Anticancer therapy with novel tubulin-interacting drugs

Kavallaris et al.

Anticancer therapy with novel tubulin-interacting drugs Maria Kavallaris,1 Nicole M. Verrills,1,2 Bridget T. Hill3 1

Children’s Cancer Institute for Medical Research, Randwick, NSW, Australia,

2

Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW,

Australia, 3 Division de Cancerologie Experimentale, Centre de Recherche Pierre Fabre, Castres, France

Abstract Antimitotic agents that target tubulin, including the taxanes and vinca alkaloids, are important components of current anticancer therapy. Whilst these antimitotic drugs are highly effective in the treatment of a number of cancers, both acquired and intrinsic resistance to these agents is a major clinical problem. Furthermore, the systemic toxicity, and in some cases lack of oral availability, make these agents less than ideal. Recently much effort has been directed on the isolation and synthesis of new antimitotic drugs that target the tubulin/microtubule system and display efficacy against drug-refractory carcinomas. Newly described compounds include structurally diverse natural products, such as dolastatin, epothilones and discodermolide, derivatives and structural analogues of traditional antimitotics, and novel synthetic molecules. Additionally, new developments in drug targeting are improving efficacy and therapeutic indices of traditional agents. A number of promising ‘new generation’ antimitotics are now undergoing clinical testing. These new agents are reviewed here in terms of their mechanism(s) of action on microtubules, effectiveness against drug-resistant tumour cells and clinical C 2002 Elsevier Science Ltd. All rights reserved. potential. °

INTRODUCTION hemotherapeutic agents that target tubulin are important in the treatment of both childhood and adult cancers. The success of these drugs is related to their mechanism of action, that leads to disruption of cell division and induction of apoptosis (Fig. 1). Unfortunately, the clinical usefulness of these agents is limited by the emergence of drug- resistant tumour cells and, in some patients, unacceptably high levels of neurological and bone marrow toxicity. To overcome these obstacles and to improve therapy, investigators in academia and the pharmaceutical industry have focused their efforts on identifying and developing new agents that target tubulin. It is well established that tumours derived from different cells and tissues display a wide variation in their responses to antimitotic drugs, although the reason(s) for this is far from clear. One likely source of tumour-cell differences is that associated with reduced drug accumulation and the multidrug resistance (MDR) phenotype which includes overproduction of the ATP-binding cassette (ABC) transmembrane transporters such as P-glycoprotein (Pgp), the family of multidrug resistance-associated proteins (MRPs)

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and the breast-cancer resistance protein (BRCP) (reviewed in refs 1–4). Interestingly, whilst Pgp and MRP1 have been shown to have a clear role in resistance to antimitotics,1–3 an elevated expression of BRCP has been associated with sensitivity to vinca alkaloids and to paclitaxel. Another less studied, but important source of tumour-cell differences, is the differential or altered expression of specific microtubule protein family members.5–8 These are likely in turn to affect microtubule dynamics and influence the effects of antimitotic drugs. Moreover, tubulin mutations can affect microtubule stability or interfere with drug-target binding.8–11 Alterations in microtubule structure resulting in altered microtubule dynamics and/or altered binding of antitubulin agents may well constitute a significant mechanism of drug resistance. To date, two of the most clinically useful classes of antimitotic drugs are the vinca alkaloids and the taxanes. Both are from natural products and are used extensively in the treatment of a range of human cancers. The vinca alkaloids (e.g. vincristine, vinblastine and vinorelbine) are cell-cycle specific, blocking cells at the metaphase/anaphase junction of mitosis, and in common with other antimitotic drugs such as colchicine, nocadazole and podophyllotoxin, destabilise microtubules. Taxanes (e.g. paclitaxel and docetaxel) are potent inhibitors of cell proliferation and arrest cells in mitosis, but in contrast to vinca alkaloids, promote the polymerisation of purified tubulin, causing stabilisation and bundling of microtubules.12–14 Both groups of agents target the tubulin/microtubule system. Microtubules are dynamic structures that are constantly growing and shortening and drugs such as the vinca alkaloids and taxanes affect both dynamic instability and treadmilling by interacting with their specific cellular target, β-tubulin.14,15 The clinical success of tubulin as a target for anti-cancer drugs has led the search for new agents that disrupt the tubulin/microtubule system (See Tables 1 and 2). These new agents will be reviewed in terms of their mechanism of action on microtubules, effectiveness against drugresistant tumour cells and clinical potential.

ANTI-MITOTIC DRUGS THAT DESTABILISE MICROTUBULES Vinca alkaloids Vinca alkaloids are natural products isolated from the periwinkle plant Catharanthus roseus. During the past 30 years, the vinca alkaloids vincristine and vinblastine have been used extensively in the treatment of cancer. Innovative chemistry has permitted the semisynthesis of derivatives modified in the velbanamine or ‘upper’ portion of the vinblastine structure.16 From these studies vinorelbine (Navelbine® ) was the first new second-generation vinca alkaloid to emerge and is now used both as a single agent and in combination therapy for cancers as diverse as lung (non small-cell), breast and ovary.17 More recently, a bis-fluorinated vinorelbine derivative, vinflunine, has been synthesised by the application of superacid chemistry.16 Of interest is that whilst all four vinca alkaloids interact with the vinca binding domain on tubulin, there is a clear hierarchy in terms of their overall affinities for purified tubulin. Vinorelbine and, even more so vinflunine, proved weak binders contrasting with the strong binding of vincristine and the

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doi: 10.1054/drup.2002.0230, available online at http://www.idealibrary.com on

New tubulin-targeted cancer treatments

Fig. 1 Effects of tubulin targeting drugs on cancer cells. Tubulin-targeting drugs disrupt microtubule dynamics that are crucial for cell division. Tumour cells that are drug sensitive undergo cell-cycle arrest at the G2/M phase of the cell cycle and subsequently undergo cell death (apoptosis). Resistance to tubulin-targeting drugs can lead to cell survival. Mechanisms responsible for drug resistance include those associated with the multidrug-resistance phenotype (MDR) and alterations in microtubule and associated proteins.

.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. Cryptophycins .. . Cryptophycins, isolated from the cyanobacterium Nostoc sp., ... are microtubule-destabilising agents and potent suppressors of ... . microtubule dynamics.25 Their binding to tubulin is competed .

intermediate level of vinblastine. These data suggested that the newer generation compounds may demonstrate reduced neurotoxicity.18,19 More recently, vinorelbine and vinflunine have been shown to affect microtubule dynamics very differently from vinblastine.20 A finding now extended by studying the effects on centromere dynamics which have provided evidence that the specific mechanisms of these three vinca alkaloids are distinct from one another.21 Vinflunine induces cell-cycle arrest in both a time- and concentration-dependent fashion and preclinical evaluations demonstrated that vinflunine displayed superior antitumour activity in vivo (reviewed in refs. 18,19). Evidence has also been presented indicating that the efficacy observed with both vinorelbine and vinflunine is likely to be due to their antivascular effects.18,22,23 Although vinflunine is a substrate for Pgp, the level of cross resistance in MDR-overexpressing cells is much lower than that observed for vinorelbine or vincristine. This correlates with the observation that vinflunine does not induce resistance as readily as vinorelbine following selection under either in vitro or in vivo conditions.24 Overall, vinflunine is a promising new agent that has completed phase I clinical trials and is now undergoing phase II testing. Vinorelbine is also attracting further interest with its oral formulation now in phase I.

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by vinca alkaloids. Certain synthetic analogues of cryptophycin, cryptophycin 52 and 55, were identified as potent inducers of Bcl-2 phosphorylation26 and were found to be active in a broad range of murine and human tumour xenografts.27,28 The cryptophycins are active in breast and ovarian tumour cells that overexpress Pgp. In addition to their effectiveness as single agents, they also show great promise in combination with either radiation or with 5-fluorouracil, doxorubicin, paclitaxel or irinotecan.27–29 Cryptophycin 52 is currently in early clinical trials for the treatment of solid tumours. Dolastatin Dolastatin-10 is a novel pentapeptide originally isolated from the marine mollusk Dolabella auricularia. Dolastatin-10 inhibits microtubule assembly and tubulin polymerization and is a non-competitive inhibitor of the binding of vinblastine to tubulin. 30 Although Dolastatin-10 is well tolerated clinically,31 in recent Phase II clinical trials as a single agent it lacked significant activity either in the treatment of hormone refractory prostate cancer32 or at 400 mg/m2 in previously untreated patients with advanced melanoma.33 However, new derivatives of dolastatin-10 such as TZT-1027 have now been identified with superior preclinical activity both in vitro and in vivo.34,35 Their recently reported33,36 anti-vasculature effects and reduced neurotoxicity in animal models further suggest that they may prove valuable new antimicrotubule agents and phase I trials are in progress.

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Kavallaris et al. Table 1 Microtubule destabilising agents under evaluation Agent Vinca alkaloids Vinflunine Onco-TCS Cryptophycin 52 & 55 Dolastatin Dolastatin-10 TXT-1027 Rhizoxin (NSC 332598) Synthetic Compounds D-24851 A-204197 Ab-conjugated drug C242-DM1

Compound

Derivative of vinflunine Liposomal vincristine Synthetic analogue of Cryptophycin that was originally isolated from cyanobacterium Nostoc sp, Noval pentapeptide originally isolated from marine mollusk Derivative of Dolastatin-10 Novel macrolide antitumor antibiotic

Development stage

Reference

Phase I clinical trials Phase II/III clinical trials for Non Hodgkins Lymphoma Phase I (cryptophysin 52)

19 87, 88 27–29

Phase I/II clinical trials

31–34

Preclinical Phase I/II clinical trials

34–36 97

N-(pyridin-4-yl)-{1-(4-chlorbenzyl)-indol-3-yl}glyoxyl-amid (4-{4-acetyl-4,5-dihydro-5-(3,4,5-trimethoxyphenyl)1,3,4-oxadiazol-2-yl}-N,N-dimethylbenzeneamine)

Preclinical/entering Phase I

37

Preclinical

38

Maytansine-antibody conjugate (tumour activated immunotoxin)

Phase I clinical trials

93

Table 2 Microtubule stabilizing agents under evaluation Agent Taxanes IDN5109 BMS-188797 BMS-184476 BMS-185660 RPR109881A TXD258 (RPR11625A) BMS275183 PG-TXL CT-2103 Polymeric micellar paclitaxel Taxoprexin PTX-DLPC PNU-TXL (PNU166945) Epothilones EpoB dEpoB BMS-247550 (aza-EpoB) dEpoF Discodermolide Laulimalides FR182877 (WS9885B) Synstab A

394

Compound

Development stage

Reference

14β-hydroxy-10-deacetylbaccatin III derivative Semi-synthetic derivative of paclitaxel Ether derivative if paclitaxel Semi-synthetic derivative of paclitaxel Taxane derivative Taxane derivative Novel oral taxane Conjugated poly(L-glutamic acid)-paclitaxel Conjugated poly(L-glutamic acid)-paclitaxel Polymeric (poly(DL-lactide)-block-methoxy polyethylene glycol) micellar paclitaxel DHA-conjugated paclitaxel Aerosol–liposomal paclitaxel Polymer-conjugated paclitaxel

Phase I Clinical Trials PhaseI/II Clinical Trials Phase I/II Clinical Trials Preclinical Phase II Clinical Trials Phase I/II Clinical Trials Phase I/II Clinical Trials Preclinical Phase I Clinical Trials Preclinical

56, 98 52 52 55 51 49, 50 99 100–102 94 103–106

Phase I/II Clinical Trials Preclinical Phase I Clinical trials

91, 92 89 107

Natural product and belongs to 16-membered ring macrolides Epothilone derivative Epothilone derivative Epothilone derivative Polyhydroxylated alketrane

Phase I/II Clinical Trials

58, 59

Derived from Streptomyces sp Small synthetic compound

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Final stages of preclinical evaluation Phase I Preclinical Preclinical Preclinical Early preclinical Early preclinical

69, 70, 73 65 73 80–83 77 108, 109 96

New tubulin-targeted cancer treatments .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ANTI-MITOTIC DRUGS THAT STABILISE .. .. MICROTUBULES .. .. .. Taxanes .. Paclitaxel (Taxol® ) was the first natural product described to ... interact with microtubules. Orginally isolated from the bark ... . of the Pacific yew, Taxus brevifolia,40 paclitaxel is a complex . Synthetic compounds Antimitotic compounds that make promising agents for clinical development should have high curative effects in vivo, be effective at destroying multidrug-resistant cells and hopefully have low levels of neurotoxicity. Tubulin-targeted compounds such as the vinca alkaloids and taxanes often cause peripheral neuropathy due to interference of neuronal vesicular transport in axons.6 A recently described microtubule inhibitor, D-24851, appears to fit these criteria. D-24851 or N-(pyridin4-yl)-{1-(4-chlorbenzyl)-indol-3-yl}-glyoxyl-amide is a synthetic compound identified from a cell-based screening assay that destabilises microtubules.37 It was found to be cytotoxic to a range of human tumour cell lines including ovarian (SKOV3), glioblastoma (U87), and pancreatic cancer (ASPC-1). It was also active on tumour cell lines expressing either the Pgp- or MRP-related resistance phenotypes. D-24851 is novel in that it does not compete for binding to either the vincristine- or colchicine-binding sites, implying a distinct tubulin binding profile. Oral D-24851 induced complete tumour regressions in rats bearing Yoshida AH13 sarcoma, markedly superior to the effects obtained with maximal tolerated i.p. doses of either paclitaxel or vincristine.37 Of significance was the absence of any systemic or neuro-toxicity at curative doses of D-24851, although neurotoxicity is difficult to identify in mice. It will be interesting to see whether this molecule with an oral formulation will also have any anti-vascular activity and results of Phase I clinical testing are eagerly awaited. A-204197, a novel oxadiazoline derivative (4-{4-acetyl-4,5dihydro-5-(3,4,5- trimethoxyphenyl)-1,3,4-oxadiazol-2-yl}-N,Ndimethylbenzeneamine), that binds tubulin and causes microtubule depolymerization has recently been reported.38 A-204197 is not a substrate for Pgp, displaying similar antiproliferative properties on cells that either lack, or express Pgp. As with other antimitotic drugs, A-204197 causes cell cycle arrest in G2 -M, increased phosphorylation of G2 -M regulatory proteins and Bcl-2 and induces apoptosis. A-204197 competitively inhibits the binding of 3 H-colchicine but not of {3 H}paclitaxel.38 To date, the number of cell lines examined have been limited and no data for A-204197 in in vivo tumour models have yet been reported. This same group though has now identified indolyloxazoline (A-259745) which maintains all the in vitro activities of the series and showed dose-dependent in vivo activity against the M5076 murine solid tumour, which was unresponsive to vincristine or paclitaxel.39 Again this in vivo activity was reported following administration via the oral route. It still remains to be determined whether this novel compound will be effective in cells resistant to other microtubule agents due to known tubulin/microtubule alterations.6,7 This new series of colchicine-site binders emanating from Abbott Pharmaceuticals are an interesting example of newer antimitotics.

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diterpenoid that blocks cell division and induces cell death.41 Paclitaxel-stabilised microtubules were used to elucidate the structure of tubulin42 and the docking analyses that were made possible by this achievement43 increased our understanding of paclitaxel binding and stabilization of microtubules. Paclitaxel binds to the β-tubulin subunit of microtubules at the M-loop, and stabilises lateral contacts between protofilaments,43,44 although the precise conformation of paclitaxel binding remains controversial (for review see45 ). Apart from paclitaxel being an MDR substrate, another limitation is that paclitaxel and its derivative docetaxel are highly hydrophobic, and thus require solubilisation in Cremophor EL® and polysorbate 80 respectively. Some of the toxic reactions observed in patients are thought to be due to these drug vehicles.46–48 The availability of the tubulin:paclitaxel structure has allowed for extensive structure- activity relationship (SAR) analyses and the design of novel taxane derivatives aimed at surmounting some of these limitations. Several such derivatives are in current development by pharamaceutical companies based on their activity against Pgp-expressing tumours. TXD258 is a new taxoid that, like paclitaxel, promotes tubulin assembly in vivo and stabilizes microtubules against cold-induced depolymerization.49 TXD258 has undergone extensive preclinical evaluation and showed excellent tumour regressions and long term survival in xenograft models of pancreas, head and neck, and prostate cancers. Importantly TXD258 is cytotoxic to P-glycoproteinexpressing cells in culture and in a docetaxel-resistant human tumour xenograft model.49 TXD258 also showed antitumour activity in mouse models of intracranial glioblastomas, indicating this agent can cross the blood brain barrier and hence may be useful in the treatment of CNS tumours. Phase I/II clinical trials are in progress with one partial response and a number of minor responses reported.50 Additionally, TXD258 has been shown to be active through oral administration in mouse models, thus circumventing another limitation of the traditional taxanes. RPR109881A is another taxane derivative with a similar mechanism of action to the natural taxanes, shows broad antitumour activity in vitro and in vivo but with minimal recognition by Pgp, and again an ability to cross the blood brain barrier (reviewed in reference 49). In a Phase I clinical trial partial responses were seen in a patient with non-small cell lung cancer and one patient with head and neck cancer, with minor responses in two other patients.51 Various dosing regimes were investigated and Phase II clinical trials are currently underway. Three novel taxane analogues, BMS184476, BMS185660 and BMS188797, have been recently reported on. BMS184476 showed efficacy superior to paclitaxel in three human tumour xenograft models following i.v. administration, with evidence of some activity against paclitaxel-resistant tumours, but not others.52 A therapeutic advantage for BMS188797 over paclitaxel after i.v. administration was also reported in four tumour models, two with partial resistance to paclitaxel.52 It remains to be seen if any therapeutic advantage is to be gained as these newer analogues enter clinical trials. Results of phase I trials reported at ASCO in 200153,54 provided evidence of some partial responses with acceptable toxicity profiles for these two analogues. A water-soluble paclitaxel derivative, BMS185660, with both oral and i.v. activity against human

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Kavallaris et al. tumour xenografts, has also been reported as a new lead compound in this series.55 Overall though it remains to be established as to whether these newer derivatives have any real therapeutic advantage over paclitaxel or docetaxol. IDN5109 is a new taxane, derived from 14β-hydroxy-10deacetylbaccatin III, selected for its lack of cross-resistance in tumour cell lines expressing the MDR phenotype.56 Encouraging in vivo preclinical data were recently published, indicating that after oral delivery a high level of activity against human ovarian carcinoma xenografts with differing sensitivities to paclitaxel was noted. The good oral bioavailability (48%), coupled with potent antitumour activity makes IDN5109 another attractive candidate for clinical study. Non-taxane microtubule stabilising agents As outlined above, many advances have occurred in the past few years that should improve the therapeutic index of taxanes. Whilst taxanes were the only known compounds to stabilise microtubules for twenty years after their initial discovery, the last decade or so has seen the identification of a number of other, structurally unrelated compounds that appear to act in a taxane-like manner and show great potential as new antimicrotubule chemotherapy agents. These new agents include the natural product epothilones, eleutherobins, sarcodictyins, and their respective analogues, as well as novel synthetic small molecules. Epothilones The 16-member macrolides, epothilone A (EpoA) and epothilone B (EpoB), are natural products first isolated in 1993 from the myxobacterium, Sorangium cellulossum, and initial assessment demonstrated their potency as antifungal agents.57 The epothilones were later shown to have a paclitaxel-like mechanism of action,58 and in contrast to paclitaxel, demonstrated remarkable growth inhibition of MDR cell lines.58–60 Epothilones were the first novel structural class of compounds to be described since the discovery of paclitaxel, that stabilise microtubules. Epothilones were shown to be active in Pgp-expressing and β-tubulin mutated paclitaxel resistant cells, so triggering a surge of investigations to synthesise these molecules. The first solid phase synthesis was described by Nicolaou and colleagues,61 and thus paved the way for the generation of combinatorial libraries containing numerous epothilone analogues. This influx of studies aimed at synthesizing the epothilones has also resulted in the culmination of substantial SAR data.62–65 SAR data point towards a common phamacophore for binding of the epothilones and taxanes.66,67 These compounds competitively inhibit {3 H}paclitaxel binding to microtubules58,59 which, together with data from mutational and pharmacophore analyses, strongly suggests a common binding site.9,67,68 The cytotoxicity of epothilones has been investigated in numerous cancer cell lines,9,58,59,62,64,69,70 with EpoB generally being more cytotoxic than either EpoA or paclitaxel. Most interesting though is the excellent cytotoxicity profiles of epothilones in multidrug resistant cell lines and in a number of paclitaxel resistant cell lines with mutations in β-tubulin.9 Mild resistance to epothilones in culture can be induced by continuous exposure of cultured cells to drug, however this develop396

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ment of resistance is far slower than for paclitaxel.64 Analyses of resistant cell lines detected mutations in β-tubulin either in the paclitaxel binding site,68 or in regions that influence microtubule stability,11 in the absence of MDR-1 expression. In in vivo models, EpoA and EpoB had only moderate antitumour activity, attributable to poor metabolic stability, pharmacokinetics and a narrow therapeutic window.70,71 However, results of Phase I trials of EpoB were encouraging and this agent has moved into Phase II clinical testing. BMS-247550 (aza-EpoB) is a semisynthetic EpoB analogue undergoing Phase I clinical trials.65,72 Preclinical studies showed it to be twice as potent as paclitaxel in inducing tubulin polymerization in vitro, and it induced cytotoxicity in tumour cells at low nanomolar concentrations. BMS-247550 retained its antineoplastic activity against human cancers that are naturally insensitive to paclitaxel or those that have developed resistance to paclitaxel, both in vitro and in vivo.71 Two other epothilone analogues which have been studied are 12,13-desoxyepothilones B (dEpoB) and 21-OH-dEpoB (dEpoF). Preclinical evaluation of dEpoB demonstrated it to have superior in vivo antitumour activity than EpoB or paclitaxel, although only small numbers of mice were evaluated.69,70 It was recently reported that dEpoB is at the final preclinical stage undergoing toxicology and pharmacokinetic testing in murine and dog models.73 Although at an earlier stage of development, dEpoF has also shown impressive curative effects in human tumour xenografts in nude mice.73 Eleutherobins, sarcodictyins and laulimalides The natural products eleutherobin, from Eleutherobia sp. and the sarcodicytins A-D, from Sarcodictyon roseium and Eleutherobia aurea, are coral-derived antimitotic agents. Sarcodictyins were originally described as having taxoidlike activity on microtubules, but with much lower relative cytotoxicity.74 The eleutherobins demonstrated similar cell proliferation inhibition to that of paclitaxel, with essentially comparable effects on microtubules.75 Both compounds inhibited the tubulin binding of radiolabelled paclitaxel and proved efficient substrates for Pgp. The successful synthesis of eleutherobin, sarcodictyins A and B, and a variety of analogues76 is now providing sufficient material for further characterisation, and has already provided a methyl ketal sarcodictyin A analogue that shows comparable activity to eleutherobin, yet also exhibiting activity in Pgp-expressing cells. Laulimalide and isolaulimalide are another group of active microtubule-stabilising natural products isolated from a lipophilic extract of the marine sponge Cacospongia mycofijensis, which also maintain their potency in Pgp-expressing cells.77 As the relative antimitotic activity of these agents is generally less than other tubulin stabilising agents in drug sensitive cells, it is unlikely that these agents will progress as anticancer chemotherapeutics. They may however provide the basis for chemical derivatization. Discodermolide Isolated from the marine sponge Discodermia dissoluta, discodermolide, a lactone- bearing polyhydroxylated alkatetraene, was originally realised as a potent immunosuppressor.78,79 Discodermolide inhibits cell proliferation,

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New tubulin-targeted cancer treatments inducing cell cycle arrest in the G2/M phase, mitotic bundling and affecting microtubule assembly in vivo more rapidly than paclitaxel.80–82 Discodermolide is significantly cytotoxic in Pgp- expressing cells, however not to the extent of the epothilones.82,83 To date, limited supplies from the natural source have hampered in vivo studies. Discodermolide has recently been shown to act synergistically with paclitaxel.83 Furthermore it was found that discodermolide, unlike epothilones and eleutherobin, could not substitute for paclitaxel in a paclitaxel-resistant cell line that requires low concentrations of paclitaxel for normal growth.83 Current progress in the total synthesis of discodermolide.84,85 will hopefully alleviate the supply problem and permit in vivo analysis of this exciting synergism. It will also be interesting to see if structurally altered discodermolides, such as the various acetylated derivatives recently described as showing enhanced antiproliferative activity in the murine leukemia cell line P38886 also exhibit synergistic properties. New delivery for ‘old’ drugs The success of the vinca alkaloids and taxanes is exemplified by their extensive use in the treatment of a wide range of human cancers. As mentioned previously, some clinical drawbacks to treatment with these agents is inadequate delivery of the drug to the tumour cells, the emergence of MDR and neurotoxicity. A number of new formulations for vinca alkaloids and taxanes that aim to overcome these obstacles are now in preclinical or clinical development. One approach has been improved targeting of drugs to tumours using liposomal formulations. Vincristine has been successfully encapsulated into liposomes and is now in phase III clinical trials for the treatment of relapsed non-Hodgkin’s lymphoma and in phase II clinical trials for first line lymphoma, small cell lung cancer and a number of childhood cancers.87,88 Paclitaxel has demonstrated therapeutic potential in the treatment of ovarian, breast and lung cancer.48 However, a number of difficulties have been encountered in the treatment of lung cancer and lung metastasis including reduced active drug accumulation in the tumour due to inactivation of the drug in the blood and liver prior to reaching the tumour. Using a localized delivery system to help overcome this obstacle, a recent preclinical study employed liposome encapsulated paclitaxel and delivered it as an aerosol to mice containing renal cell carcinoma lung metastases.89 A significant reduction in lung weights and visible tumour foci was observed and this also correlated with increased survival in mice inoculated with the tumour cells. Other formulations of paclitaxel include PEG- paclitaxel, dextran conjugated paclitaxel, poly-glu-conjugated paclitaxel, and micellar paclitaxel (reviewed in).90 Another approach to improving the efficacy of taxanes is to enhance the specific targeting of the drug to tumour cells. Anti-tumour agents typically have half-lives far shorter than the cell cycle transit times of most tumour cells. By specifically targeting the tumour the drug concentration will remain high for longer, with more cells to move into cycle, and thus enhanced tumour activity should result. Conjugation of a natural fatty acid to paclitaxel (DHA-paclitaxel or Taxoprexin) has shown superior therapeutic effects in animal models,91,92 with significant increases in the area-under-curve and therapeutic concentration sustainability relative to paclitaxel. Phase I clinc °

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ical trials with this formulation are in progress in patients with a variety of solid tumours. The idea of conjugating a drug to an antibody that recognises a specific tumour antigen has been around for a long time. Recent progress in the selection of antigens and drug conjugation made the feasibility of this approach more viable. C242-DM1 is a tumour-activated immunotoxin that consists of a humanized antibody, C242, conjugated to a maytansine derivative DM1. Maytansine is a tubulin binding agent and preclinical studies with the antibody-drug conjugate resulted in complete tumour regression in animal models of human pancreatic and non-small cell lung tumours.93 Phase I clinical trials are currently underway using this antibody-tubulin antagonist. If this approach is successful, it could lead to the development of a range of antibody-tubulin antagonist combinations. One advantage, already mentioned, for the newer generation of vinca alkaloids, vinroelbine and vinflunine, is their good oral bioavailability in preclinical in vivo models. Phase I evaluations of oral vinorelbine are underway and similar trials with vinflunine are planned. Other taxane derivatives aimed at improving their solubility and oral bioavailability are also in clinical trials. The conjugation of a poly (L-glutamic acid) to paclitaxel creates a water-soluble molecule that is currently being trialed.94 The ability to dispense with Cremophor EL® and ethanol vehicles is predicted to achieve a significant improvement in the pharmocokinetics of these taxanes. BMS275183 is a novel oral taxane that has good oral availability in rats and dogs, and preliminary Phase I clinical data indicate effective bioavailability in humans.95 Small molecule drugs The tubulin/microtubule system still remains one of the most important targets for cancer design. The search for small molecules as drugs that disrupt cell division led Haggarty and colleagues to utilise a high-throughput phenotype-based screen for identifying cell-permeable small molecules that affect mitosis.96 Of the 139 compounds found to increase the amount of phosphorylated nucleolin, indicating likely mitotic arrest, in asynchronous A549 lung epithelial tumour cells, 52 compounds were shown to destabilize microtubules, and one compound to stabilize microtubules. This compound, designated Synstab A, stabilised purified microtubules through a direct interaction with tubulin in a similar manner to paclitaxel, and led to microtubule bundles in interphase, disrupted spindles and caused abnormal mitotic chromosome distribution in kidney epithelial cells. The observed effects were reversible and Synstab A partially displaced fluorescently labeled paclitaxel, indicating a potential overlap in the tubulin binding site. The structure of this molecule is distinct from previously described microtubule stabilising agents, and highlights the potential for phenotype-based screening to identify novel anti-microtubule agents. This same approach is now being utilized by a number of pharmaceutical companies and offers the potential for identifying a number of novel antimitotics from natural product sources and chemical libraries. CONCLUSIONS AND FUTURE PERSPECTIVE In recent years the enormous effort invested in identifying new antimitotic therapies that target the tubulin/microtubule system has yielded a number of promising drugs for the treatment

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Kavallaris et al. of advanced stage cancers (Tables 1 and 2). In some cases, these new or modified anti-microtubule agents inhibit the growth of tumour cells that are MDR, and/or resistant tumour cells with paclitaxel-induced β-tubulin mutations. The ability of many of these agents to by-pass resistance associated with tubulin/microtubule changes including tubulin mutations, altered expression of tubulins and microtubule-associated proteins, still remains to be determined. An important parameter in evaluating any new anti-cancer agent is its therapeutic index, whereby the drug selectively kills tumour cells in the clinical setting. New agents that are highly effective in vivo may fail Phase I trials due to unacceptable toxicities. Many of the newer agents discussed in this review are now in early Phase I/II clinical trials. Whilst preliminary results for a number of these new tubulin targeted agents are encouraging, it is likely that the true potential of certain of these drugs will be not as single agents, but rather in combination therapies.110,111 In this respect, the various studies identifying synergistic interactions between these newer agents and ‘standard’ cytotoxics are encouraging. Combinations of agents with differential effects on the same overall target, namely the tubulin/microtubule system, may also prove effective in our search for active therapies to use against drug refractory cancers.

Received 18 January 2002; Revised and Accepted 4 February 2002 Correspondence to: Dr Maria Kavallaris, Children’s Cancer Institute Australia for Medical Research, High Street (PO Box 81), Randwick, NSW, Australia 2031, Tel: 61-2-9382 1823; Fax: 61-2-9382 1850; E-mail: [email protected]

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