Figure 46-1 Targets for anticancer drugs Anticancer drugs work by interfering with the processes underlying normal cellular physiology. These include receptor-activated signal transduction pathways culminating in transcriptional activation, DNA replication, protein synthesis, and cell division. (Modified by permission from Macmillan Publishers Ltd: Downward J. The ins and outs of signaling. Nature. 2001;411:759).
The specificity/selectivity of a drug for a particular target is, in general, proportional to the affinity constant, Ka, more accurately defined for competitive drug target interactions as the Ki, which is the reciprocal of the concentration of drug required to inhibit 50% of the target’s activity when controlled for all possible ligand or substrate concentrations. The activity of a drug refers to its effectiveness independent of dose or concentration.
There are several factors that help explain why cancer cells are more sensitive to cancer therapeutic drugs than normal tissues. For any drug, the therapeutic index is related to absorption, uptake, distribution, and metabolism. Differences in tumor vasculature, intratumoral pressure, and drug binding may alter drug uptake in a favorable or unfavorable way. Classically, the therapeutic index of intravenously administered cancer chemotherapy has been thought to be due primarily to cell-cycle kinetics. Many chemotherapeutic agents are more effective against cycling than noncycling cells and are tested under cell culture conditions where cancer cells rapidly proliferate (“log phase”); this a posteriori conclusion was derived from these observations. However, many solid tumors have a relatively long doubling time, yet a therapeutic index remains. Therefore, alternative explanations must exist. One includes differences in energy requirements between normal and malignant cells. For example, whereas normal tissues use oxidative phosphorylation to metabolize glucose, malignant tissues are often dependent on aerobic glycolysis. This is thought to reflect the selection pressure placed on tumor cells to cope with relatively hypoxic and nutrient-deprived conditions. Rather than using the electron transfer chain within the mitochondria to yield 36 mol ATP per mol glucose, cancer cells metabolize glucose via glycolysis, generating a net 2 mol ATP per mol glucose metabolized (the Warburg effect). As a result, cancer cells are metabolically fragile and are unable to cope as readily with cellular damage. This may be particularly relevant for drugs that block the effects of growth factors, because growth factor depletion produces rapid downregulation of nutrient transporters, which would lead to metabolic crisis in cancer cells more rapidly than in normal cellular counterparts.
Table 46-1
Chemotherapeutic Drug Overview
Table 46-2
Drugs That Alter Nucleic Acid Synthesis and Function
Another concept is that tumor cells exhibit “oncogene addiction” and that inhibition of one or more of these oncogene products rapidly results in apoptotic cell death in “addicted” cancer cells but not in normal counterparts. Thus, tumor cells that depend on their survival by overexpression of a growth factor receptor (e.g., EGFR) would be more susceptible to inhibitors than are normal cells.
Table 46-3
Drugs with Other Mechanisms
Drugs Affecting Growth Factors and Growth Factor Receptors
Cancer cells usurp the mechanisms of normal cell division, which results from the interaction of growth factors with specific receptors (plasma membrane, cytoplasmic, or nuclear). This initiates a signal transduction cascade culminating in activation of nuclear transcription factors that produce cell-proliferation and cell-viability molecules. Thus, it stands to reason that some of our most effective drugs target growth factors or their receptors (see Table 46-1) and the downstream consequences of this interaction that include activation of protein kinases, replication of DNA, transcription of mRNA, synthesis of new proteins, formation of the mitotic spindle through microtubule polymerization, and creation of interphase daughter cells via microtubule depolymerization (see Table 46-2). In addition, the nutrient requirements of cancer cells create an increased dependence on the uptake of glucose (the basis for positron emission tomography or PET scan) and the ability to sustain energy requirements through frequent alterations in the PI3K/AKT/mTOR pathway and activation of autophagic cell survival (Figure 46-2 ).
Drugs Affecting Growth Factors
Sex Hormones
Aromatase is an enzyme complex made up of two proteins, aromatase cytochrome P450 (CYP19) and NADPH-cytochrome P450 reductase. Inhibition of aromatase blocks the conversion of androgens (androstenedione) to estrone in peripheral tissues including fat, liver, muscle, and breast without detectable effects on adrenal synthesis of corticosteroids or aldosterone. Following the reports by Santen and colleagues that aminoglutethimide could inhibit the conversion of androstenedione to estradiol, 3 aromatase became an attractive target for new drug development. Three aromatase inhibitors are used in the clinic, including letrozole (Femara), anastrozole (Arimidex), and exemestane (Aromasin). Whereas letrozole and anastrozole are reversible, nonsteroidal inhibitors of aromatase, exemestane is a steroidal derivative of androstenedione that binds irreversibly to the enzyme and targets the protein for degradation. Aromatase inhibitors further deplete circulating estradiol in postmenopausal women and are highly effective in the treatment of breast cancer in the adjuvant and metastatic settings. These well-tolerated medications can produce osteopenia and are often prescribed with a bisphosphonate, calcium, and vitamin D to prevent this complication.
Cyp17A1 is a cytochrome P450 enzyme complex that has both hydroxylase and lyase activity. It catalyzes the hydroxylation of pregnenolone and progesterone to their 17-OH derivatives and the conversion of 17-hydroxyprogesterone and 17-hydroxypregnenolone to DHEA and androstenedione via its lyase activity, leading to the synthesis of androgenic steroids in the gonads, adrenals, fat, and tumor stroma. Abiraterone acetate (Zytiga) is a prodrug of abiraterone, a potent and selective Cyp17 inhibitor shown to increase overall survival in patients with castration-resistant prostate cancer. 4
Gonadotropin-Releasing Hormones
Drugs that target receptors for gonadotropin-releasing hormones (GnRHs) decrease the production of ovarian or testicular hormones. The most widely used agents (leuprolide, goserelin) are agonists of GnRH receptors that cause an immediate increase in gonadotropins and eventually produce castration levels of sex hormones by the desensitization of GnRH receptors. A newer agent, abarelix (Plenaxis), is a GnRH receptor antagonist that immediately decreases GnRHs without the disadvantage of an initial hormone surge.
Figure 46-2 Energy regulation through PI3 kinase signaling Cancer cells require exquisite control of energy utilization because of a dependence on aerobic glycolysis to generate ATP. The PI3 kinase pathway serves as an energy sensor with links to self-preservation through autophagic cell survival. (A) When there are adequate nutrients, the pathway is activated, protein synthesis is increased, and autophagy is inhibited. In contrast, in the case of nutrient deprivation, protein synthesis is suppressed and autophagy is activated. (B) The process of forming the autophagosome in response to nutrient deprivation. (From Moreau P, Pylypenko H, Grosicki S. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440).
Vascular Endothelial Growth Factor
The observation by Folkman and colleagues that tumors stimulate blood vessel formation, coupled with the knowledge that angiogenesis is required for tumor growth and metastasis, led to a search for effective inhibitors of this process. 5 Vascular endothelial growth factor (VEGF) is produced by normal and neoplastic cells and regulates angiogenesis. The demonstration by Kim and colleagues 6 that a murine monoclonal antibody against VEGF had preclinical activity led to the development of bevacizumab, a human monoclonal antibody that binds to and inhibits VEGF, preventing its interaction with VEGF receptors (Flt-1 and KDR) that are present on the surface of endothelial cells, 7 thus inhibiting endothelial cell proliferation.
Bevacizumab (Avastin) was first approved for first-line treatment of metastatic colorectal cancer in combination with 5-fluorouracil–based chemotherapy and now has several other indications. Its most common side effects include hypertension, thrombosis, and proteinuria, but asthenia, gastrointestinal perforation, wound dehiscence, hemorrhage, and nephrotic syndrome have been reported, as has been a possible increase in congestive heart failure. Recently, a recombinant fusion protein, ziv-aflibercept (Zaltrap), referred to as a “VEGF trap,” has been developed and approved in combination with FOLFIRI for refractory colorectal cancer. The VEGF trap fuses the extracellular domain of VEGF receptors 1 and 2 with an Fc domain of human IgG1, thereby acting as a soluble receptor for VEGFs. 8
Drugs Affecting Growth Factor Receptors
Steroid Hormone Receptors
The interaction between steroid hormones and intracellular receptors recruits co-activators and co-repressors to the nuclear transcription complex, leading to transcriptional activation of genes containing specific steroid response elements.
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) bind with high affinity to cytoplasmic and nuclear estrogen receptors, then recruit transcriptional co-activators and co-repressors to the transcription complex, where they bind to estrogen response elements within promoter regions of estrogen-regulated genes. In certain tissues SERMs are antiestrogenic, whereas in others they are estrogenic; this is believed to be due to differential recruitment of co-repressors versus repressors in a specific tissue type. For example, tamoxifen (Nolvadex) behaves as an estrogen receptor antagonist in breast tissue, but as an agonist in the uterus, bone, and liver. As a result, tamoxifen is a highly effective drug for the treatment of breast cancers that express hormone receptors but has the disadvantage of also increasing endometrial proliferation and the risk of uterine cancer. The estrogenic effect of tamoxifen on bone prevents osteopenia, while its estrogenic effects on the liver lower cholesterol and increase the incidence of thrombosis. In contrast, raloxifene (Evista) is a SERM that behaves as an antiestrogen in breast, uterus, and liver, but retains estrogenic activity in the bone. Although results with raloxifene were disappointing for the treatment of metastatic breast cancer, it is effective for breast cancer prevention. 9 Fulvestrant (Faslodex) is a pure antiestrogen that binds to the estrogen receptor and targets it for ubiquitin-mediated proteasomal degradation.
Enzalutamide (MDV 3100) 1 is a potent and selective androgen receptor antagonist that has recently been shown to increase survival in patients with castration-resistant prostate cancer. 10
Bexarotene (Targretin) is an analog of vitamin A that binds with high affinity to retinoid “X” receptors. It is approved for use against refractory cutaneous T-cell lymphoma. Its side effects include cheilitis, headache, myalgias, and arthralgias, as well as an increase in liver function tests, hypertriglyceridemia and hypercalcemia, and hypothyroidism.
Drugs that Affect Oncogenic Growth Factor Pathways
Epidermal Growth Factor Receptor Family
Her-2/Neu. The discovery of a transforming element in the DNA of a malignant glial cell line by Weinberg and colleagues led to the identification of HER-2/neu. 11 When Slamon’s group observed that HER-2/neu was over-expressed in aggressive breast cancers, a search ensued for a means to inhibit this membrane receptor. 12 The biology of HER-2/neu activation is complex with both putative and proven ligands. Intracellular signaling occurs after receptor activation that leads to hetero- and homodimerization with other members of the EGFR receptor family, including HER-1, HER-3, and HER-4.
Trastuzumab. Trastuzumab (Herceptin) is approved for use alone or in combination with paclitaxel for the treatment of metastatic breast cancers that overexpress HER-2/neu. In the 25% to 30% of patients who respond to treatment, a substantial number survive for long periods of time. Unfortunately, these patients relapse, often in the central nervous system (CNS), probably because of the inability of trastuzumab to cross the blood-brain barrier rather than a predilection of these cells for the CNS. Trastuzumab is also effective in breast cancer patients receiving adjuvant chemotherapy. 13
Her-1 (epidermal growth factor receptor [EGFR]). EGFR is overexpressed in 60% to 80% of colorectal cancers and in many other tumor types. It can be transforming in laboratory models. The demonstration by Mendelsohn and colleagues that antibodies directed against the EGFR extracellular domain inhibited the growth of cancer cells led to the development of several types of EGFR antagonists. 14 Cetuximab (Erbitux) is a humanized mouse monoclonal antibody used in the treatment of Kras wild-type colorectal cancer alone or in combination with irinotecan, and more recently in combination with the FOLFOX regimen. Cetuximab has activity in head and neck cancers and is synergistic with radiation in preclinical models. Cetuximab is well tolerated. The major side effects include asthenia and an acneiform rash.
Several drugs have been developed to target the tyrosine kinase domain of the EGFR. For example, gefitinib (Iressa) received accelerated U.S. Food and Drug Administration (FDA) approval for the treatment of refractory non–small-cell lung cancer (NSCLC), but failed to show a survival advantage in larger randomized clinical trials. In contrast, erlotinib (Tarceva), a structurally similar molecule, produced a survival advantage in patients with NSCLC and is approved for use in this group of patients. Two reports demonstrated that gefitinib was particularly active in patients whose tumors harbored activating mutations in the tyrosine kinase catalytic domain of EGFR. 15,16 This alteration was particularly prevalent in nonsmokers, women of Japanese descent, and tumors of bronchoalveolar histology. Erlotinib also received approval in combination with gemcitabine for the treatment of pancreatic cancer. Acneiform rash and diarrhea are the most common side effects of these generally well-tolerated medications.
Bcr:abl. Of all the newer “targeted” therapies, none has been more impressive than imatinib (Gleevec; 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate) for use in chronic myelogenous leukemia, gastrointestinal stromal tumors, and a chronic myeloproliferative disease characterized by eosinophilia. 17 Imatinib targets the tyrosine kinase domain of the fusion protein formed by the reciprocal translocation involving the long arms of chromosomes 9 and 22 [t(9;22)(q34.1;q11.21)], referred to as the Philadelphia chromosome (Figure 46-3 ). Imatinib is also active against the tyrosine kinase activity of c-kit and the platelet-derived growth factor receptor (PDGFR), the former accounting for its activity against GIST and the latter for its activity against the chronic myeloproliferative syndrome. Denileukin diftitox, or DAB389IL-2 (ONTAK), is a fusion protein consisting of cytotoxic A and B chain fragments (Met[1]-Thr387-His) of diphtheria toxin fused to interleukin-2 (IL-2). 18 It is approved for the treatment of persistent or recurrent cutaneous T-cell lymphoma expressing the CD25 component of the IL-2 receptor. Denileukin thereby delivers this potent exotoxin, which ADP ribosylates elongation factor-2 and terminates protein synthesis. Side effects include flulike symptoms, acute hypersensitivity reactions, nausea and vomiting, vascular leak syndrome, infections, and transient elevation of liver function tests.
Figure 46-3 Genetic and structural changes underlying the activity of imatinib (A) The 9:22 chromosomal translocation that produces the bcr/abl oncogenic tyrosine kinase. (B) Ribbon drawing of the structure of the Abl kinase domain (green) in complex with imatinib (Gleevec). The activation loops and the van der Waals surfaces corresponding to the inhibitor are colored. Helix α C and the interlobe connector are shown in dark green. (From Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645-652).
bRaf. Sequencing of the melanoma genome revealed a bRaf mutation in approximately 60% that replaced a valine with a negatively charged glutamic acid, creating constitutive activation of the enzyme. Vemurafenib (Zelboraf) selectively inhibits the mutant form of the kinase. In a 55-patient dose escalation trial, Flaherty and co-workers 19 demonstrated that among 32 patients with the bRaf(V600E) mutation, 24 had PRs and 2 had CRs for an 81% objective response rate (ORR). A notable adverse event was the appearance of cutaneous squamous-cell carcinomas, mostly of the low-grade keratoacanthoma variety. Resistance appears to emerge rapidly because of NRAS mutation, PDGFR upregulation, and overexpression of the map kinase COT, which suggests ways of further improving results in the future.
Drugs that target multiple signal transduction enzymes. Signaling in malignant tissues is often complex. Therefore drugs that target a single pathway may not be as effective as those that have multiple targets. Protein kinase inhibitors are rarely completely selective for a given target, given the similarities in the catalytic domains of these enzymes. Two drugs have recently been approved that have relatively permissive activities (i.e., they inhibit multiple kinases including those that phosphorylate tyrosines, serines, or threonines in substrate proteins). For example, sorafenib (Nexavar) was approved for the treatment of renal-cell carcinoma and was initially believed to be specific for bRaf kinase, a serine/threonine kinase downstream of Ras that is mutated in melanoma and activated in several other malignancies. However, sorafenib is also a potent inhibitor of the VEGF receptor tyrosine kinases VEGFR-2 and -3, FLT-3, Kit, and PDGFR-β. 20 Similarly, sunitinib (Sutent), which was recently approved for treatment of renal-cell carcinoma and for GIST patients who have progressed following treatment with imatinib, can also inhibit multiple kinases including PDGFR-α and -β, VEGFR-1, -2, and -3, Kit, FLT-3, CSF-1, and RET. 21 These drugs possess a different spectrum of untoward side effects from that of classical cytotoxic agents. For example, hypertension, bleeding (including tumor hemorrhage), diarrhea, mucositis, skin rash, and taste abnormalities occur more frequently than for placebo. Sorafenib was associated with hand-foot syndrome (palmer plantar dysesthesia), and both drugs appear to increase cardiac events. Patients receiving sunitinib were more likely to have decreases in their left ventricular ejection fraction (10%) than placebo-treated controls (1%), and those on sorafenib were more likely to experience cardiac ischemic events (2.9%) than controls (0.4%).
Crizotinib (Xalkori). Fewer than 6% of NSCLCs harbor a fusion of EML4 with ALK. Crizotinib, an MTKi originally developed for the inhibition of cMET, also is active against ALK. This led to the rapid demonstration that crizotinib was highly effective for this subset of patients who rarely harbor ras or EGFR abnormalities. 22 In a disease with a historical response rate of about 10%, they observed a response rate to crizotinib of 57% and a disease control rate of 90%. ALK-positive patients tend to be younger, light or never smokers, and have a histology characterized by abundant mucin production and the presence of signet ring cells.
Drugs That Target Cancer Stem Cells
Like normal marrow, skin and colon stem cells, CSCs are relatively resistant to chemotherapy and radiation. Mechanisms of resistance include an increase in drug efflux pumps, an increase in DNA repair capacity, and aberrant or overexpression of key signaling pathways such as hedgehog and notch. Vismodegib (Erivedge), an inhibitor of hedgehog signaling, has been found useful to treat basal-cell carcinoma, a malignancy characterized by upregulation of this pathway. 23 Inhibitors of the notch pathway are also being tested in the clinic, in particular when upregulation of this pathway can be found, as in T-cell leukemia.
Drugs That Target the Immune System
The observation that melanoma can be immunogenic, as manifested by spontaneous regression and vitiligo, focused attention on directing an immune response against this disease. The pioneering work of Rosenberg and colleagues demonstrating that activation of cytotoxic T cells by interleukin-2 could produce dramatic responses 24 led to the approval of aldesleukin (Proleukin) for the treatment of melanoma and renal-cell carcinoma.
CTLA4. Allison and colleagues hypothesized that inhibiting the function of immune inhibitory Treg cells would be an effective treatment for patients with advanced melanoma. Hodi and co-workers randomized 676 patients who were progressing on therapy for metastatic disease to ipilimumab (Yervoy), a monoclonal antibody targeting CTLA, alone or in combination with the gp100 protein and measured overall survival (OS) as the primary endpoint. Unlike most other therapies, ipilimumab significantly improved OS and ORR. 25 This result, however, came at the cost of autoimmune reactivity in the skin, gastrointestinal tract, and endocrine system and rare drug-related deaths (7 of 540). As physicians have gained experience with this form of treatment and learned how to manage these untoward effects, the safety profile is improving.
Programmed death 1 2 (PD-1). PD-1 is a cell surface receptor on T cells that functions to dampen immune response to certain antigens. Recent evidence suggests that targeting this receptor with an anti–PD-1 antibody (BMS-936558) can restore immune reactivity, resulting in tumor responses in melanoma, NSCLC, and renal-cell carcinoma. 26 Serious drug-related adverse events occurred in approximately 14% of patients.
Drugs That Alter Nucleic Acid Synthesis and Function
Growth factor/growth factor receptor interactions activate signal transduction cascades that initiate DNA synthesis through transcriptional activation of cell proliferation genes, culminating in DNA replication and cell division. A good example is phosphorylation of the retinoblastoma protein (Rb) by CDK4 and CDK6 followed by CDK2. This releases a family of bound transcription factors, E2F(s), which activate genes critical for progression into S phase and are overexpressed in malignancies (e.g., thymidylate synthase, dihydrofolate reductase). For DNA to then be transcribed, it must be made accessible to transcription factors. This is accomplished by releasing DNA from histone packaging via histone acetylases and unwinding of the double helical structure via the action of helicases and topoisomerases. Therefore, it is not surprising that some of our most effective chemotherapeutic drugs target these downstream events, including DNA synthesis, transcription, topoisomerase, and histone deacetylase and methylase activities.
Inhibitors of Nucleic Acid Synthesis
Dihydrofolate reductase (DHFR), the enzyme that replenishes reduced folate pools, was one of the earliest targets for cancer chemotherapy drugs that included aminopterin and methotrexate. By inhibiting DHFR, methotrexate and its polyglutamated derivatives deplete reduced folates and thereby block the synthesis of thymidylate and de novo purine synthesis. Similarly, targeting thymidylate synthase (TS) to interfere with DNA synthesis led to the development of 5-fluorouracil and 5-fluorodeoxyridine; these drugs remain critically important in the modern oncologist’s armamentarium.
Pralatrexate (Folotyn) is a second-generation antifolate that also targets dihydrofolate reductase. 27 Compared to methotrexate, this compound is transported more efficiently into tumor cells via the reduced folate carrier and has better retention because it is a better substrate for polyglutamate synthetase, the enzyme that adds glutamates to reduced folates and folate analogs. In patients with relapsed or refractory peripheral T-cell lymphoma, a Phase II study showed a 29% response rate and duration of response of 10.1 months. Because patients with this disease have limited treatment options, it was approved by the FDA in 2009. It has subsequently been shown to be effective in patients with refractory or relapsed cutaneous T-cell lymphoma, with response rates of 30% to 40%. The dose-limiting toxicity to this drug is stomatitis rather than marrow suppression. Pretreatment of patients with folic acid and vitamin B12 can ameliorate this toxicity, presumably without affecting antitumor effects.
Pemetrexed (Alimta) is a unique antifol containing a 6-5 fused pyrrolo[2,3,-d]pyrimidine nucleus that inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase, folate-dependent enzymes involved in the synthesis of thymidine and purine nucleotides. Like methotrexate, pemetrexed is transported into cells by the reduced folate carrier and membrane folate-binding proteins, where it is metabolized to polyglutamates by folylpoly-gamma-glutamate synthetase. Polyglutamated forms are retained intracellularly and have greater affinity for TS and GARFT than pemetrexed monoglutamate. Pemetrexed also inhibits DHFR. Therefore, this drug interrupts de novo synthesis of thymidine and purine nucleosides. 28 Pemetrexed is approved for the treatment of mesothelioma and NSCLC. Pretreatment with folic acid and vitamin B is now used to ameliorate the most frequent side effects, including bone marrow suppression, fatigue, and skin rash.
Capecitabine (Xeloda) is an orally administered carbamate derivative of 5′-deoxy-5-fluorouridine that acts as a prodrug of 5-FU. 29 It is approved for use as a single agent in metastatic breast cancer that is resistant to anthracyclines and taxanes and in combination with docetaxel for metastatic breast cancer after relapse from anthracyclines. It is also approved as a single agent in the first-line treatment of metastatic colorectal cancer. Capecitabine is converted to 5′-deoxy-5-fluorocytidine (DFCR) by carboxylesterases in the liver. DFCR is then converted to 5′-deoxy-5-fluorouridine (DFUR) by cytidine deaminase in the liver and tumor tissue. DFUR is then converted to 5-FU by thymidine phosphorylase. The therapeutic index of capecitabine may be based on an increased activity of thymidine phosphorylase in tumor compared to normal tissues; therefore, capecitabine may have additional selectivity over 5-FU, although this has not been rigorously demonstrated in the clinic. Its side effects—neutropenia, diarrhea, stomatitis, and palmar-plantar dysesthesia (hand-foot syndrome)—are similar to those seen when 5-FU is given by continuous intravenous infusion.
Gemcitabine (Gemzar) is the 2′-deoxy-2′,2′-difluorocytidine analog of deoxycytidine, which was selected for development because of its activity against murine solid tumors. 30 It is approved for the treatment of recurrent pancreatic cancer and for front-line treatment of inoperable, locally advanced, or recurrent/metastatic NSCLC as well as breast and ovarian cancer.
Gemcitabine inhibits DNA synthesis by intracellular conversion by deoxycytidine kinase to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides that lead to competitive inhibition of DNA polymerase. In addition, gemcitabine diphosphate inhibits ribonucleotide reductase, thereby blocking the synthesis of deoxynucleoside triphosphates for DNA synthesis. Gemcitabine triphosphate also competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into DNA (self-potentiation). Side effects include myelosuppression, nausea, vomiting, transaminitis, diarrhea, stomatitis, proteinuria, hematuria, fever, maculopapular rash, peripheral edema, and flu-like symptoms.
Clofarabine (Clolar) is a purine nucleoside antimetabolite approved for treating relapsed or refractory acute lymphocytic leukemia (ALL) in children after at least two other types of treatments have failed. 31 Efficacy and safety were demonstrated in a single multicenter trial in patients aged 2 to 19. Six patients (12%) achieved a complete remission (CR), 4 patients (8%) achieved a complete remission without total platelet recovery, and 5 patients (10%) achieved a partial response. Of the 15 responding patients, 6 had post-clofarabine bone marrow transplantation. The principal clofarabine toxicities were nausea, vomiting, and marrow suppression with febrile neutropenia. Clofarabine can produce systemic inflammatory response syndrome/capillary leak syndrome, manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multiorgan failure. It can also cause left ventricular systolic dysfunction and tachycardia.
Inhibitors of DNA Topoisomerase
Topoisomerases correct the altered DNA topology that occurs during DNA replication and transcription by inflicting transient single-strand (topoisomerase I) or double-strand (topoisomerase II) breaks in DNA. Several natural-product antineoplastic drugs inhibit topoisomerase I or topoisomerase II. The effect of drugs on topoisomerases is different from that on most other enzyme inhibitors (i.e., they “poison” the enzymes by inhibiting religation of the DNA nicks produced during topoisomerase catalysis, thereby locking the enzyme in the “on” or catalytic conformation). 32
Topoisomerase activity is increased during S phase, and cancer cells appear to have greater topoisomerase activity than their normal counterparts. Thus topoisomerase-targeting drugs inflict greater drug-induced DNA damage and cell death on cancer cells than on normal cells. Differences in the processing of topoisomerase-mediated DNA damage by malignant versus normal cells may also be important in the therapeutic index of these drugs.
Currently approved topoisomerase II inhibitors such as doxorubicin, daunomycin, mitoxantrone, etoposide, and teniposide are part of many combination chemotherapy regimens and form the basis for some of our earliest curative regimens (e.g., non-Hodgkin lymphoma [doxorubicin], acute myelogenous leukemia [daunorubicin], and germ-cell malignancies [etoposide]). Additional topoisomerase II formulations include liposomal doxorubicin (Doxil), originally approved in 1995 for Kaposi sarcoma (Doxil is now approved for relapsed ovarian cancer) and epirubicin (Ellence), an anthracycline that is approved as a component of adjuvant therapy for node-positive breast cancer.
Currently approved topoisomerase I inhibitors include the camptothecin derivatives topotecan and irinotecan. Camptothecin was identified in the early 1960s by Wani and Wall as a potent anticancer alkaloid present in extracts from Camptotheca acuminata (the Chinese yew tree). 33 The sodium salt entered clinical trials in the 1970s but was discontinued because of severe and unpredictable toxicities. The appreciation of its unique mechanism of action by the Liu laboratory 32 and the pH dependence of lactone ring cleavage led to the development of stabler and safer derivatives. Topotecan (Hycamtin), a semisynthetic analog of camptothecin produced by adding a basic side chain at the 9-position of the A-ring of 10-hydroxycamptothecin, has increased water solubility without requiring hydrolysis of the lactone (E-ring). Topotecan was the first topoisomerase I inhibitor approved for clinical use and is indicated for refractory ovarian cancer and “sensitive” small-cell lung cancer after first-line chemotherapy. Its major untoward side effects include myelosuppression, fatigue, moderate nausea and vomiting, diarrhea, and alopecia.
Irinotecan (Camptosar; CPT-1) is another semisynthetic analog of camptothecin approved in 1996 for the treatment of colorectal cancer refractory to 5-FU. It is a prodrug that is converted to the active compound (SN-38) by carboxylesterases, which are present at relatively high concentrations in the intestine. Indications now include first-line treatment in combination with 5-FU and leucovorin for metastatic colon or rectal cancer and for colorectal cancer that has progressed or reoccurred following initial treatment with 5-FU. Its myeloid and gastrointestinal toxicities are enhanced when given in combination with 5-FU and leucovorin. Patients with Gilbert’s disease or other polymorphisms in the UGT1A1 glucuronyl transferase have an increased risk of toxicity. 34 The combination of irinotecan and 5-FU/LV was approved in combination with bevacizumab for first-line treatment of metastatic colorectal cancer.
Alkylating Agents
DNA replication requires that the bases be accessible for Watson-Crick pairing. This normal biochemistry is interrupted by the alkylating agents. 35 The work of Alfred Gilman and Louis Goodman and their colleagues at Yale University demonstrated that nitrogen mustard could abolish lymphomas in experimental animals and had chemotherapeutic effects in man. These studies, carried out during World War II, were the start of cancer chemotherapy. The classes of alkylating agents include the nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, bendamustine), nitrosoureas (e.g., BCNU), ethyleneimines (e.g., thiotepa), alkyl sulfonates (e.g., busulfan), and the triazines (e.g., dacarbazine, temozolomide).
Temozolomide (Temodar) is the 3-methyl derivative of mitozolomide, which was discovered when screening a series of 1,2,4-triazenes and triazinones synthesized in the 1960s and 1970s. 36 Mitozolomide was the most promising compound, but it had severe and unpredictable side effects. Temozolomide, like DTIC, methylates N-7 and O-6 of guanine to produce the cytotoxic lesion. Temozolomide is approved for the treatment of adult patients with refractory anaplastic astrocytoma (disease progression after nitrosourea or procarbazine) and as adjuvant treatment when given with radiation to patients with glioblastoma multiforme. The most common side effects are lymphocytopenia, transaminitis, nausea and vomiting, hyperglycemia, anemia, and thrombocytopenia.
Bendamustine (Treanda) was used extensively to treat lymphoma in the 1980s in East Germany, but only became available in the United States in 1990. 37 It was approved by the FDA in 2008 for the treatment of CLL and indolent B-cell non-Hodgkin lymphoma that progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. It acts as an alkylating agent causing intrastrand and interstrand crosslinks between DNA bases. The role of the purine ring in the molecule is not clear. It is usually used in combination with rituximab for the treatment of CLL and lymphoma. Common adverse reactions include nausea, fatigue, vomiting, diarrhea, fever, constipation, loss of appetite, cough, headache, unintentional weight loss, difficulty breathing, rashes, and stomatitis, as well as immunosuppression, anemia, and low platelet counts.
Platinating Agents
The therapeutic properties of cisplatin were deduced from studies of bacterial motility in electric currents, where bacterial cell death was observed adjacent to platinum electrodes. 38 Platinating agents consist of platinum complexed with ligands that are displaced by nucleophilic attack to produce inter- and intrastrand DNA adducts. Currently approved platinating agents include cisplatin, carboplatin, and oxaliplatin, which differ in their spectrum of activity and untoward side effects. For example, cisplatin is active against lung cancer, head and neck cancer, and in combination with vinblastine and bleomycin led to the first reliable cures of testicular cancer. Cisplatin is highly emetogenic and is a potent oto- and nephrotoxin. In contrast, carboplatin appears to be less active than cisplatin against tumors of the head and neck and perhaps NSCLC. It is less emetogenic and nephrotoxic than cisplatin, but more myelotoxic. Oxaliplatin (Eloxatin; trans-l-diaminocyclohexane oxalatoplatinum) is a divalent coordination complex of platinum consisting of an oxalato group and a 1,2-diaminocylohexane (DACH) ligand. This third-generation platinum derivative is more active than cisplatin against colon cancer. Unlike cisplatin or carboplatin, renal dysfunction, ototoxicity, and alopecia are uncommon. The dose-limiting toxicity is peripheral neuropathy, which can be acute (lasting less than 14 days) or persistent (14 days or greater); an acute syndrome of pharyngolaryngeal dysesthesia can be exacerbated by exposure to cold (temperature, objects, or liquids). Oxaliplatin is approved for the treatment of colorectal cancer in either the adjuvant or metastatic settings. The activity of oxaliplatin is dependent on the formation of intrastrand (Pt)-DNA adducts/crosslinks, similar to that of other Pt compounds. DNA crosslinks inhibit replication and transcription and activate apoptosis. Oxaliplatin has been reported to also downregulate TS and increase sensitivity to fluoropyrimidines. 39 Oxaliplatin forms 2- to 10-fold fewer Pt-DNA adducts than cisplatin at equimolar and equitoxic concentrations, suggesting that these adducts may be more cytotoxic or that alternative mechanisms of action exist. DACH-Pt-DNA adducts formed by oxaliplatin are bulkier and more hydrophobic than cis-diamine-Pt-DNA adducts and may have greater inhibitory effects on DNA repair. DNA mismatch repair complexes do not recognize DACH-Pt-DNA adducts.
Epigenetic Modulators
The modification of DNA sequences by methylation and acetylation provides a remarkably diverse and powerful control over gene expression. The work of Peter Jones, Steve Baylin, and many others highlighted the types of epigenetic modifications that appear to be part of malignant transformation. 40 Furthermore, drugs that alter these epigenetic “marks” through enzyme inhibition of histone methyltransferases, such as decitabine (Dacogen) and azacitidine (Vidaza), or histone deacetylases, such as suberoylanilide hydroxamic acid (SAHA; vorinostat, Zolinza) and romidepsin, have had some success in the clinic.
Romidepsin. Romidepsin, isolated from a culture of Chromobacterium violaceum, was found to have cytotoxic effects against several human cancer cell lines in vitro and against xenografts. It was subsequently found to inhibit histone deacetylase. 41 Romidepsin acts as a prodrug, with the disulfide bond undergoing reduction within the cell to release a zinc-binding thiol. The thiol reversibly interacts with a zinc atom in the binding pocket of Zn-dependent histone deacetylase to block its activity. The FDA approved romidepsin for treatment of peripheral T-cell lymphoma (PTCL) in 2011 based on a Phase II study that showed a 25% response rate with 15% of patients achieving a CR. 40 The median duration of response was 17 months. The most common side effects were nausea and vomiting, fatigue, infection, loss of appetite, and anemia, thrombocytopenia, and leukopenia.
Vorinostat (SAHA, suberoylanilide hydroxamic acid) is a potent histone deacetylase inhibitor approved by the FDA for treatment of refractory cutaneous T-cell lymphoma based on a large Phase II study. 42 Response and duration of responses were similar to romidepsin. Side effects include fatigue, diarrhea, nausea, hyperglycemia, and thrombocytopenia.
Drugs that Affect the Mitotic Apparatus
Vinca Alkaloids, Taxanes, and Epothilones
Microtubules are essential for normal cellular function. They form the mitotic spindle, maintain cell shape, organize the location of organelles, mediate intracellular transport and secretion, and neurotransmission as well as axonemal flow and cell motility. Microtubules are composed of α– and β-tubulin dimers organized in bundles of 13 protofilaments that form hollow cylinders. The protofilaments are aligned with the same polarity. The (+) or fast-growing end moves outward from the nucleus to the plasma membrane, whereas the (−) or slow-growing end marks the site of nucleation of the microtubule, which often begins in the centrosome. Time-lapse microscopy has demonstrated that microtubules grow in spurts or may disappear altogether. This process, termed dynamic equilibrium, is an essential feature of microtubule physiology. For microtubules to elongate they require the addition of both α– and β-tubulin bound to GTP. Once bound to GTP, β-tubulin forms a GTP cap at the elongating end. Rapid microtubule growth requires bound GTP to increase the affinity for other tubulin molecules. During depolymerization, GTP is hydrolyzed more rapidly than it can be added, resulting in weakening of the bonds that hold the tubulin molecules together.
Drugs Affecting Microtubule Polymerization
Paclitaxel (Taxol) was isolated in 1971 by Wani and Wall as an active moiety from the bark of the pacific yew, Taxus brevifolius. 43 The taxanes are large alkaloid esters consisting of a taxane ring linked to a four-member oxetan ring at positions C-4 and C-5. Docetaxel (Taxotere), a semisynthetic derivative produced from 10-deacetylbaccatin III, is more water soluble and more potent in vitro. Initially, the difficulties encountered in formulating this insoluble compound and its toxicities in patients diminished enthusiasm for developing this new agent. However, interest in paclitaxel was renewed when the Horowitz laboratory identified its unique mechanism of action (i.e., stabilization of polymerized microtubules 44 ). Paclitaxel and docetaxel share broad-spectrum antitumor activity including breast, lung, ovarian, and bladder cancers. Both have effects against lymphoid malignancies. Nab-paclitaxel (Abraxane) is a derivatized formulation of paclitaxel bound to albumin nanoparticles, allowing the drug to be administered at a higher maximum tolerated dose and without Cremophor-El, thereby eliminating the need for extensive premedication. The albumin moiety may help target this agent to tumors expressing SPARC, the albumin receptor. 45
Taxanes preferentially bind to the N-terminal 31 amino acids of the β-subunit of tubulin oligomers or polymers and inhibit microtubule depolymerization. At nanomolar concentrations, the taxanes produce a mitotic block without increasing microtubule polymer mass. At stoichiometric concentrations (1 M drug per 1 M tubulin dimer), taxanes polymerize and stabilize microtubules in the absence of GTP or microtubule-associated proteins (MAPs); these microtubules are resistant to depolymerization by calcium or low temperature.
The taxanes have broad-spectrum anticancer activity. They are used predominantly in the treatment of solid tumors (ovarian, breast, lung, bladder, head, and neck). Although docetaxel is more potent than paclitaxel, there is little direct evidence that it is more effective. The combination of docetaxel with estramustine or prednisone prolongs survival of patients with hormone-refractory prostate cancer. 46 Preclinical studies demonstrated that unlike most chemotherapeutic agents, taxanes are more active against cancer cells harboring p53 mutations; this may help explain their widespread activity and therapeutic index. 47 Both paclitaxel and docetaxel produce peripheral neuropathy, dose-limiting bone marrow suppression, and alopecia. Nausea, vomiting, and diarrhea occur with both drugs but are rarely severe. Docetaxel can cause vascular permeability (peripheral edema, pleural effusions, and ascites). Fluid retention occurs at cumulative doses above 400 mg/m 2 and may be decreased by lower single doses (less than 60 to 75 mg/m 2 ) or premedication with dexamethasone. Docetaxel also produces skin toxicities including an erythematous maculopapular rash of the forearms and hands. Both paclitaxel and docetaxel cause type I hypersensitivity reactions characterized by flushing, bronchospasm, dyspnea, and hypotension.
Ixabepilone (Ixempra) is a member of the epothilone family of natural product macrolides initially discovered as cytotoxic metabolites from the myxobacterium Sorangium cellulosum. They have a similar mechanism of action to the taxanes and compete for a binding site on polymerized microtubules. 48
Drugs Affecting Microtubule Depolymerization
The vinca alkaloids were identified as extracts from the pink periwinkle plant (Catharanthus roseus G. Don.) that produced granulocytopenia in rats. This observation led to the isolation of four active alkaloids, of which two, vincristine and vinblastine, became active therapeutic agents. Today, this class also includes vinorelbine and vindesine.
The vinca alkaloids are large symmetrical molecules consisting of a dihydroindole nucleus (vindoline) connected to an indole nucleus (catharanthine) by a methylene bridge. Vincristine and vinblastine differ by a single R1 substituent, whereas vinblastine and vindesine differ in the R2 and R3 positions; vinorelbine has a modification of the catharanthine ring.
The mechanism of action of these drugs is concentration related. At substoichiometric concentrations, they bind to high-affinity sites at the ends of microtubules (Ka 5.3 × 10 −5 M) and prevent microtubule polymerization. At higher concentrations, vincas bind to low-affinity, high-capacity sites (Ka 3-4 × 10 −3 M) and lead to the disintegration of formed microtubules.
Despite structural similarities, the spectrum of activity and toxicities of the vinca alkaloids are different. For example, vincristine is highly effective against non-Hodgkin lymphoma, Hodgkin’s disease, and pediatric solid tumors, yet vincristine has little activity against adult solid tumors. In contrast, vinorelbine is active against breast and lung cancer. Vinblastine is most frequently used in the treatment of testicular cancer and non-Hodgkin lymphoma and is an active agent in the treatment of breast cancer. Vinca alkaloids are potent inhibitors of angiogenesis, which may contribute to their activity. 49 Major toxicities include dose-limiting myelosuppression and neurotoxicity. Vinblastine and vinorelbine produce far greater neutropenia than vincristine, with nadirs occurring at 4 to 10 days with recovery seen in most patients by 7 to 21 days. All three agents cause mild alopecia and are severe vesicants. Vinorelbine may cause chest pain and other deep-seated pain of unspecified origin. Respiratory reactions include acute bronchospasm and subacute cough; dyspnea and pulmonary infiltrates have also been reported and appear responsive to steroids. The most frequent neurotoxicities are numbness and tingling of the extremities, loss of deep tendon reflexes, and distal muscle weakness. Although the sensory changes are bothersome, they usually reverse over time and may not require discontinuation of the drug. Loss of motor function is a later and more ominous side effect, requiring discontinuation of the medication and or a search for other contributing factors.
Brentuximab vedotin is a chimeric anti-CD30 antibody conjugated to four molecules of a potent tubulin inhibitor, monomethyl auristatin. 50 This antibody-drug conjugate targets CD 30, a surface protein fairly specific to Reed-Sternberg cells and anaplastic large-cell lymphoma (ALCL). Key to the success of brentuximab vedotin is the cleavable dipeptide linker that is stable in serum, but once internalized is cleaved by lysosomes releasing auristatin. This drug was approved in 2011 for the treatment of relapsed Hodgkin’s lymphoma patients and of systemic ALCL after failure of at least one multiagent chemotherapy regimen. The response rate in Hodgkin’s patients with refractory disease was 75%, with 34% complete remissions. In ALCL there was an 86% response rate and 53% complete remissions. Similar to other antitubulin agents, brentuximab vedotin causes peripheral neuropathy, with 52% experiencing neuropathy of any grade, and 8% grade 3 or 0% grade 4 neuropathy. The neuropathy, usually sensory, can also be motor and irreversible; patients need to be monitored carefully during treatment. Other side effects include marrow suppression, fatigue, and gastrointestinal effects.
Drugs That Affect Protein Synthesis and Degradation
Few drugs affecting protein synthesis and/or degradation have been used for the treatment of cancer. This is somewhat surprising given that the complexity of the process provided important targets for the development of antibacterial antibiotics. The process of protein synthesis includes initiation, elongation, and termination requiring an array of amino acids, structural proteins, enzymes, and substrates including ribosomes, initiation factors, elongation factors, termination factors, and protein kinases that regulate the function of many of these elements. Historically, L-asparaginase has been the prototype of this class of drug. Recent attention has turned to the factors that control protein degradation. The ansamycins (e.g., geldanamycin) represent a class of agents that interfere with protein chaperones (i.e., proteins that bind to and stabilize newly formed or damaged proteins). Proteins targeted for degradation due to damage, improper folding, or cellular excess may proceed through one of two pathways, lysosomal or proteasomal. Bortezomib (Velcade), a drug that broadly inhibits proteases that are present in the proteasome, has been approved for the treatment of refractory myeloma. 51 It interferes with proteasomal degradation of proteins such as the NFκB inhibitor, IκB. NFκB is a constitutively activated transcription factor in myeloma52 shown to promote oncogenesis by increasing growth factors (IL-6, VEGF), cellular adhesion molecules (ICAM1, VCAM1), and anti-apoptotic proteins (bcl-2, IAP). For a drug that interferes with a fundamental cellular process, bortezomib is relatively well tolerated. Peripheral neuropathy is the most troublesome side effect, which can be ameliorated by subcutaneous administration. 53
Recent attention has focused on the PI3K/AKT signaling pathway because it is frequently altered during malignant transformation. This pathway provides exquisite control over energy utilization (see earlier discussion and Figure 46-3) by regulating protein synthesis, 54 the most voracious energy consumer. Inhibitors of mTOR such as everolimus (Afinitor) and PI3Kδ are recent examples of this class of agent.
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∗ We focus primarily on drugs that have achieved approval from the U.S. Food and Drug Administration (FDA); numerous drugs against new targets are in development, but a comprehensive description is beyond the scope of this chapter.
