Novel cytotoxic drugs: Old challenges, new solutions

Cancer Treatment Reviews (2008) 34, 81– 91

available at www.sciencedirect.com

journal homepage: www.elsevierhealth.com/journals/ctrv

NEW DRUGS

Novel cytotoxic drugs: Old challenges, new solutions Gustavo F.V. Ismael Ahmad Awada a

a,b

, Daniela Dornelles Rosa

a,c,*

, Max S. Mano

a,d

,

a

´ Libre de Bruxelles, Belgium Department of Medical Oncology, Jules Bordet Institute, Universite Department of Haematology and Oncology, Hospital Amaral Carvalho, Jau, Brazil c Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 4BX, United Kingdom d Department of Medical Oncology, Cliniques Universitaires Saint Luc, Brussels, Belgium b

Received 30 March 2007; received in revised form 26 July 2007; accepted 7 August 2007

KEYWORDS Chemotherapy; Cytotoxic agents; Novel drugs; Drug development

Summary The discovery of cytotoxic agents was revolutionary for anticancer therapy in the last century, improving survival rates and the quality of life of patients with different types of tumours. However, the development of agents that combine efficacy, safety and convenience remains a great challenge, due to the narrow therapeutic index of some drugs, the fact that they may damage not only cancer cells, but also normal and healthy tissue and the occurrence of resistance, limiting anticancer efficacy. Novel cytotoxic agents have brought certain advantages over the conventional ones, such as shorter administration time, mechanisms to overcome drug resistance and lower incidence of adverse events. In this review we highlight the development of promising novel cytotoxic drugs that will hopefully offer not only gains in efficacy, but also in safety, tolerability and convenience in the treatment of patients with cancer. c 2007 Elsevier Ltd. All rights reserved.

 Introduction

In the last century, the development of cytotoxic agents was revolutionary for cancer therapy. It has made possible to achieve cure for certain neoplasms such as childhood acute leukaemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, gestational trophlobastic disease and germ cell tumours. Adjuvant treatment with cytotoxic drugs for * Corresponding author. Address: Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 4BX, United Kingdom. Tel.: +44 79 1372 2813; fax: +44 161 446 3269. E-mail address: [email protected] (D.D. Rosa).



several types of cancer also offered a clear survival benefit additionally to that obtained with surgical management alone. In patients with recurrent or metastatic disease, cytotoxic agents have demonstrated the ability not only to provide unequivocal tumour control, but also to offer a better quality of life with reasonable symptom relief. However, several limitations became clear, mainly in patients with advanced malignant diseases, where the adverse effects of cytotoxic chemotherapy may preclude its potential benefits.1 The development of cytotoxic therapy faces several challenges, as the narrow therapeutic index of some drugs and the fact that cytotoxic drugs damage not only cancer

0305-7372/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2007.08.001

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Figure 1 (a) Structure of a cell, with microtubules playing a role in the many cellular functions. (b) During mitosis replicated chromosomes are positioned near the middle of the cytoplasm and then segregated so that each daughter cell receives a copy of the original DNA. To do this cells utilize microtubules (referred to as the spindle apparatus) to pull chromosomes into each cell. The centrioles are paired cellular organelle which functions in the organization of the mitotic spindle during cell division in eukaryotes. (c) Microtubules are composed of heterodimers of alpha- and beta-tubulin. Paclitaxel binds to beta-tubulin on the inner surface of the microtubule, stabilizing it and blocking its normal dynamics. (d) Illustration of a surfactant vehicle. The surfactant heads are hydrophilic moieties and the surfactant tails are hydrophobic moieties. According to the drug hydrophobicity, there may be different loci of solubilization in surfactant micelles.

cells, but also normal and healthy tissue. The occurrence of resistance may also limit its efficacy. The development of agents that combine efficacy, safety and convenience remains a great challenge. A large number of cytotoxic drugs are administered intravenously and some of them may require continuous intravenous infusion, what may be translated into higher costs and the need for hospitalization. Convenience is also an important factor in the choice of treatment for cancer patients; therefore, the development of new and effective oral cytotoxic agents has been a subject of great interest. The development of novel cytotoxic drugs may improve cancer treatment and patient care. In this review we highlight the development of promising novel cytotoxic drugs that will hopefully offer not only gains in efficacy, but also in safety, tolerability and convenience.

New taxanes The taxanes are a unique class of hydrophobic antineoplastic agents that exhibit cytotoxic activity by binding to tubulin and promoting inappropriately stable, non-functional, microtubule formation (Fig. 1a–c; Table 1).2 Over the past

two decades, these agents have played a significant role in the treatment of various solid malignancies. However, due to the poor solubility of these compounds, surfactant vehicles have to be included in commercial formulations (Fig. 1d), like the Cremophor EL (CrEL) solvent system, a polyoxyethylated castor oil vehicle that may be responsible for clinically relevant acute hypersensitivity reactions and peripheral neuropathy.3 A number of strategies to develop formulations of surfactant-free taxanes have been explored, which include albumin nanoparticles, polyglutamates, taxane analogs and prodrugs.

Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) Nab-paclitaxel (ABI-007; Abraxaneä) is a novel formulation of paclitaxel that does not employ the CrEL solvent system. It is prepared by homogenization of paclitaxel in the presence of human serum albumin at a concentration of 3–4%, which results in a nanoparticle colloidal suspension.4 Enhanced efficacy and reduced toxicity of nab paclitaxel when compared with paclitaxel at the maximum tolerated doses (MTDs) were demonstrated in animal models.5 Several phase

Novel cytotoxic drugs: Old challenges, new solutions Table 1

Mechanisms of action of microtubule-targeting drugs95

Class of drugs

Binding site

Microtubule-destabilizing agents Vinca alkaloids (vinblastine, Beta-tubulin – vinca vincristine, vindesine, domain (located adjacent vinorelbine and vinflunine) to the GTP binding site)

Colchicine

83

Beta-tubulin – colchicine site (located at the interface between beta-tubulin and alpha-tubulin)

Microtubule-stabilizing agents Taxanes (paclitaxel and Beta-tubulin – taxane site docetaxel) (located at the lateral interface within the lumen of the microtubule)

I trials have been performed to examine the toxicity profile, MTD and pharmacokinetics of nab particles.6–8 Phase II studies with single-agent nab paclitaxel in the treatment of patients with metastatic breast cancer (MBC) reported overall responses rates of 48% with complete responses (CR) in 3% of patients.9 The median overall survival was 63.6 weeks. Grade 4 neutropenia occurred in 24% of patients and grade 3 peripheral neuropathy, in 11% of patients. No grade 4 neuropathy was reported. Hypersensitivity reactions were not reported, despite the absence of premedication with steroids or antihistamines. A phase III trial compared the efficacy and safety of nab paclitaxel with paclitaxel in 460 patients with MBC.10 Based upon an intention-to-treat analysis, nab paclitaxel demonstrated significant improvements in response rates when compared to paclitaxel (33% vs. 19%, respectively; p = 0.001). Median time to progression was significantly longer with nab paclitaxel (23 vs. 16.9 weeks, respectively; p = 0.006). Despite higher cumulative doses of paclitaxel, grade 4 neutropenia occurred less frequently in the nab paclitaxel arm than in the paclitaxel arm (9% vs. 22%, respectively; p < 0.001). On the other hand, grade 3 sensory neuropathy was reported in 10% of patients treated with nab paclitaxel and in only 2% of patients receiving standard paclitaxel (p < 0.001). Nevertheless, nab paclitaxel demonstrated greater efficacy and a favourable safety profile when compared with standard paclitaxel, in addition to the elimination of corticosteroid premedication required for solvent-based taxanes, making it an important advance in

Action

Other ligands to the same binding site

At high concentrations: microtubule depolymerization, dissolution of spindle microtubules and arrest of cells at mitosis At low concentrations: suppression of microtubule dynamics without depolymerizing spindle microtubules, but still with the ability to arrest mitosis and induce apoptosis At high concentrations: microtubule depolymerization. At low concentrations: suppression of microtubule dynamics

Halichondrins Hemiasterlins Spongistatin Dolastatins

At high concentrations: microtubule polymerization and stabilization of microtubules At low concentrations: suppression of microtubule dynamics without affecting microtubule polymer mass, but retaining the capability of inducing mitotic arrest and apoptotic cell death

Cryptophycins

Combretastatins 2-methoxyestradiol (2ME2)

Discodermolide Epothilones Eleutherobin Sarcodictyins

the treatment of MBC. This concept was recently supported by the results of a phase III study comparing the toxicity and antitumoural activity of three regimens of nab-paclitaxel (q3w and 2 weekly) with each other and that of docetaxel in MBC.11 Nab-paclitaxel resulted in higher response rates than docetaxel, with comparable PFS and less toxicity. Nab paclitaxel has also been studied in the treatment of patients with non-small cell lung cancer (NSCLC). The results of a phase II open-label trial of first-line weekly nab paclitaxel associated with carboplatin in patients with recurrent stage IIIB/IV NSCLC has brought encouraging results.12 For the 56 patients treated, the overall response rate was 48% and 17 had stable disease. The median time to progression was 30 weeks. These results have motivated investigators to further explore the role of Nab paclitaxel in the treatment of NSCLC.

DHA-paclitaxel Docosahexaenoic acid-paclitaxel (DHA-paclitaxel; TaxoprexinÒ) is formed by covalently linking the natural fatty acid DHA to paclitaxel (Fig. 2a). This conjugate was designed to function as a prodrug and accumulate preferentially in tumour tissue.13 This agent has been studied in phase I13 and in phase II studies in patients with NSCLC,14 prostate cancer,15 breast cancer,16 pancreatic cancer,17 malignant melanoma18 and gastroesophageal cancer.19 In a phase II study of DHA-paclitaxel as first-line treatment for 26 patients with malignant melanoma, the overall response

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Figure 2 (a) Structure of docosahexaenoic acid (DHA)-paclitaxel, which is formed by covalently linking the natural fatty acid DHA to paclitaxel. (b) Multidrug resistance (MDR) efflux pump actively extrudes many types of drugs from cancer cells, keeping their intracellular levels below a cell-killing threshold. (c) Liposomal encapsulation of daunorubicin. The liposomes consist of distearoylphosphatidylcholine and cholesterol, dispersed in an aqueous medium containing sucrose, glycine and calcium chloride dihydrate. (d) Kinesin spindle proteins are capable of utilizing chemical energy from ATP hydrolysis to generate mechanical force. In the presence of ATP, they can bind to and move on microtubules. Kinesin motors are necessary to establish spindle bipolarity, positioning chromosomes on the metaphase plate, and maintaining forces in the spindle. They also appear to facilitate microtubule depolymerization.

rate was 7.6% and 46% of patients had stable disease (SD).18 The median survival was 10.2 months, which is comparable to that previously shown with either single-agent dacarbazine or temozolamide. These results have prompted the initiation of a phase III study comparing single-agent dacarbazine with DHA-paclitaxel in this setting.

Paclitaxel poliglumex Paclitaxel poliglumex (CT-2103; Xytotaxä) is another novel agent expected to enhance solubility of hydrophobic drugs, increase tumour permeability and retention of paclitaxel, minimize normal tissue exposure to free drug and evade multidrug resistance (MDR) efflux pumps via pinocytotic tumoural uptake (Fig. 2b).20 Two phase I trials were conducted to determine the safety and pharmacokinetic profile of this agent.21,22 In a phase II trial in patients with epithelial ovarian, primary peritoneal or fallopian tube carcinoma, paclitaxel poliglumex was administered every 3 weeks without premedication to patients with platinum-sensitive (n = 42) or platinum-resistant or refractory (n = 57) disease.23 All patients had received at least one prior chemotherapeutic regimen, and the majority (61%) had received three or more prior regimens. The overall response rate in all patients was 10%. In the minimally pretreated subgroup, the response rate was 28% in sensitive and 10% in patients

with resistant disease. This activity is comparable to that reported with paclitaxel in the same setting. Paclitaxel poliglumex was also evaluated as a single-agent for the first-line treatment of advanced NSCLC in a mixed cohort of elderly and poor performance status patients.24 Twenty-five patients were evaluable for response, 18 (72%) of whom achieved disease control. Based on these results, two international, multicentre, randomized phase III studies designed to demonstrate superiority of paclitaxel poliglumex in the overall survival of patients with NSCLC are ongoing.25 In addition, paclitaxel poliglumex is also being evaluated in combination with radiotherapy with or without chemotherapy in the treatment of oesophageal and gastric carcinoma.26

Paclitaxel vitamin E emulsion Paclitaxel vitamin E emulsion (paclitaxel injectable emulsion/PIE; Tocosol; S-8184) is a CrEL-free, vitamin E-based paclitaxel emulsion designated to minimize toxicity.27 The possibility to administer higher doses of paclitaxel established an advantage for this drug in animal models. Phase I studies were performed in a wide selection of patients with solid tumours, including those who were previously resistant to taxanes. These studies showed that PIE could be safely administered either weekly or every 3 weeks, with

Novel cytotoxic drugs: Old challenges, new solutions neutropenia being the major toxicity associated with the treatment.27,28 Phase II studies showed promising activity and a reasonable safety profile in patients with refractory urothelial transitional cell carcinoma, NSCLC and ovarian cancer.29–31 Neutropenia and anaemia were the main problems in terms of toxicity and no grade 4 neuropathy was documented.

EndoTAG-1 EndoTAG-1, a formulation of paclitaxel encapsulated in positively charged lipid-based complexes, is another compound under investigation. Phase II clinical trials in patients with advanced pancreatic cancer are ongoing.32

Taxane analogs With the aim to overcome the toxicity of conventional taxanes and to improve antitumoural activity, several taxane analogs are in development: DJ-927, BMS-184476, BMS275183, ortataxel and RPR-109881A. Among these agents, DJ-927 may be mentioned.

DJ-927 DJ-927 is a novel oral tubulin inhibitor that causes apoptosis and DNA cell division arrest. It has shown excellent activity in preclinical studies, especially in colorectal cancer models. DJ-927 displayed higher intracellular concentrations in P-glycoprotein-expressing tumours and enhanced efficacy compared to conventional taxanes,33 with a comparable pharmacokinetic profile in animal models.34 Its oral bioavailability eliminates the need for toxic vehicles and may minimize the risk of hypersensitivity reactions. In a phase I study of patients with advanced malignancies receiving DJ-927 as a single oral agent every 3 weeks, neutropenia was dose-related and dose-limiting.35 Phase II studies are ongoing, with a special focus on gastrointestinal tumours. A two-stage, multi-center, phase II trial assessed the efficacy of DJ-927 administered initially as second-line therapy for patients with advanced colorectal cancer following failure of irinotecan- or oxaliplatin-based therapy.36 The objective response rate was 10.3% for the 39 patients enrolled. There were two CRs confirmed as per the RECIST criteria. Fourteen patients (35.9%) had SD, including six patients (15.4%) with SD >12 weeks. The most common grade 3 or 4 adverse events (AEs) were neutropenia (48.7%), fatigue (10.3%), neuropathy (7.8%), and nausea (5.0%). Six patients experienced febrile neutropenia, all requiring hospitalization. The treatment was well tolerated with subsequent dose reduction. More modest results were reported in another phase II study using DJ-927 as second-line therapy for patients with advanced gastric cancer who have failed 5FU and non-taxanes-based regimens.37 Available response data from 26 of 30 evaluable patients showed PR in five patients, SD in 15 and PD in the remaining six patients. Toxicities higher than grade 3 in 33 evaluable patients included neutropenia (n = 17), anaemia (n = 5), thrombocytopenia (n = 4), diarrhoea (n = 7), fatigue (n = 5), lethargy (n = 4) and neutropenic sepsis (n = 5). Further studies evaluating DJ-927 in combination with other active agents are planned in patients with gastric cancer.

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New anthracyclines Daunorubicin and doxorubicin are anthracyclines that have been used for the treatment of a wide variety of cancers for more than 30 years.38 The main limitation of these drugs is the cumulative cardiac toxicity associated with their use, leading to congestive heart failure.39 Therefore, the development of more effective approaches for limiting cardiac toxicity while maintaining antitumoural efficacy was needed. During the last years, drug carrier technology has been intensively developed with the aim to reduce the cardiac toxicity of anthracyclines. Encapsulation of daunorubicin and doxorubicin in liposomes was first studied 10 years ago. Three main liposomal formulations have been marketed for doxorubicin: LipodoxÒ (or TLC D-99),40 DoxilÒ and CaelyxÒ;41 and one liposomal formulation for daunorubicin, DaunoxomeÒ (Fig. 2c).42 These drugs showed promising results in patients with AIDS-related Kaposi’s sarcomas43 and in those with advanced recurrent malignant tumours of the central nervous system.44 In a randomized phase III trial in patients with recurrent or refractory epithelial ovarian cancer comparing CaelyxÒ with topotecan,45 there were no significant differences in response rates, time to progression, overall survival or quality of life between the two treatments. Patients receiving topotecan had more side effects requiring admission to hospital. This trial culminated with the approval of liposomal doxorubicin by the US Food and Drugs Administration for use in patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. In a phase I study, pegylated liposomal doxorubicin (PLD) was associated with an evident clinical benefit in anthracycline-pretreated patients with MBC.46 A phase II trial in patients with MBC showed response rates of 52%, with an additional 38% of SD with the use of PLD. Cardiac toxicity was limited to asymptomatic declines in LVEF.47 In a phase III study with patients with taxane-refractory advanced breast cancer, PLD was compared to a common salvage regimen (vinorelbine or mitomycin plus vimblastine).48 PFS and OS were similar for the PLD arm when compared to the common salvage regimen arm (PFS: 2.9 vs. 2.5 months, respectively, p = 0.11; OS: 11 vs. 9 months, respectively, p = 0.71). However, in anthracycline-naı¨ve patients, the PFS was longer in the PLD arm (5.8 vs. 2.1 months; p = 0.01). Nausea, vomiting and fatigue were similar among treatment groups. There was more palmar–plantar erythrodysesthesia in the PLD group and more neuropathy, constipation and neutropenia in the vinorelbine group. Therefore, PLD was shown to be a useful therapeutic option in the group of patients included in this trial. Regarding other adverse events (mainly the risk of cardiotoxicity), another phase III trial showed that, in the first-line treatment of MBC, PLD had comparable efficacy to conventional doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.49

Epothilones Drugs that target microtubules are among the most commonly prescribed anticancer therapies (Table 1).

86 Epothilones represent a novel class of drugs that inhibit the cell cycle and strongly disturb cell division. These agents can potentially escape the mechanisms underlying the development of the MDR phenotype commonly associated with recurrent cancers (Fig. 2b). Ixabepilone (BMS-247550) is a semi synthetic derivative of epothilone B with a mechanism of action analogous to that of paclitaxel. It showed impressive antitumoural activity in preclinical studies, including taxane-resistant models, and in phase I trials as well.50,51 Encouraging results have been reported in phase II studies evaluating patients with MBC who had failed to taxanes52,53 or anthracyclines,54,55 in chemotherapy-naive patients with hormone-refractory prostate cancer56 and in patients with advanced pancreatic cancer.57 Patupilone, a natural epothilone B, is a secondary macrolide metabolite that exhibits more potent binding to tubulin and stabilizes tubulin polymerization at lower concentrations when compared with standard taxanes.58 This agent has been evaluated in phase I trials, where it showed partial responses in patients with solid tumours previously treated with taxanes.59,60 In patients with recurrent platinum-sensitive ovarian cancer, the combination of patupilone with carboplatin was well tolerated and showed antitumoural activity similar to established regimens. EPO906 (epothilone B), ZK-EPO,61 KOS-862 (epothilone 62 D) and BMS-310705 are also under clinical evaluation and are promising candidates among epothilones for cancer therapy.

Halichondrine analogs E7389, a synthetic macrocyclic ketone analog of halichondrin B, that was isolated from a marine sponge, has broad anti-proliferative activity at nanomolar levels and a unique profile of tubulin interactions. Whereas its mechanism of action has not been fully elucidated, its main target seems to be tubulin and/or the microtubules responsible for the construction and proper function of the mitotic spindle. Like most microtubule-targeted antitumoural drugs, it binds to tubulin and inhibits microtubule polymerization (Table 1). This agent was studied in phase I and II clinical trials.63 In an open-label, single-arm phase II trial as monotherapy for patients with refractory breast cancer (P2 prior chemotherapy regimens, which must have included an anthracycline and a taxane), it was administered as an IV bolus of 1.4 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group 1), or on days 1 and 8 of a 21-day cycle (group 2).64 At the end of cycle 4 there were 10 (15.2%) confirmed PR out of 66 evaluable patients in group 1, and one confirmed PR (5.6%) out of 18 evaluable patients in group 2. The major toxicity related to the drug was neutropenia. Among 73 patients with preliminary safety data available, two had grade 3 febrile neutropenia, and 31 had grade 3 or 4 neutropenia or leukopenia. Based on the safety and efficacy showed in this population, E7389 appears to be promising in patients with heavily pretreated breast cancer. This agent also showed interesting results in a phase II study with patients with recurrent and/or metastatic NSCLC who progressed during or after platinum-based doublet chemotherapy.65 Based on the RECIST criteria, 6 PR were observed among

G.F.V. Ismael et al. 94 evaluable patients. For 33 patients, the best response was SD (35.1%). Major toxicities related to the study drug included myelosuppression, nausea, fatigue, dehydration, arthralgias, dyspnoea, and peripheral neuropathy. Based on this data, E7389 showed to be safe and effective in the treatment of NSCLC patients. Several other marine natural products or derivatives are advancing through anticancer clinical trials,66 highlighting the importance of microbial processes in the generation of bioactive and useful products.

Kinesin spindle proteins inhibitors Kinesin spindle proteins (KSP) are motor proteins that play an essential role in mitotic spindle formation (Fig. 2d). Ispinesib (SB715992), an experimental KSP inhibitor, has been shown to interfere with bipolar spindle formation, thus making it an excellent candidate for an anti-cancer agent. A phase I study was performed with 27 patients with various tumour types: colorectal (n = 7), renal (n = 5), bladder (n = 2), lung (n = 2), pharynx (n = 2), pancreas (n = 2) and others (n = 7).67 SD in two patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. This agent is currently under investigation in phase II studies including patients with MBC.

Camptothecin analogs Camptothecins are pentacyclic ring structures that interact with the topoisomerase I enzyme, with specificity for the Sphase of the cell cycle. Camptothecin and its analogs, such as topotecan and irinotecan, have potent activity against a wide range of solid tumours and several haematological malignancies. Gimatecan (ST1481) is an oral, lipophilic modified camptothecin analogue with a favourable therapeutic index in several tumour xenograft models68–71 and with documented antitumoural activity in breast, endometrial and NSCLC cancer in phase I trials. A phase II trial was performed in women with pretreated MBC72 who failed anthracyclines and taxanes-based treatment. The drug was administered to 21 patients for 5 days every week on weeks 1 and 2 (every 4 weeks) at 4–5 mg/m2 total dose per cycle. Using a Simon two-step design, antitumoural activity of 27% was observed in the first step of the study. Since this response was unusual for camptothecins, the study was prompted to continue to the second step, enrolling a total of 43 patients. The toxicity included thrombocytopenia (any grade: 36%, G3 9%); neutropenia (G3 18%), diarrhoea (1 case), nausea (any grade: 81%, G3 18%), vomiting (G1 18%), and asthenia (G1 36%). Three PR were seen. There are a number of other camptothecin analogs that are in earlier stages of preclinical or clinical development including DX-8951f and karenitecin (BNP1350).

New platinum compounds Despite being the mainstay of treatment for a number of cancers, platinum analogs carry the disadvantage of necessity of intravenous administration. In addition, their utility

Novel cytotoxic drugs: Old challenges, new solutions is often limited by toxicity, particularly neurotoxicity, ototoxicity and renal toxicity. Satraplatin is a novel, orally bioavailable, platinum anticancer drug. It has preclinical antitumoural activity comparable with that of cisplatin and, clinically, has a more manageable side-effect profile.73 Satraplatin has demonstrated significant clinical benefits for the treatment of hormone-refractory prostate cancer. A multinational randomized double blind phase III study compared satraplatin plus predinisone vs. placebo plus predinisone in patients with hormone-refractory prostate cancer.74 Satraplatin was associated with a 31% reduction in the risk of PFS events and a 33% reduction in the risk of pain progression. Moreover, superior PSA reduction (25% vs. 12%, p = 0,0007), objective tumour response (7% vs. 1%, p < 0,002), pain response (24% vs. 14%, p < 0,005) and duration of pain response were observed with satraplatin. This agent was generally well tolerated; myelossupression was the most frequent side effect, but grade 4 neutropenia was uncommon (4%). These data have prompted the submission of a new drug application to the US FDA for this indication. Combination trials are also ongoing with paclitaxel, erlotinib and radiotherapy.75

Pemetrexed Pemetrexed (Alimta, LY231514) is a novel antifolate agent that is active in multiple tumour types, including mesothelioma, small cell lung cancer (SCLC) and NSCLC. The primary mechanism of action of this agent is the inhibition of the enzyme thymidylate synthase, resulting in decreased thymidine necessary for pyrimidine synthesis, leading to the interruption of DNA synthesis. Pemetrexed also inhibits dihydrofolate reductase and glycinamide ribonucleotide formyl transferase, the latter of which is a folate-dependent enzyme involved in purine synthesis. Since early studies, pemetrexed has shown very interesting activity in the treatment of NSCLC. Phase II studies in previously untreated patients with NSCLC documented promising single-agent response rates of 17–23%.76,77 A phase II study of pemetrexed in patients with advanced NSCLC, who had progressed during or within 3 months of completing first-line chemotherapy, demonstrated a response rate of 8.9% and median survival time of 5.7 months.78 The high inhibition level of pyrimidine and purine synthesis initially has appeared as a problem in terms of toxicity, but folic acid and vitamin B12 supplementation resulted in a significantly lower incidence of haematologic and non-heamatologic toxicity.79 A non-inferiority phase III study has demonstrated that treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC.80 This trial consolidated pemetrexed as an effective and less toxic option in the second-line treatment of advanced NSCLC. More recently, another phase III study documented that pemetrexed combined with carboplatin showed the same efficacy and less haematological toxicity when compared to gemcitabine and carboplatin in the first-line treatment of advanced NSCLC.81 Therefore, this agent appears as an alternative in the choice of the first-line treatment of NSCLC patients.

87 Pemetrexed has proven to be a very solid option in the treatment of mesothelioma82 and to have a very promising activity in SCLC,83 gynecologic tumours84 and in head and neck cancer.85

Vinca alkaloids Vinflunine is a bi-fluorinated, semisynthetic tubulin-targeted vinca alkaloid obtained by the introduction of two fluorine atoms in the vinorelbine molecule.86 It has mitotic-arresting and tubulin-interacting properties, like other vinca alkaloids, but with reduced neurotoxicity, since has less affinity for the microtubules involved in axonal transport than those involved in mitosis.87,88 In preclinical studies, vinflunine was identified as having marked antitumoural activity in vivo against a large panel of tumour models, superior to that of vinblastine.89,90 Vinflunine showed synergism when combined with cisplatin, mitomycin C, doxorubicin and 5-fluorouracil.91 In a phase I trial with 31 patients with advanced malignancies, the toxicity profile of vinflunine consisted mainly of mucositis, constipation and neutropenia of short duration.92 Of concern, a patient developed grade 3 cardiac dysfunction confirmed on echocardiogram 90 min after the end of the vinflunine infusion, which responded to medical treatment. There were three PR (2 in breast carcinoma, 1 in renal cell carcinoma) out of 25 patients assessable for response, warranting exploration of the drug in phase II trials. A phase II trial of vinflunine as second-line treatment in MBC after anthracycline-taxane failure showed a response rate of 30% in 60 treated patients.93 The median duration of response was 4.8 months (95% CI: 4.2–7.2), median PFS was 3.7 months (95% CI: 2.8–4.2) and median OS was 14.3 months (95% CI: 9.2–19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients), with no febrile neutropenia observed. Similarly encouraging results were seen in patients with NSCLC who had failed first-line platinum containing treatment.94 The response rate was 8% in 63 treated patients. Median duration of response, median PFS and median OS were 7.8 months, 2.6 months and 7 months, respectively. Grade 3–4 neutropenia was reported in 50% of patients and febrile neutropenia, in 2 patients (3.2%). Nevertheless, in chemotherapy naive patients with metastatic melanoma, the results of vinflunine in a phase II study were disappointing. Based on the reports of anticancer activity in refractory breast cancer and NSCLC, phase III trials in these tumour types are anticipated.

Conclusions Despite the emerging and explosive increase in the understanding of molecular events underlying cancer progression, and the consequent development of molecular targeted anti-cancer agents, the current treatment for malignant tumours is still based predominantly on cytotoxic agents. There is an unquestionable demand for safer and more effective anticancer therapies that specifically target cancer cells and that overcome resistance path-

88 ways. The development of new taxanes is a good example of how to put together a better safety profile with a well established antitumoural efficacy. The new formulations of surfactant-free taxanes have been very successful in minimizing normal tissue exposure to free drug and escaping multidrug resistance efflux pumps, in addition to avoiding hypersensitivity reactions caused by the Cremophor EL solvent system present in the conventional formulations of paclitaxel. The cumulative cardiac toxicity associated with the use of anthracyclines may be overcame with the encapsulation of daunorubicin and doxorubicin in liposomes, as shown in clinical trials in ovarian and breast cancer. The development of the new platinum compound satraplatin incorporated the efficacy of platinum agents with the convenience of an oral presentation in the treatment of advanced prostate cancer. Of note is the importance of several marine natural products or derivatives as anticancer agents, emphasizing the potential role of microbial processes in the generation of bioactive and useful products. Novel cytotoxic agents have substantially increased the therapeutic portfolio for cancer patients, bringing not only gains in efficacy, but decreasing the frequency of adverse events and offering a better convenience in administration. Some of these new agents, like pemetrexed and liposomal doxorubicin, have already been incorporated into clinical practice worldwide. Several new cytotoxic agents are currently undergoing phase III trials and their results are optimistically expected to bring more advances in the treatment of cancer.

G.F.V. Ismael et al.

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Conflict of interest statement The authors disclose no conflicts of interests.

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Acknowledgement Dr. D.D. Rosa has received a post-doctoral grant from Coordenac ¸˜ ao de Aperfeic ¸oamento de Pessoal de Nı´vel Superior (CAPES), Brazil.

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