Cancer Therapeutics

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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

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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.
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