Drugs2011;7ini):1386-1396 0012-667/11/0011-136S/S65.55/0 2011 Adis Dato Information BV. Ail rigiits reserved.

Cellular Redox Pathways as a Therapeutic Target in the Treatment of Cancer

Alberto J. Montero^ and Jacek Jassem^
1 Department of Internal Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA 2 Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland

Abstract

The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the Superoxide anin radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage. There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting ^-glutathionylation have direct anticancer effects via cell signaUing pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents. NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer.

Cytotoxic chemotherapy has been a focus of anticancer drug development since 1945. At that time, wartime research was made publicly avail-

able and demonstrated the potential anticancer effects of nitrogen mustards.''' Since then, cytotoxic chemotherapy has been used successfully

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Table I. Known mechanisms of action of classic cytotoxic anticancer agents'^' Class Cytotoxic antibiotics Antimetabolites Alkylating agents Plant derivatives (i.e. taxanes) Mechanism of action Prevent mammalian cell division Impede or destabilize metabolic pathways invoived in DNA synthesis Form covalent bonds with DNA and thus inhibit DNA replication Inhibit formation of the mitotic spindle or inhibition of topoisomerases Agents Doxorubicin, epirubicin, bleomycin Methotrexate, pentostatin cytarabine, fluorouracil. capecitabine, gemcitabine Cisplatin. carboplatin Etoposide, paclitaxel, docetaxel, irinotecan

for a wide range of tumour types. The drug class later expanded to include a large number of therapeutic agents in four mechanistic sub-classes: cytotoxic antibiotics, antimetabolites, alkylating agents and plant derivatives, e.g. vinca alkaloids, topoisomerase inhibitors and taxanes. Although their detailed mechanisms of action differ, all of these drugs share the same basic effect - the inhibition of cell division (table I).'-' In addition to their well characterized effects on cell division, many cytotoxic agents also exploit the vulnerability of some cancer cells to oxidative signals. Research has shown that chemotherapeutics can induce oxidative stress by modulating levels of reactive oxygen species (ROS; table 11)'-'"'^] such as the Superoxide anin radical, hydrogen peroxide and hydroxyl radicals.''-^^ Tumour cells are known to be particularly sensitive to oxidative stress because they typically have higher levels of ROS than normal cells.''^ Differences in ROS levels between normal and neoplastic cells are due to the dysregulation of redox balance in cancer cells that develops when, for instance, intracellular production of ROS increases, or when levels of antioxidant agents become depleted.'''*' Of the classic cytotoxic agents known to modulate cellular redox balance, the anthracyclines doxorubicin and epirubicin are among the most widely used. Anthracyclines are approved for the treatment of a broad range of malignancies, and are frequently used for the treatment of breast cancer, gastric cancer, sarcoma, ovarian cancer and other malignancies.f'^'^1 They induce cyclical redox reactions (redox cycling) that result in S-glutathionylation (thiolation) of cellular proteins (table 11).'^' Analogous to phosphorylation, thiolation is a reversible post-translational mod 2011 Adis Data information BV. AN rights reserved.

ification of protein structure, which affects protein function and activity,'^"' and in some cases eventually leads to apoptosis. Many cytotoxic agents have been traditionally viewed as working primarily through inhibifion of mitosis; however, emerging data have demonstrated that they also have redox activity.f''"'^' Recent studies have not only revealed the redox capability of existing drugs, but have also developed specific new agents to target the redox regulation of tumour cells and enhance the redox capability of other drugs. In this article, the role of redox regulation in carcinogenesis and its potential as a therapeutic target is reviewed.

Table II. Examples of approved cytotoxic agents that modulate cellular redox balance Agent Arsenic trioxide Impact of redox modulation Covalent adduction and oxidation of redox-sensitive cysteine residues in GSH and proteins, leading to intraceliular glutathione f^etai-dependent generation of oxygen free radical leading to DNA fragmentation'^'^! Induction of apoptosis by ROS''' Induction of apoptosis by ROS'^' Redox cycling resulting in S-glutathionylation and induction of apoptosis"' Induction of apoptosis by ROS''' Caiicheamicin y^ induces oxidative DNA strand breaks at pyrimidinerich recognition sites'^' Induction of apoptosis by
'2'

Bleomycin

Bortezomib Cisplatin Anthracyclines (e.g. doxorubicin, epirubicin, daunorubicin, idarubicin) Etoposide Gemtuzumab (containing caiicheamicin) Taxanes (e.g. docetaxei and paciitaxel)

GSH = reduced glutathione; ROS = reactive oxygen species.

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1. The Importance of Redox Modulation in Cancer 1.1 Glutathione System of Redox Control The overall cellular redox state is regulated by three systems, two of which are dependent on glutathione: the reduced glutathione (GSH)/oxidized glutathione (GSSG) system; the glutaredoxin (Grx) system; and the thioredoxin (Trx)/Trx reductase system.'"^'--' GSH, Grx and Trx each modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides.'-'' GSH acts directly as an electron donor, while Grx uses GSH or GR as the electron donor and is, therefore, also dependent upon intracellular GSH concentration. In contrast, Trx uses nicotinamide adenine dinucleotide phosphate (NADPH) as its electron donor, and is independent of GSH.'-'1 Therefore, homeostatic control of intracellular redox status is largely exerted by GSH, which usually exists in its reduced state to protect the cell from oxidative stress. In the cytoplasm, the ratio of reduced GSH to GSSG may be as high as 100: 1. In the endoplasmic reticulum the ratio is lower at approximately 3: 1 .'-1 .,2 Reactive Oxygen Species in the Development of Concer ROS are thought to play an important role in the development of cancer by the mediation of oxidative DNA damage:''-'' ROS have been found to directly induce DNA damage,''^' and have also been implicated in the inhibition of DNA repair.'-'' When mutations occur in genes critical to cellular proliferation, such as oncogenes and tumour suppressor genes, ROS-mediated DNA damage or prevention of repair can lead to the initiation and progression of cancer.'-''*^' Not only do excess ROS levels have the potential to contribute to oncogenesis, but high levels of ROS also persist in tumour cells, and can contribute to reduced susceptibility to apoptosis.'-*! The presence of excess ROS in cancer cells means that tumours often exist under mildly oxidative conditions. Because of this heightened basal level of oxidative stress, cancer cells may be more sus 2011 Adis Data Information BV. Ali rights reserved.

ceptible to further oxidative stress than normal cells because their endogenous antioxidant systems can be overwhelmed.'-^' This important biological difference between normal and neoplastic cells may potentially be exploited therapeutically by agents that further augment ROS levels or weaken antioxidant defenses in cancer cells.'^'*' The vulnerabilities of cancer cells to oxidative signals are now recognized as a potential target for the rational design of new anticancer agents. Agents that exploit these pathways would synthetically increase the lethality of anticancer agents in neoplastic cells, while leaving normal cells undamaged. 1.3 Redox Regulation and S-Glutathionylation The function of GSH in cellular detoxification is widely recognized, and research is continuing to define its role, and the role of its oxidized counterpart GSSG, in the general regulation of cell function via redox balance (figure 1). The ability to modulate the function of a cell via redox balance is based on the principle that the degree of oxidative stress applied to a cell can result in dramatic differences in outcome. For example, extreme oxidative stress may lead to necrotic cell degradation. However, GSSG, through S-glutathiolynation and induction of mild oxidative stress, regulates important cellular functions such as the elimination of reactive thiol-containing proteins.'^"*' S-glutathionylation occurs when a disulfide bond is formed between a reactive protein cysteinyl residue and GSH. Like phosphorylation, ^-glutathionylation is a reversible mechanism of protein regulation.'-"' Specifically, it modulates the activity of a variety of proteins, such as nuclear factor KB, caspase 3 and p53. As a consequence, these modifications can affect various cell signalling cascades.'-**' S-glutathionylation can also lead to phenotypic changes such as increased cell proliferation, increased cell invasiveness and apoptosis, all of which are features of oncogenesis, tumour progression, and the control of immune function.'-"'' The remainder of this review explores the range of anticancer drugs that are in development to target cellular redox activity.
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Regulation of cell function

Detoxification

Activates/inhibits reactive thiol (SH)-containlng proteins e.g. PTEN, MEKKI (JNK), p53, thioredoxin, GST, peroxiredoxin

Protein S-glutathionylation

Reduces free radicals and reactive oxygen species Detoxifies cells through conjugation with, and elimination of. toxins

Fig. 1. The glutathione system of redox control: oxidized and reduced glutathione have contrasting roles. Redox modulation via GSH:GSSG has the potentiai to reguiate a number of pathways, and net response to redox modulation depends on cell type and status. JNK = Jun-Nterminal kinase; GSH = reduced glutathione; GSSG = oxidized glutathione; GST = glutathione-S-transferase; MEK = mitogen-activated protein kinase kinase; MEKKI = MEK kinase inhibitor; PTEN = phosphatase and tensin homologue.

2. Targeting Redox Modulation in Cancer: Drugs in Development

The realization that many currently utilized chemotherapy drugs have actions on redox pathways that potentially contribute to their antitumour activity has led researchers to explore the potential of specifically targeting cellular redox balance, particularly because of differences in levels of ROS between normal and cancer cells as well as differences in their capacity to repair DNA damage from alterations in ROS. There are several agents in development for cancer treatment with mechanisms of action that have an impact on cellular redox regulation (table 111).^-^'-'") 2.1 Targeting the Glutathione System As described in section 1.2, persistently elevated levels of ROS and increased oxidative stress present in cancer cells can lead to oncogenic mutation through DNA damage. This damage can result in the generation of mutant peptide gene products that diminish or cancel the effectiveness of chemotherapeutic agents, particularly molecularly targeted therapies.'^' Drugs that target S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. As such, these drugs have the potential to allow traditional anticancer chemotherapies and targeted anticancer drugs to overcome the risks of developing mutationmediated resistance.'^!

Of the agents in development that modulate redox status or mediate their effects through 5-glutathionylation, NOV-002 has been most extensively studied, with a phase III trial completed in advanced non-small cell lung cancer (NSCLC)!'*'-'*^) and data available from phase II trials in breast''*'' and ovarian cancers.''**' NOV-002 is a proprietary product containing oxidized glutathione that has been shown to alter the GSH : GSSG ratio by increasing GSSG levels, creating a mild, transient oxidative intracellular signal and inducing S-glutathionylation.'""' NOV002-induced 5'-glutathionylation has been shown to have inhibitory effects on tumour cell invasion,'*'' prohferation and survival,'"'''' and differential effects on myeloid cell lines.''^'' These properties of NOV-002 are likely to have contributed to the significant enhancement of the antitumour effect of adoptive T-cell therapy in a murine melanoma model'^^' in addition to significantly increasing the efficacy of cyclophosphamide chemotherapy in a murine model of colon cancer.'^^' In a randomized phase II trial conducted in the US, NOV-002 in combination with standard chemotherapy has shown promising effects in patients with stage Illb/IV NSCLC.!"^-^! Positive results were also obtained from a phase II trial in patients with neoadjuvant breast cancer therapy'''^' and chemotherapy-resistant ovarian cancer.'""*' In a single-arm, phase II trial, 41 patients with stage II-III human epidermal growth factor receptor (HER)-2 negative breast cancer were treated with daily NOV-002 injections in combination with
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four cycles of doxorubicin and cyclophosphamide (AC: 60/600 mg/m^) every 21 days followed by docetaxel (T: 100 mg/m^).'-'''*' The primary endpoint of this trial was pathological complete response (pCR). The trial utilized a Simon 2-stage optimal design (a = 0.05 and = 80%), assuming a doubling of the historical pCR rate for AC/T with the addition of NOV-002 from a pO of 0.16 to a pi of 0.32. According to the trial design, the treatment regimen would be declared active if >12 patients experienced a pCR by the end of the trial. Results reported recently from 38 patients assessable for response demonstrated a pCR rate of 37.5%.''*^' These data compare favourably to results reported in the large, phase III NSABP (National Surgical Adjuvant Breast and Bowel Project) B-27 trial,'-''''' which also assessed AC/T in patients with breast cancer. The results are also comparable with those from the recent GeparQuattro study, where the pCR rate was 22.3% following application of a similar chemotherapy regimen.'-^*' Another study evaluated NOV-002 followed by carbopiatin in 15 patients with confirmed platinum-resistant ovarian cancer. A higher than expected clinical response rate (one partial response and seven stable disease) was achieved, with a median progression-free survival (PFS) of 15.4 weeks compared with 8 weeks for historical controls in similar patients. The regimen was well tolerated with no apparent additive toxicity of NOV-002.''**' A recently completed randomized, open-label, phase III trial evaluated NOV-002 plus paclitaxel and carbopiatin (PC) versus PC alone in patients
Table III. Redox-modulating anticancer agents n development Target class Glutathione system L-buthionine-S. R-sulfoximine^^' Agent

with advanced NSCLC (stage IIIB with malignant pleural or pericardial effusion, or stage IV), ECOG performance status 0-1 and adequate end-organ function.'''''I Eligible patients (n = 903) were randomized to carbopiatin (area under the plasma concentration-time curve [AUC] 6), paclitaxel (200mg/m-) and NOV-002 (group A) or PC alone (group B). NOV-002 was administered as two 60 mg intravenous infusions on day -1 of cycle 1, and as one intravenous bolus on day 1 of each cycle, followed by daily 60 mg subcutaneous injections. Median overall survival (OS) for groups A and B were 10.2 and 10.8 months, respectively (p = 0.375), and median PFS for groups A and B were 5.3 and 5.6 months, respectively. Both group A and B achieved an objective response rate of 26%. The addition of NOV-002 did not add to the overall toxicity of chemotherapy.''*''' L-Buthionine-S,R-sulfoximine (buthionine sulfoximine; [BSO]) has long been known to induce cellular oxidative stress via intracellular glutathione depletion,'-^'-^^-'^^1 and it has also been shown to synergize with cytotoxic chemotherapy agents, including arsenic trioxide, cisplatin, doxorubicin and melphalan.''^' BSO is being evaluated in neuroblastoma where it has been shown to inhibit GSH biosynthesis, leading to upregulation of ROS production, and triggering of apoptosis of neuroblastoma cells amplified with MYCN (V-myc myelocytomatosis viral related oncogene, neuroblastoma derived).'''^' Following promising early-phase studies in combination with melphaIjjjj 160.61] gQ pi^jg melphalan is undergoing clinical evaluation in children with neuroblastoma,'''-''-''

Mecbanism of redox modulation Induction of S-glutathonylationl^'l Glutathione depletion leading to induction of apoptosis Inhibition of glutathione-S-transferasel*"' Inhibition of giutathione-S-transferase'^' Depletion of cellular thiols leading to induction of apoptosis by ROS'^^' Induction of glutathione oxidation'^'

Thioredoxin system Dimesna'"'! Motexafin gadoiinium'"^'

Inhibition of thioredoxin-i'""! Inhibition of tbioredoxin-1 and glutaredoxinl''^' Inhibition of thioredoxin-1l''^l induction of oxidative stress and subsequent apoptosis by ROSl"'

Darinaparsinl""' Arsenic derivatives ROS = reactive oxygen species.

2011 Adis Data Informotion BV. All rights reserved.

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and in patients with persistent or recurrent stage III malignant melanoma.'^"' Canfosfamide (TLK286)[^''' has been shown to inhibit glutathione-S'-transferase Pl-1 (GSTpi)I^^-^-34] and, therefore, may block a potential route for cellular resistance to cytotoxic agents. GSTpi is frequently overexpressed in several different solid tumours, particularly those that are resistant to chemotherapy, and overexpression has been associated with poor prognosis.'*^'*^' Inhibition of GSTpi may also be particularly important for overcoming resistance to platinum agents.'"'' Canfosfamide has demonstrated cytotoxic activity in combination with carboplatin and paclitaxel in advanced first-line NSCLC,'***' although no improvements in median PFS or OS were observed in a phase III trial in ovarian carcinoma (third-line) with the drug as a single agent compared with cytotoxic chemotherapy alone.'^'' Ezatiostat hydrochloride (TLK199) is a prodrug that, once bioactivated to TLK117, binds to GSTpi and subsequently leads to the activation of Jun-N-terminal kinase (JNK).''"'' It is thought that activation of JNK leads to growth and differentiation of normal cells and apoptosis of malignant cells.'-**' In vitro, ezatiostat has been shown to stimulate multilineage differentiation of haematopoietic progenitors and induce myeloblast differentiation in leukaemia cell lines with ineffective myelopoiesis.'^^' It is currently being developed primarily for the treatment of spontaneously occurring and chemotherapy-induced cytopenias. Ezatiostat is also undergoing clinical evaluation in patients with myelodysplastic syndrome'-^*'^'' and severe, chronic neutropenia.'^^' Imexon is a pro-oxidant small molecule that depletes cellular thiols, leading to oxidative stress and, subsequently, apoptosis.'"' Successful phase I trials have been completed in combination with cytotoxic chemotherapy in advanced breast, NSCLC, prostate'^^' and pancreatic'^'*' tumours. Results from a randomized phase II trial with gemcitabine plus imexon versus gemcitabine alone as first-hne therapy in patients with advanced pancreatic cancer has recently been reported.'^''! This study did not meet its primary endpoint of the addition of imexon to gemcitabine prolonging survival by 40%.
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' is an approved alcohol-abuse deterrent that can undergo thiol-disulfide exchange.'''' It is currently undergoing evaluation as an anticancer treatment due to its ability to induce apoptosis through oxidization of glutathione leading to DNA fragmentation as well as through proteasome inhibition.'''^''^^' Disulfiram has been shown to preferentially target human melanoma cells in vitro through oxidative stress-induced apoptosis, without exerting cytotoxicity in primary melanocytes.'^**' A phase I/II trial in patients with metastatic melanoma has recently been completed'^^' and other early-phase studies are ongoing in NSCLC'^''' and treatment-refractory liver tumours.'**'! A phase II study conducted approximately 20 years ago examined the activity of disulfiram (2000 mg/m-) plus cisplatin (lOOmg/m-) in a range of different cancers, and showed differences in response rates between tumour types. However, this study was underpowered, with only 50 patients in total, nearly half of which (n = 23) were not valuable for response.'^^' 2.2 Targeting the Thioredoxin System PX-12 irreversibly inactivates Trx-l.'""' Trx-1 is overexpressed in many human tumours and it is associated with aggressive tumour growth and decreased patient survival.''*"' Trx-1 regulates the hypoxia-inducible transcription factor, which may contribute to the inhibition of vascular endothelial growth factor expression when cultured cells and human tumour xenografts are treated with PX-12.''*"' PX-12 has shown promising pharmacokinetics and pharmacodynamics in a phase Ib trial in patients with advanced chemotherapy refractory solid tumours.'*''^' A recent randomized phase II trial with PX-12 in patients with advanced pancreatic cancer was recently published.f**"*! This was an open-label trial evaluating two different doses of PX-12, with patients randomized to receive either 54 or 128mg/m' as daily intravenous infusions for 5 consecutive days;'^^' patients were stratified based on CA 19-9 (carbohydrate antigen 19-9) level (>1000 vs <1000U/mL) and standardized uptake values on PET scans (>7.0 vs <7.0). The primary endpoint was PFS. PX-12 was well tolerated, with grade
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toxicities being uncommon. The most common adverse effects included: cough (mild to moderate), a garlic-like odour, fatigue, nausea and anorexia. However, the median PFS in both doses of PX-12 was only 0.9 months and median OS only 3.2 months, both of which are clearly inferior to results previously reported with conventional cytotoxic chemotherapy as second-line therapy in advanced pancreatic cancer. Moreover, plasma Trx-1 levels were measured and no objective declines in levels relative to pretreatment levels were observed. One of the observed problems was that only a small percentage of patients screened for this study (11%) had elevated Trx-1 levels. Trx-1 remains a promising target; however, these results suggest that PX-12 should be further evaluated in combination with cytotoxic chemotherapy, and also that more sensitive predictive biomarkers need to be developed that can better identify patients likely to benefit from PX-12. Dimesna (BNP7787)'4'' is a novel chemoprotective disulfide compound'**'"' that targets Trx and Grx,'"*-' which are overexpressed in many tumours. Its mechanism of action is unclear, but it has been postulated that dimesna interferes with key components of the Trx and Grx systems that are associated with tumour survival.'"*^' Dimesna has undergone early clinical assessment in various solid tumours, including ovarian carcinoma and NSCLC.'**^i In addition, it is currently undergoing phase III clinical evaluation, in combination with rst-hne taxane and platinum chemotherapy, in patients with newly diagnosed or relapsed advanced (stage IIIB/IV) NSCLC adenocarcinoma.'**^ A meta-analysis of two trials (one randomized phase II conducted in the US, and a phase III trial conducted in Japan) suggested that dimesna combined with a taxane plus cisplatin as first-line therapy results in significant increases in median OS and 1-year OS in patients with stage IIIB/IV NSCLC with adenocarcinoma histology.'"*^' Motexafin gadolinium (MGd)'"*-^' is a Trx inhibitor and redox catalyst that reversibly accepts electrons from cellular redox factors such as NADPH, NADH, glutathione and ascorbate, with subsequent electron transfer to molecular oxygen.''*-^' A phase I trial'**-^' in patients with locally advanced pancreatic or biliary cancers, and a
2011 Adis Data Information BV. All rights reserved.

phase II trial'****' in renal cell carcinoma, have been completed with MGd. In a phase III trial with MGd plus prompt whole brain radiotherapy, NSCLC patients with brain mtastases experienced significant prolongation of the interval to neurological progression with an acceptable toxicity profile.'^'' MGd is undergoing further clinical evaluation and has recently completed phase II trials in a range of haematological malignancies'*'*'' and solid '^' 2.3 Arsenic Derivatives Arsenic trioxide (AS2O3) is approved by the European Medicines Agency^^' and US Food and Drug Administration,'**^"' for induction and consolidation chemotherapy in adult patients with relapsed/refractory acute promyelocytic leukaemia (APL), with the t(15;17) translocation and/or the presence of the promyelocytic leukaemia and retinoic-acid receptor-a (RARa) genes.'^^' AS2O3 in combination with disulfiram is being evaluated as second-line therapy in a phase I trial in patients with metastatic melanoma.'''^' For all patients receiving AS2O3, previous treatment should have included d\\-trans retinoic acid therapy and chemotherapy.'**^' AS2O3 exerts antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms that include covalent adduction and oxidation of redox-sensitive cysteine residues in glutathione and proteins.'*' The novel organic arsenic molecule darinaparsin induces high levels of oxidative stress and apoptosis with greater potency than AS2O3, but its mechanism of action remains to be elucidated.'**^' It is undergoing early clinical development in a range of tumour types.''***"'"''' Data from a phase II study with darinaparsin in hepatocellular carcinoma did not show any objective responses and the trial was terminated after the first planned stage of efficacy analysis.''"'1 However, data from other chnical trials have suggested substantial antitumour activity.''"-' 2.4 The Potential Role of Future Redox Modulators in the Clinio The apparent differences in homeostatic redox set points between tumour cells and normal cells
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allow drugs that target redox systems to be used to increase the therapeutic index of cytotoxic chemotherapy agents.'**' In this review, we have examined the modes of action of a wide range of drugs with specific redox activity and described the various ways that they can modulate oxidative stress. The diversity of agents and their modes of action in the modification of redox balance suggests that it is likely that redox chemotherapeutics will have differential effects in individual cancers depending on the particular oncogenic pathways upregulated in that tumour type. Initial clinical investigations with many of these drugs have been promising. Most notably, NOV-002 has shown clinical activity in breast'"'-^' and ovarian cancer,''"*' while dimesna has shown promising clinical data in combination with first-hne taxane and platinum chemotherapy in patients with inoperable advanced primary adenocarcinoma histology NSCLC.'^-' The pleiotropic activity of potential redox modulators is of particular interest, as they offer a range of anticancer effects, such as direct antitumour activity, chemopotentiation, chemoprotection/ stimulation of haematopoiesis, immunomodulation and inhibition of metastasis. Importantly, they also offer a viable means of reducing the impact of resistance to cytotoxic chemotherapies by virtue of their ability to target multiple signalling pathways. This is evident from examples, such as BSO'''''' and canfosfamide,''''*' which have shown potential in overcoming acquired resistance to cytotoxic compounds. NOV-002 also has immunomodulatory effects, suggesting that a promising alternative strategy may be to enhance the effects of cancer immunotherapy.''"^' While these pleiotropic redox activities have been shown to provide clinically relevant potentiation of cytotoxic chemotherapy, use of redox agents in single-drug regimens has been less successful. The failure of single-agent canfosfamide versus cytotoxic chemotherapy in a phase III trial'"'^' suggests that these compounds may be best developed in combination with chemotherapy rather than as single agents. We should recognize that drugs affecting a range of cellular pathways have the potential to elicit a wider range of adverse effects than agents
2011 Adis Data information BV. Ail rights reserved.

with more specific targets. On the other hand, the fundamental differences in ROS status between normal and cancer cells may confer a more favourable therapeutic index for such agents.'^''' The clinical community awaits the long-term outcomes of trials with these agents to obtain a clearer picture of their clinical activity and potential for adverse effects. 3. Conclusions While physicians may have previously been unfamiliar with the concepts of redox regulation and S-glutathionylation in the treatment of cancer, they have, in fact, been using anticancer agents that have redox activity for years. Recent research has focused on exploiting the oxidative vulnerabilities of cancer cells, and has led to the development of drugs specifically designed to disrupt cellular redox balance and potentiate the clinical effects of existing chemotherapy agents. Several such agents have entered into clinical development, and hopefully successful candidates will become available to increase the armamentarium of anticancer therapeutics. Acknowledgements
The author acknowledges the contribution of Kerry Acheson (GeoMed) for medical writing and Sarah Wright (GeoMed) for editorial assistance, funded by Mundipharnia International. Cambridge, UK; and Christopher Pazoles (Nvelos Therapeutics, Inc.. Newton. MA. USA) and Terri Cameron (Mundipharma International) for critical review of the manuscript. Jacek Jassem declares no conflict of interest. Alberto Montero has received research funding from Nvelos Therapeutics. Inc.

References
1. Connors T. Anticancer drug development: the way for ward. Oncologist 1996; 1 (3): 180-1 2. Rang HP. Dale MM. Ritter JM. Pharmacology. 4th ed Edinburgh: Churchill Livingstone, 1999 3. Fruehauf JP. Meyskens Jr FL. Reactive oxygen species: a breath of life or death? Clin Cancer Res 2007; 13 (3): 789-94 4. Lu J. Chew EH. Holmgren A. Targeting thioredoxin reductase is a basis for cancer therapy by arsenic Irioxidc, Proc Nati Acad Sei USA 2007; 104 (30): 12288-93 5. Chen J. Stubbe J. Bleomycins: towards better therapeutics Nat Rev Cancer 2005; 5 (2): 102-12 6. Chow MS. Liu LV. Solomon EL Further insights into the mechanism of the reaction of activated bleomyciti

Drugs 2011.71 (11)

Redox Modulation in Cancer

1393

7.

K.

4.

10.

11.

12.

13. 14.

15.

16.

17. IS.

19. 20.

21. 22.

23.

with DNA. Proc Nati Acad Sei USA 2008; 105 (36): 13241-5 Fribley A, Zeng Q. Wang CY. Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol 2004; 24 (22); 9695-704 Berndtsson M. Hagg M. Panaretakis T. et al. Acute apoptosis by cisplatin requires induetion of reactive oxygen species but is not associated with damage to nuclear DNA. Int J Cancer 2007; 120 ( 1 ); ! 75-80 Wondrak GT. Redox-directed cancer therapeutics; molecular mechanisms and opportunities. Antioxid Redox Signal 2009; II (12); 3013-69 Oh SY, Sohn YW, Park JW. et al. Selective cell death of oncogenic Akt-transduced brain cancer cells by etoposide through reactive oxygen species mediated damage. Mol Cancer Ther 2007; 6 (8); 2178-87 Alexandre J. Batteux F, Nicco C. et al. Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int J Cancer 2006; 119 (I): 41-8 Alexandre J. Hu Y, Lu W, et al. Novel action of paclitaxel against cancer cells; bystander effect mediated by reactive oxygen species. Cancer Res 2007; 67 (8); 3512-7 Loft S. Poulsen HE. Cancer risk and oxidative DNA damage in man. J Mol Med 1996; 74 (6); 297-312 Ballatori N. Krance SM. Notenboom S, et al. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 2009; 390 (3); 191-214 Electronic Medicines Compendium (eMC). Epirubicin summary of product characteristics [online]. Available from URL; http;/,'emc.medicines.org.uk/medicine,'186O9/ SPC/Epirubicin+Hydrochloride-(-2+mg+ml+Injection+(Hos pira+UK+Ltd); [Accessed 2010 Feb 3] Electronic Medicines Compendium (eMC). Doxorubicin summary of product characteristics [online]. Available from URL; http;//emc.medicines org uk/medicine/8270/ SPC/Doxorubicin%20hydrochloride%2050mg%20Powder %20for%20Injection%20(Hospira%20UK%20Ltd)/ [Accessed 2010 Feb 5] Pfizer Inc. Doxorubicin (Adriamycin) prescribing information [online]. Available from URL; http;//www.pnzer com/files/ products/uspi_adriamycin pdf [Accessed 2010 Sep 29] Pfizer Inc. Epirubicin (Ellence) prescribing information [online]. Available from URL; http;//niedia.pf"izer com/ files/products/uspi_ellence pdf [Accessed 2010 Feb 3] Zelnak A. Overcoming taxane and anthracycline resistance. Breast J 2010; 16 (3); 309-12 Townsend DM. S-glutathionylation; indicator of cell stress and regulator of the unfolded protein response. Mol Interv 2007; 7 (6); 313-24 Giles GI. The redox regulation of thiol dependent signaling pathways in cancer. Curr Phann Des 2006; 12 (34); 4427-43 Tew KD. Townsend DM. Redox platforms in cancer drug discovery and development. Curr Opin Chem Biol 2011; 15(1); 156-61 Qin XJ. Hudson LG, Liu W, et al. Dual actions involved in arsenite-induced oxidative DNA damage. Chem Res Toxicol2008;2l (9); 1806-13

24. Ames BN. Shigenaga MK. Gold LS. DNA lesions, inducible DNA repair, and cell division; three key factors in mutagenesis and carcinogenesis. Environ Health Perspect 1993; 101 Suppl. 5; 35-44 25. Mller P. Wallin H. Adduct formation, mutagenesis and nucleotide excision repair of DNA damage produced by reactive oxygen species and lipid peroxidation product. Mutat Res 1998; 410 (3); 271-90 26. Clerkin JS, Naughton R, Quiney C. et al. Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett 2008; 266 ( I ); 30-6 27. Trachootham D. Lu W. Ogasawara MA. et al. Redox regulation of cell survival. Antioxid Redox Signal 2008; 10(8); 1343-74 28. Schumacker PT. Reactive oxygen species in cancer cells; live by the sword, die by the sword. Cancer Cell 2006; 10(3); 175-6 29. Chandra J. Samali A, Orrenius S. Triggering and modulation of apoptosis by oxidative stress. Free Radie Biol Med 2000; 29 (3-4); 323-33 30. Ghezzi P. Casagrande S, Massignan T. et al. Redox regulation of cyclophilin A by glutathionylation. Proteomics 2006; 6 (3); 817-25 31. Townsend DM. Pazoles CJ. Tew KD. NOV-002, a mimetic of glutathione disulfrde. Expert Opin Investig Drugs 2008; 17(7); 1075-83 32. Griffith OW. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem 1982; 257 (22); 13704-12 33. Tew KD. TLK-286; a novel glutathione S-transferaseactivated prodrug. Expert Opin Investig Drugs 2005; 14(8); 1047-54 34. Edelman MJ. Novel cytotoxic agents for non-small cell lung cancer. J Thorac Oncol 2006; 1 (7); 752-5 35. Ruscoe JE. Rosario LA, Wang T. et al. Pharmacologie or genetic manipulation of glutathione S-transferase Pl-1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther 2001; 298 (1); 339-45 36. Raza A. Galili N. Smith S. et al. Phase 1 multicenter doseescalation study of ezatiostat hydrochloride (TLKl 99 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. Blood 2009; 113 (26); 6533-40 37. Dvorakova K. Payne CM. Tome ME. et al. Induction of oxidative stress and apoptosis in myeloma cells by the aziridine-containing agent imexon. Biochem Pharmacol 2000; 60 (6); 749-58 38. Electronic Medicines Compendium (eMC). Antabuse summary of product characteristics [online]. Available from URL; http;//emc.medicines org uk/medicine/519/SPC/Antabuse+ Tablets-H-200ing/ [Accessed 2010 Feb 17] 39. Drugs.com. Disulfiram prescribing information [online]. Available from URL; http;//www.drugscom/pro/disulfiram html [Accessed 2010 Feb 17] 40. Baker AF. Dragovich T. Tte WR, et al. The antitumor thioredoxin-1 inhibitor PX-12 (l-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma. J Lab Clin Med 2006; 147 (2); 83-90 41. Hausheer FH. Shanmugarajah D. Leverett BD. et al. Mechanistic study of BNP7787-mediated cisplatin nephroprotection;

<i< 2011 Adis Data information BV. Aii rigints reserved.

Drugs 2011; 71 (11)

1394

Montero & Jassem

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

modulation of gamma-glutamyl transpeptidase. Cancer Chemother Pharmacol 2010; 65 (5); 941-51 Hausheer F, Bain S, Perry M, et al. Comprehensive metaanalysis of survival outcomes from two randomized multicenter trials in first-line advanced non-small cell lung cancer in patients treated with the novel investigational antitumor-enhancing and chemoprotective agent Tavocept. Eur J Clin Med Oncol 2009; 1:7-19 Magda D. Miller RA. Motexafm gadolinium; a novel redox active drug for cancer therapy. Semin Cancer Biol 2006; 16 (6); 466-76 Quintas-Cardama A, Verstovsek S, Freireich E, et al. Chemical and clinical development of darinaparsin, a novel organic arsenic derivative. Anticancer Agents Med Chem 2008; 8; 904-9 Nvelos Therapeutics. Study of NOV-002 in combination with chemotherapy to treat lung cancer [ClinicalTrials. gov identiHer: NCT003474121. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL; http://www.clinicaltrials.gov [Accessed 2010 Apr 27] Fidias P. Ciuleanu TA, Gladkov O. et al. A randomized, open-label, phase III trial of NOV-002 in combination with paclitaxel (P) and carbopiatin (C) versus paclitaxel and carbopiatin alone for the treatment of advanced nonsmall cell lung cancer (NSCLC). J Clin Oncol 2010; 28 (18s); Abstract LBA7007 Montero AJ, Diaz-Montero CM. Slingerland J, et al. Phase 2 study of neoadjuvant treatment with cellular redox modulator NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel (AC T) in patients with stage II-III HER-2 (-) breast cancer [abstract Pl-ll-05]. 33rd Annual Breast Cancer Symposium; 2010 Dec 8-12; San Antonio (TX) Krasner CN, Seiden MV, Penson RT, et al. NOV-002 plus carbopiatin in platinum-resistant ovarian cancer [abstract no. 5593]. J Clin Oncol 2008; 26 (May 20 Suppl.); 315s Gumireddy K. Pazoles C. Vulfson E. et al. Inhibition of tumor cell invasion and ErbB2/PI3K signalling pathways by the glutathione disulfide-mimetic NOV-002 [abstract 1807]. Proceedings of the lOOth Annual Meeting of the American Association for Cancer Research; 2009 Apr 18-22; Denver (CO) Townsend DM. Bowers R. Pazoles CJ, et al. NOV-002 suppresses tumor cell growth by modulating redox-sensitive cell signaling. Mol Cancer Ther 2009; 8(12 Suppl. I); Abstract C301 Bowers R. Townsend D. Manevich Y. et al. The redox modulator NOV-002 inhibits proliferation of ovarian tumor cells but increases proliferation of myeloid cells. Proceedings of the lOlst Annual Meeting of the American Association for Cancer Research [abstract 1615]; 2010 Apr 17-21; Washington (DC) Montero AJ. Naga O. Xu M. et al. Nov-002. a cellular redox modulator, enhances the antitumor effect of adoptively transferred T cells in a murine melanoma model. Mol Cancer Ther 2009; 8 (12 Suppl. 1); Abstract C238 Pazoles CJ. Gerstein H. NOV-002, a chemoprotectant/ immunomodulator. added to first-line carboplatin/paclitaxel in advanced non-small cell lung cancer (NSCLC); a randomized phase 1/2. open-label, controlled study [abstract 17021]. J Clin Oncol 2006; 24 18S Pt 1 (Jun 20 Suppl.); 668s

54. University of Miami Sylvester Comprehensive Cancer Center. Oxidized glutathione (NOV-002). doxorubicin, cyclophosphamide, and docetaxel in treating women with newly diagnosed stage MB, or stage IIIC breast cancer [ClinicalTrials.gov identifier; NCT00499122]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL; http;//www.clinicaltrials.gov [Acces.sed 2010 Apr 27] 55. Bear HD. Anderson S. Brown A. et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide; preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003; 21 (22); 4165-74 56. von Minckwitz G. Rezai M. LoibI S. et al. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer; phase 111 GeparQuattro study. J Clin Oncol 2010; 28 (12); 2015-23 57. Arrick BA, Griffith OW. Cerami A. Inhibition of glutathione synthesis as a chemotherapeutic strategy for trypanosomiasis. J Exp Med 1981; 153 (3); 720-5 58. Martensson J. Jain A, Stole E, et al. Inhibition of glutathione synthesis in the newborn rat; a model for endogenously produced oxidative stress. Proc Nati Acad Sei USA 1991 ; 88 (20); 9360-4 59. Marengo B. De CC, Verzola D, et al. Mechanisms of BSO (L-buthionine-S,R-sulfoximine)-induced cytotoxic effects in neuroblastoma. Free Radie Biol Med 2008; 44 (3); 474-82 60. Bailey HH. Ripple G. Tutsch KD, et al. Phase I study of continuous-infusion L-S.R-buthionine sulfoximine with intravenous melphalan. J Nati Cancer Inst 1997; 89 (23); 1789-96 61. O'Dwyer PJ. Hamilton TC. LaCreta FP. et al. Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer. J Clin Oncol 1996; 14(1); 249-56 62. Children's Hospital Los Angeles. Chemotherapy in treating children with neuroblastoma [ClinicalTrials.gov identifier; NCTOOOO273O]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL; http;//www.clinicaltrials.gov [Accessed 2010 Apr 27] 63. New Approaches to Neuroblastoma Therapy Consortium. Melphalan and buthionine sulfoximine followed by bone marrow or peripheral stem cell transplantation in treating children with resistant or recurrent neuroblastoma. ClinicalTrials.gov identifier; NCTOO()O5835 [online]. Available from URL; http;//www.clinicaltrials.gov/ct2/show/ NCTOOOO5835?term=NCTOOOO5835&rank=l [Accessed 2010 Apr 27] 64. Duke University. Buthionine sulfoximine and an isolated limb infusion of melphalan in treating patients with persistent or recurrent stage 111 malignant melanoma [ClinicalTrials.gov identifier; NCT00661336]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL; http;//www.clinicaltrials.gov [Accessed 2010 Apr 27] 65. Hsu CH, Chen CL, Hong RL, et al. Prognostic value of multidrug resistance; 1, glutathione-S-transferase-pi and p53 in advanced nasopharyngeal carcinoma treated wilii systemic chemotherapy. Oncology 2002; 62 (4); 305-12 66. Shiga H. Heath El, Rasmussen AA, et al. Prognostic value of p53. glutathione S-transferase pi. and thymidylate

2011 Adis Data information BV. Aii rights reserved.

Drugs 2011; 71 (11)

Redox Modulation in Cancer

1395

67.

6X.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer. Clin Cancer Res 1999; 5 (12): 4097-104 Su F. Hu X. Jia W. et al. Glutathion S transferase pi indicates chemotherapy resistance in breast cancer. J Surg Res 2003; 113(1): 102-8 Sequist LV. Fidias PM. Temel JS. et al. Phase l-2a multicenler dosc-ranging study of canfosfamide in combination with carboplatin and paclitaxel as first-line therapy for patients with advanced non-small cell lung cancer. J Thorac Oncol 2009; 4 ( 11 ): 1389-96 Vergote I. Finkler N. del Campo J. et al. Phase 3 randomised study of canfosfamide (Telcyta. TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer 2009; 45 (13): 2324-32 Raza A. Galili N. Smith S. et al. Phase ImuUicenter doseescalation study of ezatiostat hydrochloride liposomes for injection (Telintia(R). TLK199). a novel glutathione analog prodrug in patients with myelodysplastic syndrome. Blood 2009 Jun 25: 113 (26): 6533-40 Telik. Phase 2 study comparing two dose schedules of Telintra in myelodysplastic syndrome (MDS) [ClinicalTrials.gov identifier: NCT007O02061. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http:/7www.clinicaltrials.gov [Accessed 2010 Apr 27] Telik. Study of ezatiostat (Telintra tablets) lor treatment of severe chronic neutropenia [ClinicalTrials.gov identifier: NCT00909584]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http: 'www. clinicaltrials.gov [Accessed 2010 Apr 27] Moulder S. Dhillon N. Ng C. et al. A phase I trial of imexon. a pro-oxidant. in combination with docetaxel for the treatment of patients with advanced breast, non-small cell lung and prostate cancer. Invest New Drugs 2010; 28: 634-40 Cohen SJ. Zalupski MM. Modiano MR. et al. A phase 1 study of imexon plus gemcitabine as first-line therapy for advanced pancreatic cancer. Cancer Chemother Pharmacol 2009: 66: 287-94 Cohen SJ. Zalupski MM. Conkling P. et al. A phase II randomized double blind multicenter trial of gemcitabine (Gem) plus imexon (lMX) versus Gem plus placebo (P) in patients with chemotherapy-naive pancreatic adenocarcinoma (PC). J Clin Oncol 2010: 28 (15s): abstract 4076 Cvek B. Targeting malignancies with disulfiram (antabuse): multidrug resistance, angiogenesis. and proteasome. Curr Cancer Drug Targets 2011: II (3): 332-7 Kona FR. Buac D. Burger AM. Disulfiram. and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies. Curr Cancer Drug Targets 2011: 11 (3): 338-46 Cen D. Brayton D. Shahandeh B. et al. Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells. J Med Chem 2004; 47 (27): 6914-20 University of California. Disulfiram in metastatic melanoma [ClinicalTrials.gov identifier: NCTOO25623O]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Acces.sed 2010 Apr 27]

80. Hadassah Medical Organization. Initial assessment of the effect of the addition of disulfiram (Antabuse) to standard chemotherapy in lung cancer [ClinicalTrials.gov identifier: NCT003I28I9]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http:// www.clinicaltrials.gov [Accessed 2010 Apr 27] 81. University of Utah. Phase I study of disulfiram and copper gluconate for the treatment of refractory solid tumors involving the liver [ClinicalTrials.gov identifier NCT007429II]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27] 82. Verma S. Stewart DJ, Maroun JA. et al. A randomized phase II study of cisplatin alone versus cisplatin plus disulfiram. Am J Clin Oncol 1990; 13 (2): 119-24 83. Ramanathan RK. Fakih M. Mani S. et al. Phase I and pharmacokinetic study of the novel redox-active agent, motexafin gadolinium, with concurrent radiation therapy in patients with locally advanced pancreatic or biliary cancers. Cancer Chemother Pharmacol 2006: 57 (4): 465-74 84. Oncothyreon Inc. A trial of PX-12 in patients with a histologically or cytologicaily confirmed diagnosis of advanced or metastatic cancer [ClinicalTrials.gov identifier: NCTOO736372]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http:// www.clinicaltrials.gov [Accessed 2010 Apr 27] 85. Boven E. Verschraagen M. Hulscher TM. et al. BNP7787. a novel protector against platinum-related toxicities. does not affect the efficacy of cisplatin or carboplatin in human tumour xenografts. Eur J Cancer 2002: 38 (8): 1148-56 86. Roswell Park Cancer Institute. Dimesna in treating patients with solid tumors who are undergoing treatment with cisplatin and paclitaxel [ClinicalTrials.gov identifier: NCT0O0O3569]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http:// www.clinicaltrials.gov [Accessed 2010 Apr 27) 87. BioNumerik Pharmaceuticals L Phase 3 study of tavocept vs placebo in patients with newly diagnosed or relapsed advanced (stage IIIB/IV) primary adenocarcinoma of the lung treated with doeetaxel or paclitaxel plus cisplatin [ClinicalTrials.gov identifier: NCT00966914]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27] 88. Amato RJ. Jac J. Hernandez-McClain J. Motexafin gadolinium for the treatment of metaslatic renal cell carcinoma: phase II study results. Clin Genitourin Cancer 2008; 6 (2): 73-8 89. Mehta MP. Shapiro WR. Phan SC. et al. Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain mtastases: results of a phase ill trial. Int J Radit Oncol Biol Phys 2009: 73 (4): 1069-76 90. Phamiacyclics. Study of motexafin gadolinium (MGd) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma [ClinicalTrials.gov identifier: NCT00100711]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http:// www.clinicaltrials.gov [Accessed 2010 Apr 27] 91. Phamiacyclics. A study of motexafin gadolinium for the treatment of chronic lymphocytic leukemia (CLL)

2011 Adis Data information BV. Aii cigiits reserved.

Drugs 2011; 71 (11)

1396

Montero & Jassein

92.

93.

94.

95.

96.

97.

98.

[ClinicalTrials.gov identifier: NCT00076401]. US National Institutes of Health. ClinicalTrlals.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27] Pharmacyclics. Trial of motexaHn gadolinium and pemetrexed (Alimta*) for second line treatment in patients with non-small cell lung cancer [ClinicalTrials.gov identifier: NCTOO365183]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http:// www.clinicaltrials.gov [Accessed 2010 Apr 27] Pharmacyclics. Study of motexafin gadolinium for the treatment of renal cell (kidney) cancer [ClinicalTrials.gov identifier: NCTOO 1.^4186]. US National Institutes of Health, ClinlcalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27] Radiation Therapy Oncology Group, Motexafin gadolinium. temozolomide. and radiation therapy in treating patients with newly diagnosed glioblastoma multilomie or gliosarcoma [ClinicalTrials.gov identifier: NCT00305864]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Acces.sed 2010 Apr 27] European Medicines Agency. Trisenox summary of product characteristics [online]. Available from URL: http://www. ema.europa.eu/docs/en_GB/document_library/EPAR_-_ Product_Information/human/000388/WC500042844 pdf [Accessed 2010 Sep 29] US Food and Drug Administration. Trisenox package insert and prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/ label/2000/212481bl.pdf [Accessed 2011 Mar 24] University of California. Evaluation of disulfiram plus arsenic trioxide in patients with metastatic melanoma and at least one prior systemic therapy [ClinicalTrials.gov identifier: NCTOO5711I6]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http:// www,clinicaltrials.gov [Accessed 2010 Apr 27] ZIOPHARM. Phase I study of oral darinaparsin (ZIO101-C) in advanced solid tumors and non-Hodgkin's lymphomas [ClinicalTrials.gov identifier: NCTOO591422]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27]

99. ZIOPHARM. Phase I study of oral ZIO-IOI-C in advanced solid tumors and lymphomas [ClinicalTrials.gov identifier: NCT0059216.3]. US National Institutes of Health. ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 Apr 27] 100. ZIOPHARM. Phase II study of ZIO-101 in advanced blood and bone marrow cancers [ClinicalTrials.gov identifier: NCT00421213]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http:// www.clinicaltrials.gov [Accessed 2010 Apr 27] 101. Wu J, Henderson C. Feun L. et al. Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma. Invest New Drugs 2009; 28 (5): 670-6 102. Mann KK. Wallner B. Lossos IS. et al. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin Investig Drugs 2009; 18(11): 1727-34 103. Diaz-Montero CM, Paphitis N. Onicescu G. et al. Daily injections of the glutathione disulfide mimetic NOV-002 ameliorates hmatologie toxicities from neoadjuvant chemotherapy in breast cancer patients enrolled in the NEO-NOVO trial, and significantly increases circulating dendritic cells [abstract 2141]. 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2008 Dec 10-14; San Antonio (TX) 104. Diaz-Montero CM, Perez A, Zidan AA, et al. Immunomodulatory activity of NOV-002 potentiates the anti-tumor efficacy of cyclophosphamide in the CT26 murine colon cancer model. Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington (DC) 105. Vergote I, Finkler N. del Campo J, et al. Single agent. canfosfamide (C. TLK286) vs pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd-line treatment of platinum (P) refractory or resistant ovarian cancer (OC): phase 3 study results [abstract LBA5528]. J Clin Oncol 2010; 25 (18s Jun 20 Suppl.); 953s Correspondence: Dr Aiherto J. Montero, Department of Internal Medicine, University of Miami Sylvester Comprehensive Cancer Center, 1475 NW 12th Ave, Miami, FL 33136, USA. E-mail: amontero2@med.miami.edu

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