolic processes interferes with the formation of DNA, RNA, and key cellular proteins (see Figure 33–3). Intracellular formation of polyglutamate metabolites, with the addition of up to

5–7 glutamate residues, is critically important for the therapeutic action of MTX, and this process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS). MTX polyglutamates are selectively retained within cancer cells, and they display increased inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX’s cytotoxic action.

CH2

COOH

Methotrexate

Several resistance mechanisms to MTX have been identified, and they include (1) decreased drug transport via the reduced folate carrier or folate receptor protein, (2) decreased formation of cytotoxic MTX polyglutamates, (3) increased levels of the target enzyme DHFR through gene amplification and other genetic mechanisms, and (4) altered DHFR protein with reduced affinity for MTX. Recent studies have suggested that decreased accumulation of drug through activation of the multidrug resistance transporter P170 glycoprotein also may result in drug resistance.

MTX is administered by the intravenous, intrathecal, or oral route. However, oral bioavailability is saturable and erratic at doses greater than 25 mg/m2. Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion. As a result, dose modification is required in the setting of renal dysfunction. Care must also be taken when MTX is used in the presence of drugs such as aspirin, nonsteroidal anti-inflammatory agents, penicillin, and cephalosporins, as these agents inhibit the renal excretion of MTX. The biologic effects of MTX can be reversed by administration of the reduced folate leucovorin (5-formyltetrahydrofolate) or by L-leucovorin, which is the active enantiomer. Leucovorin rescue is used in conjunction with high-dose MTX therapy to rescue normal cells from undue toxicity, and it has also been used in cases of accidental drug overdose. The main adverse effects are listed in Table 54–3.

Pemetrexed

Pemetrexed is a pyrrolopyrimidine antifolate analog with activity in the S phase of the cell cycle. As in the case of MTX, it is

Pancreatic cancer, bladder cancer, breast cancer, non-small cell lung cancer, ovarian cancer, non-Hodgkin’s lymphoma, soft tissue sarcoma

Non-Hodgkin’s lymphoma, CLL

Hairy cell leukemia, CLL, non-Hodgkin’s lymphoma

AML

ALL, AML

Nausea, vomiting, diarrhea, myelosuppression

Myelosuppression, immunosuppression, nausea and vomiting, fever, myalgias, arthralgias

Myelosuppression, nausea and vomiting, and immunosuppression

Myelosuppression, immunosuppression, and hepatotoxicity

Same as 6-MP

transported into the cell via the reduced folate carrier and requires activation by FPGS to yield higher polyglutamate forms. While this agent targets DHFR and enzymes involved in de novo purine nucleotide biosynthesis, its main mechanism of action is inhibition of thymidylate synthase (TS). Pemetrexed is currently approved for use in combination with cisplatin in the treatment of mesothelioma, as a single agent in the second-line therapy of NSCLC, in combination with cisplatin for the first-line treatment of NSCLC, and most recently, as maintenance therapy in patients with NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy. As with MTX, pemetrexed is mainly excreted in urine, and dose modification is required in patients with renal dysfunction. The main adverse effects include

myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome. Of note, vitamin supplementation with folic acid and vitamin B12 has been shown to significantly reduce the toxicities associated with pemetrexed, while not interfering with clinical efficacy. The hand-foot syndrome is manifested by painful erythema and swelling of the hands and feet, and treatment with the steroid dexamethasone is effective in reducing the incidence and severity of this skin toxicity.

Pralatrexate

reduced folate carrier (RFC) and requires activation by FPGS to yield higher polyglutamate forms. This molecule was originally designed to be a more potent substrate for the RFC-1 carrier protein and to serve as an improved substrate for FPGS. This agent inhibits DHFR, inhibits enzymes involved in de novo purine nucleotide biosynthesis, and also inhibits TS. Pralatrexate is presently approved for use in the treatment of relapsed or refractory peripheral T-cell lymphoma. Consistent with other antifolate analogs, pralatrexate is mainly excreted in the urine, and dose modification is required in renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, and fatigue. As with pemetrexed, vitamin supplementation with folic acid and vitamin B12 appears to reduce the toxicities associated with pralatrexate, without interfering with clinical efficacy.

FLUOROPYRIMIDINES

5-Fluorouracil

5-Fluorouracil (5-FU) is inactive in its parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP), forms a covalently bound ternary complex with the enzyme TS and the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical for the de novo synthesis of thymidylate. Formation of this ternary complex results in inhibition of DNA synthesis through “thymineless death.” 5-FU is converted to 5-fluorouridine-5′- triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. 5-FU is also converted to 5-fluorodeoxyuridine-5′-triphosphate (FdUTP), which is subsequently incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of 5-FU is thought to be mediated by the combined effects of both DNAand RNA-mediated events.

5-FU is administered intravenously, and the clinical activity of this drug is highly schedule-dependent. Because of its extremely short half-life, approximately 10–15 minutes, infusion administration schedules have been generally favored over bolus schedules. Up to 80–85% of an administered dose of 5-FU is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD). There is an autosomal recessive pharmacogenetic syndrome involving partial or complete deficiency of the DPD enzyme that is seen in up to 5% of cancer patients. In this particular setting, severe, excessive toxicity is observed with the classic triad of myelosuppression, GI toxicity in the form of diarrhea and/or mucositis, and neurotoxicity.

OO

HH

Uracil 5-FU

5-FU remains the most widely used agent in the treatment of colorectal cancer, both as adjuvant therapy and for advanced disease. It also has activity against a wide range of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus. Major toxicities include myelosuppression, gastrointestinal toxicity in the form of mucositis and diarrhea, skin toxicity manifested by the hand-foot syndrome, and neurotoxicity.

Capecitabine

Capecitabine is a fluoropyrimidine carbamate prodrug with 70–80% oral bioavailability. As with 5-FU, capecitabine is inactive in its parent form and undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5′-deoxy-5-fluorocytidine. This metabolite is then converted to 5′-deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5′-deoxy- 5-fluorouridine metabolite is finally hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer (CRC).

Capecitabine is used in the treatment of metastatic breast cancer either as a single agent or in combination with other anti-cancer agents, including docetaxel, paclitaxel, lapatinib, ixabepilone, and trastuzumab. It is also approved for use in the adjuvant therapy of stage III and high-risk stage II colon cancer, and used in the treatment of metastatic CRC as monotherapy or in combination with other active cytotoxic agents, including irinotecan and oxaliplatin. The capecitabine/oxaliplatin (XELOX) regimen is now widely used for the first-line treatment of metastatic CRC as well as in the adjuvant setting for patients with stage III and high-risk stage II colon cancer. The main toxicities of capecitabine include diarrhea and the handfoot syndrome. While myelosuppression, nausea and vomiting, mucositis, and alopecia are also observed with capecitabine, their incidence is significantly less than that observed with intravenous 5-FU.

TAS-102

TAS-102 is an oral fluoropyrimidine analog approved in 2015 by the U.S. Food and Drug Administration (FDA) for the treatment of progressive, refractory metastatic CRC. As with 5-FU, TAS-102 is inactive in its parent form. It is made up of trifluridine, a fluorinated pyrimidine nucleoside analog, and tipiracil, a thymidine phosphorylase (TP) inhibitor, in a 1/0.5 ratio. Trifluridine is metabolized to the monophosphate form, which inhibits TS, albeit a much weaker TS inhibitor than FdUMP, and also to the triphosphate form, which is directly incorporated into DNA, leading to inhibition of DNA synthesis and function. The role of tipiracil is to inhibit TP, a key enzyme that degrades trifluridine to inactive forms. Thus, tipiracil allows for higher levels of

trifluridine, which can then be activated to the active metabolite forms. The advantages of TAS-102 are that it retains clinical activity in 5-FU resistant tumors and it displays similar clinical activity in the setting of wild-type and mutant RAS colorectal cancer. The main dose-limiting toxicity is myelosuppression, with neutropenia more commonly observed than anemia and thrombocytopenia. The other adverse effects commonly observed with this oral fluoropyrimidine are GI toxicity with diarrhea and nausea/vomiting, fatigue, and anorexia.

DEOXYCYTIDINE ANALOGS

Cytarabine

Cytarabine (ara-C) is an S phase–specific antimetabolite that is converted by deoxycytidine kinase to the 5′-mononucleotide (ara-CMP). Ara-CMP is further metabolized to the diphosphate and triphosphate metabolites, and the ara-CTP triphosphate is thought to be the main cytotoxic metabolite. Ara-CTP competitively inhibits DNA polymerase-α and DNA polymerase-β, thereby resulting in blockade of DNA synthesis and DNA repair, respectively. This metabolite is also incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA. The cellular retention of ara-CTP appears to correlate with its lethality to malignant cells.

After intravenous administration, the drug is cleared rapidly, with most of an administered dose being deaminated to inactive forms. The stoichiometric balance between the level of activation and catabolism of cytarabine is important in determining its eventual cytotoxicity. The clinical activity of cytarabine is highly schedule-dependent and, because of its rapid degradation, it is usually administered via continuous infusion over a 5- to 7-day period. Its activity is limited exclusively to hematologic malignancies, including acute myelogenous leukemia and non-Hodgkin’s lymphoma. This agent has absolutely no activity in solid tumors. The main adverse effects associated with cytarabine therapy include myelosuppression, mucositis, nausea and vomiting, and neurotoxicity when high-dose therapy is administered.

Gemcitabine

Gemcitabine is a fluorine-substituted deoxycytidine analog that is phosphorylated initially by the enzyme deoxycytidine kinase to the monophosphate form and then by other nucleoside kinases to the diphosphate and triphosphate nucleotide forms. The antitumor effect is considered to result from several mechanisms: inhibition of ribonucleotide reductase by gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for DNA synthesis; inhibition by gemcitabine triphosphate of DNA polymerase-α and DNA polymerase-β, thereby resulting in blockade of DNA synthesis and DNA repair; and incorporation of gemcitabine triphosphate into DNA, leading to inhibition of DNA synthesis and function.

NH2

N

ON

HOCH2O

F

OH F

Gemcitabine

In contrast to cytarabine, which has no activity in solid tumors, gemcitabine has broad-spectrum activity against both solid tumors and hematologic malignancies. In fact, this nucleoside analog was initially approved for use in advanced pancreatic cancer and is now widely used to treat a broad range of malignancies, including NSCLC, bladder cancer, ovarian cancer, soft tissue sarcoma, and non-Hodgkin’s lymphoma. Myelosuppression in the form of neutropenia is the principal dose-limiting toxicity. Nausea and vomiting occur in 70% of patients, and a flu-like syndrome has also been observed. In rare cases, renal microangiopathy syndromes, including hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported.

PURINE ANTAGONISTS

6-Thiopurines

6-Mercaptopurine (6-MP) was the first of the thiopurine analogs found to have clinical efficacy in cancer therapy. This agent is used primarily in the treatment of childhood acute leukemia, and a closely related analog, azathioprine, is used as an immunosuppressive agent (see Chapter 55). As with other thiopurines, 6-MP is inactive in its parent form and must be metabolized by hypo- xanthine-guanine phosphoribosyl transferase (HGPRT) to form the monophosphate nucleotide 6-thioinosinic acid, which in turn, inhibits several enzymes of de novo purine nucleotide synthesis (Figure 54–6). The monophosphate form is eventually metabolized to the triphosphate form, which can then be incorporated into both RNA and DNA. Significant levels of thioguanylic acid and

6-methylmercaptopurine ribotide (MMPR) also are formed from 6-MP. These metabolites may contribute to its cytotoxic action.

6-Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion; decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis; interference with the formation of DNA and RNA; and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia.

6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important difference because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50–75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol.

The thiopurines are also metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring. Patients who have a pharmacogenetic syndrome involving partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities in the form of myelosuppression and gastrointestinal toxicity with mucositis and diarrhea.

Fludarabine

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro- arabinofuranosyladenosine and then phosphorylated intracellularly by deoxycytidine kinase to the monophosphate, which is eventually converted to the triphosphate. Fludarabine

triphosphate interferes with the processes of DNA synthesis and DNA repair through inhibition of DNA polymerase-α and DNA polymerase-β. The triphosphate form can also be directly incorporated into DNA, resulting in inhibition of DNA synthesis and function. The diphosphate metabolite of fludarabine inhibits ribonucleotide reductase, leading to inhibition of essential deoxyribonucleotide triphosphates. Finally, fludarabine induces apoptosis in susceptible cells through as yet undetermined mechanisms. This purine nucleotide analog is used mainly in the treatment of low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL). It is given parenterally, and up to 25–30% of parent drug is excreted in the urine. The main dose-limiting toxicity is myelosuppression. This agent is a potent immunosuppressant with inhibitory effects on CD4 and CD8 T cells. Patients are at increased risk for opportunistic infections, including fungi, herpes, and Pneumocystis jiroveci pneumonia (PCP). Patients should receive PCP prophylaxis with trimethoprim-sulfamethoxazole (double strength) at least three times a week, and this should continue for up to 1 year after stopping fludarabine therapy.

Cladribine

Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with high specificity for lymphoid cells. Inactive in its parent form, it is initially phosphorylated by deoxycytidine kinase to the monophosphate form and eventually metabolized to the triphosphate form, which can then be incorporated into DNA. The triphosphate metabolite can also interfere with DNA synthesis and DNA repair by inhibiting DNA polymerase-α and DNA polymerase-β, respectively. Cladribine is indicated for the treatment of hairy cell leukemia, with activity in other low-grade lymphoid malignancies such as CLL and low-grade non-Hodgkin’s lymphoma. It is normally administered as a single continuous 7-day infusion; under these conditions, it has a very manageable safety profile with the main toxicity consisting of transient myelosuppression. As with other purine nucleoside analogs, it has immunosuppressive effects, and a decrease in CD4 and CD8 T cells, lasting for over 1 year, is observed in patients.

NATURAL PRODUCT CANCER CHEMOTHERAPY DRUGS

VINCA ALKALOIDS

The vinca alkaloids inhibit the process of tubulin polymerization, which disrupts assembly of microtubules, especially those involved in the mitotic spindle apparatus. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Thus, the vinca alkaloids work in the M phase of the cell cycle. Microtubules also play an important role in maintaining cell shape and cellular motility, and they facilitate the intracellular transport of cellular proteins. As such, inhibition of microtubule formation has important consequences that can lead to cell death.

Vinblastine

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the hepatobiliary system. As such, dose modification is required in the setting of liver dysfunction.

The main adverse effects are outlined in Table 54–4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer, and germ cell cancer.