Recent developments in overcoming tumour cell multi-drug resistance

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  • Review

    Oncologic, Endocrine & Metabolic

    Recent developments in overcoming tumour cellmulti-drug resistance

    Gerhard Ecker & Peter Chiba

    The development of unspecific mechanisms of resistance re-mains a serious impediment to cancer chemotherapy. The termmulti-drug resistance (MDR) is defined as resistance of cancercells to a broad variety of structurally and functionally diversechemotherapeutic drugs. On the cellular level, several mecha-nisms responsible for MDR have been identified. In addition,numerous approaches for overcoming tumour cell MDR havebeen reported in the literature. This review focuses on patentspublished in 1995 and 1996 on modulators of MDR and relatedapproaches to therapy of multi-drug resistant tumours.

    Exp. Opin. Ther. Patents (1997) 7(6):589599

    1. Introduction

    There are close to six million deaths caused by cancerworldwide each year [1]. About half of the patientsstricken with this disease can be cured by surgery orradiation therapy because the tumour is localised tothe site of origin. The remaining cancers includesystemic haematological malignancies and tumoursthat have metastasised. From these cancer types, atpresent only a fraction (5 - 10%) can be cured bychemotherapy; the remainder are either intrinsicallyresistant towards chemotherapy or acquire resistanceduring the course of therapy.

    Clinical resistance is influenced by a wide variety offactors, such as tumour mass, stage of disease, vascu-larisation, age of the patient, pharmacokinetic and cellkinetic parameters, and the dosage and chemotherapyregimen employed. However, a correlation betweenclinical response and sensitivity of individual tumourcells can be observed. This suggests that clinicalresistance is at least in part due to biochemical resis-tance at a cellular level.

    A number of specific resistance mechanisms againstnatural and semisynthetic cytotoxins as well as against

    antimetabolites have been described [2]. These in-clude:

    lack of specific transport mechanisms which medi-ate cellular uptake of the compounds [3]

    decreased conversion to the biologically active me-tabolites [4]

    increased detoxification [5]

    alteration of the cellular target structure [6]

    increased excision-repair in the case of DNA-tar-geted compounds [7]

    In addition, a phenotype of tumour cells has beendescribed which causes simultaneous resistanceagainst a variety of structurally and functionally diversedrugs such as anthracyclines, epipodophyllotoxins,actinomycin D, vinca alkaloids, colchicine and taxanes[8]. This phenomenon has been termed MDR [9]. Twomajor causes for MDR have been identified. The firstprecludes drugs from reaching their potential intracel-lular targets and involves active efflux at the level ofthe plasma membrane [10]. The other cause is relatedto an inability of cells to undergo programmed celldeath (apoptosis) [11].

    5891997 Ashley Publications Ltd. ISSN 1354-3776

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  • Active efflux is mediated by a group of ATP-dependenttransmembrane proteins, among which P-glycoprotein(PGP) [12] and the MDR associated protein (MRP) [13]are the most well characterised members. In somecases, a direct relationship between PGP expressionand chemosensitivity has been reported. These includeleukaemias and lymphomas [14-18], myeloma [19],breast cancer [20,21], oesophageal carcinoma [22],childhood sarcomas [23] and neuroblastoma [24]. Overthe last 15 years, a number of substances or substance

    classes have been identified which are able to revertmulti-drug resistant cells to resemble their drug sensi-tive counterparts. These include:

    ion channel blockers such as verapamil [25]

    some dihydropyridines [26]

    amiodarone [27] and propafenone [28]

    steroids [29]

    cyclosporines [30]

    antipsychotic drugs like phenothiazines [31] andthioxanthenes [32]

    the antimalarial agent quinine [33]

    the triazinoaminopiperidine S 9788 (Servier) [34]

    the acridone carboxamide GF 120918 (Glaxo) [35]

    the pteridine derivative BIBW 22 (Boehringer Ingel-heim) [36]

    Several compounds are presently used in clinical PhaseII/III in conjunction with standard chemotherapy regi-mens. This article reviews the patent literature ofMDR-modulators for the past two years. For additionalinformation on clinical, biochemical and molecularaspects of MDR, the reader is referred to the compre-hensive review of Kane [37] and references therein.

    2.1 Low molecular weight multi- drug resistancemodulators

    The first MDR-modulator described in the literaturewas the calcium channel blocker verapamil (1). Vera-pamil blocks the multi-drug transporter P-glycoproteinand thus leads to resensitisation of mdr1-positivetumour cells to natural product toxins. Due to its highcardiovascular potency, dexverapamil ((R)-verapamil;Knoll [BASF]), which shows only 1/100 of the cardio-vascular activity of its antipode, was used in clinicalstudies [38]. American Cyanamid Co. claims, in EP-634401-A, a series of benzylmercaptane derivatives,whereby compound 2 is specifically claimed [101].Compound 2 shows potent in vivo activity againstvincristine-resistant murine leukaemia P388/VCR im-planted ip. in CDF1 mice, thus reducing the relativetumour growth (21 days) from 10.99 to 3.35 whenco-administered (150 mg/kg/dose) with doxorubicin.

    The potassium channel blocker amiodarone (3) is ahighly active PGP inhibitor in in vitro assays [39].Nevertheless, its clinical use as anti-arrhythmic agentis very limited because of its severe side-effects. Thesame situation might occur in the case of MDR-modu-lation. In EP-652004-A (Eli Lilly & Co.), a series ofderivatives are claimed, which show structural analogyto amiodarone [102]. The MDR-modulating activity of

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    590 Recent developments in overcoming tumour cell multi-drug resistance - Ecker & Chiba

    Ashley Publications Ltd. All rights reserved. Exp. Opin. Ther. Patents (1997) 7(6)

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  • raloxifene (4) and LY 139478 (5) in comparison to17-oestradiol and tamoxifen is given. Reversal factorsin HL60/ADR cells were 7.1 and 5.7, respectively (c.f.,oestradiol and tamoxifen which showed 1.0 and 1.4,respectively). In WO9611677-A (Eli Lilly & Co.) a seriesof 53 analogues (e.g., 6) with broader structurallyvariety is claimed [103]. They are stated to show asignificant effect on PGP, although no data are pre-sented.

    Two of the compounds more recently described are S9788 (Servier) [40] and BIBW 22 (Boehringer Ingel-heim) [41]. Both compounds show nitrogen containingcentral aromatic rings and seem to be specificallydesigned to act as inhibitors of the multi-drug trans-porter PGP. There were three patents published withinthe last two years claiming compounds with at leastsome structural analogy at the central aromatic moiety.Pfizer, Inc. claimed 24 derivatives (US5491234-A) witha central aminopyrimidine ring and two dimethoxy-benzene moieties (7), which seem to be characteristicfor verapamil-type MDR-modulators [104]. No biologi-cal data are presented. In a further invention fromPfizer, Inc. (US5583137) five diaminopurine analoguesare claimed (8) which also are stated to block PGPmediated transport of cytostatic drugs [105]. In analogyto the former patent, no biological data are presented.Dr Karl Thomae GmbH claimed a set of elevenpyrimido-pyrimidines (9) which show a resensitisationof adriamycin-resistant tumours [106]. Thus, cytotoxic-ity of the respective compounds was enhanced with asubtoxic concentration of 100 ng/ml adriamycin by afactor of 3 - 33.

    Glaxo Wellcome, Inc. claims in WO9611007-A paren-teral pharmaceutical compositions [107] containingGF-120918A (Glaxo), an acridoncarboxamide withhigh PGP inhibitory potency [42]. Xenova Ltd. claimsa series of 58 derivatives (10; WO9620190-A) whichlook like a hybrid between GF-120918A and XR-1500(Xenova). Some of the compounds specifically claimedshow EC50 values in the nanomolar range, when testedin a daunorubicin uptake assay [108]. Generally, activi-ties of the compounds were within 0.02 - 7.0 M.

    Phenothiazines are a well established class of com-pounds with regards to MDR-modulation. There areseveral studies published which show the efficacy ofthe compounds [43]. Additionally, some SAR-studieswere undertaken, which identify three important struc-tural features, including the hydrophobicity of thetricyclic ring, the length of the alkyl bridge and thecharge on the terminal amino group [44]. St. JudeChildrens Research Hospital claims a series of N-sub-stituted phenoxazines (11) structurally related to phe-nothiazines [109]. The compounds potentiate thecytotoxic activity of vincristine, vinblastine and

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