Drug Targeting Organ-Specific Strategies

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224 8 Strategies for Specific Drug Targeting to Tumour Cells moural concentration of doxorubicin at a level required to achieve regression. It is likely therefore that immunoconjugates of doxorubicin will be only effective in minimal-disease settings. In general, trials with radioimmunoconjugates reported higher response rates in patients with haematological malignancies when compared with patients with solid tumours. The most impressive studies with non-myeloablative regimens reported objective responses in 70–80% of patients with chemotherapy-refractory B-cell lymphomas, a median response duration of 12 months and minimal toxicity using 131-I-labelled anti-CD20 [134]. In trials with myeloablative regimens, performed in conjunction with autologous haematopoeitic bone marrow or stem cell transplantation, responses have been seen in 95% of patients, complete responses in 85%, with a progression-free survival of 62% and overall survival of 93% with a median follow-up of 2 years [135,136].The estimated 4-year overall and progression-free survival rates were reported to be 68 and 42%, respectively [137]. Anti-CD45 antibody BC8 labelled with 131-I may reduce the rate of tumour relapse and has acceptable toxicity in patients with AML,ALL or myelodysplastic syndrome who underwent stem-cell rescue [138]. Of 25 patients treated with advanced AML and myelodysplastic syndrome, seven were disease-free at 15–89 months post-transplantation. Of nine patients with advanced ALL, three were disease-free at 23, 58 and 70 months post-transplantation, respectively. As with the monoclonal antibody therapies described above, B-cell malignancies would be the most attractive targets for anti-CD3 bispecific monoclonal antibody-based immunotherapy [139]. Several phase I/II clinical trials have been described using BsMAb for non B-cell malignancies. BIS-1, a BsMAb directed against the TAA EGP-2 and the CD3/T-cell receptor complex on T lymphocytes was studied in renal [140] and lung cancer [141]. In carcinoma patients with EGP-2 positive malignant ascites or pleural exudates, local administration of exvivo IL-2-activated autologous lymphocytes and BIS-1, resulted in both anti-tumour effects and a strong local inflammatory reaction [141]. In patients with advanced breast or ovarian cancer administration of BsMAb directed against FcγRI or FcγRIII and HER-2/neu resulted in elevated plasma levels of cytokines [142,143]. The biological effects observed at tumour sites indicate that BsMAbs effectively penetrate tissue. However, trials are limited by the toxicity caused by induction of a ‘cytokine storm’ or by the complex pharmacokinetics. Furthermore, T-cell directed BsMAb approaches are hindered by difficulties in mobilizing and activating T and NK effector cells. Recent attention, therefore, has focused on BsMAbs which target myeloid effectors [79]. 8.6.2 Pro-drugs ADEPT strategies have been described but only the carboxypeptidase G2 approach has been tested in patients so far. In a phase I clinical trial, patients with non-resectable metastatic or locally recurrent colorectal carcinoma were treated with ADEPT. Carboxypeptidase G2 activity was found in metastatic tumour biopsies.The pro-drug was converted into the active drug but leakage into the bloodstream also occurred [22,144]. Clinical trials with ‘monotherapy’ pro-drug strategies are in progress, but have not yet been evaluated.
8.6.3 (Synthetic) (co)Polymers Soluble polymer conjugates have been introduced into clinical practice in the last decade [90,94]. Several PEG conjugates have been evaluated clinically [145] for cancer therapy including a PEG conjugate of asparaginase in the treatment of ALL in patients hypersensitive to the native enzyme [146], and a PEG conjugate of IL-2 [147]. A phase I clinical and pharmacokinetic study of PK1 comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94]. PK1 demonstrated anti-tumour activity, and that polymer–drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 8.6.4 Liposomes 8.6 Clinical Studies 225 There are three liposomal forms of doxorubicin or daunorubicin on the market (Table 8.6). Doxil ® and DaunoXome ® have been approved for the treatment of AIDS-related Kaposi’s sarcoma and are being evaluated in clinical trials for the treatment of a variety of cancers [148–151]. Evacet ® (liposomal doxorubicin) has recently been tested in large phase II and III clinical trials for the treatment of metastatic breast cancer and is awaiting approval by the FDA [151]. Data obtained from trials thus far suggest that all three liposomal drugs offer significant therapeutic benefit compared with the free drug [113]. Table 8.6. Monoclonal antibody based products and liposome formulations registered for cancer therapy in the USA and/or Europe. Generic name Trade name Company Indication Rituximaba Rituxan Roche Relapsed or refractory low- (Mabthera) c grade/follicular non- Hodgkin’s lymphoma Trastuzumaba Herceptin Genentech-Roche Metastatic breast cancer Edrecolomaba Panorex Glaxo-Wellcome Post-operative adjuvant therapy Dukes C colorectal carcinoma Doxorubicinb Doxil Alza-corporation AIDS-related Kaposi’s (Caelyx) d sarcoma Daunorubicinb DaunoXome Nexstar AIDS-related Kaposi’s Pharmaceuticals sarcoma Doxorubicinb Evacet The Liposome Metastatic breast cancer (Myocet) e Company, Inc. a MAb-based. b Liposome formulation. c Rituxan is known as Mabthera in Europe. d Doxil is known as Caelyx in Europe. e Evacet is known as Myocet in Europe.
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Drug Targeting Organ-Specific Strat
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Preface Drug Targeting Organ-Specif
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Foreword Drug Targeting Organ-Speci
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X List of Contributors Henderik W.
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XII List of Contributors Grietje Mo
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Contents Drug Targeting Organ-Speci
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Contents XVII 3 Pulmonary Drug Deli
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Contents XIX 5.2.1.6 Identification
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Contents XXI 7.5 In Vitro Technique
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Contents XXIII 9.4 Tumour Vasculatu
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Contents XXV 12.8. Tissue Slices fr
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Dexa dexamethasone DIVEMA divinyl e
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LRP lung resistance related protein
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ROS reactive oxygen species RSV res
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Index a ADEPT 217, 224, 268, 291 ad
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e E. coli expression system 292 eff
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polymers, soluble 4, 218 - dendrime
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2 1 Drug Targeting: Basic Concepts
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24 2 Brain-Specific Drug Targeting
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54 3 Pulmonary Drug Delivery: Deliv
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4 Cell Specific Delivery of Anti-In
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The sinusoids are lined by the disc
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4.2.2.2 Phagocytosis and Transcytos
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ther inflammatory cells or accessor
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4.3 Hepatic Inflammation and Fibros
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process is not yet available. Sever
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this carrier to the KCs.When the ma
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e taken up rapidly by mannose recep
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y the transcriptional regulatory pr
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4.8 Testing Liver Targeting Prepara
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4.8 Testing Liver Targeting Prepara
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4.9 Targeting of Anti-inflammatory
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4.9 Targeting of Anti-inflammatory
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with monoclonal and bispecific anti
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References 117 [50] Coleman DL, Eur
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References 119 [133] Cronstein BN,
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5 Delivery of Drugs and Antisense O
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5.1 Introduction 123 convoluted tub
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treatment of the targeted cell and
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CL uptake (ml/min/g) centration pro
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5.2.1.4 Specific Binding of Alkylgl
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5.2 Renal Delivery Using Pro-Drugs
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5.2 Renal Delivery Using Pro-Drugs
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5.3 Renal Delivery Using Macromolec
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5.4 Renal Delivary of Antisense Oli
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5.4 Renal Delivery of Antisense Oli
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5.4.8 Benefits and Limitations of A
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via reabsorption from the luminal s
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References 153 [66] Franssen EJF, M
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References 155 [145] Van Zwieten PA
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158 6 A Practical Approach in the D
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Page 243 and 244: larly cytotoxic immune effector cel
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Page 263 and 264: References 229 [43] Chaouchi NA, Va
Page 265 and 266: References 231 [126] Czuczman MS, G
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carrier is an homogenous product. I
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11.3 The Homing Device 11.3 The Hom
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malian cell lines that have acquire
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jugates for the delivery of other a
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11.5 The Linkage Between Drug and C
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actions are directed towards these
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11.5 The Linkage Between Drug and C
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homing potential if the antigen rec
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ly used promoters include T7 RNA po
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the baculovirus expression vector,
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11.8 Recombinant DNA Constructs 297
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11.8 Recombinant DNA Constructs 299
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toxic activity. Anthrax and tetanus
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11.9 Recombinant Domains as Buildin
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References 305 [16] Milstein C, Wal
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References 307 [99] Verma R, Boleti
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12 Use of Human Tissue Slices in Dr
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are also extensively used in a vari
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Meanwhile many incubation systems h
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12.3 Incubation and Culture of Live
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to investigate the effect of differ
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The mechanisms of uptake and excret
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12.6 The Use of Liver Slices in Dru
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12.7 Efficacy Testing of the Drug T
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NO x µM 80 60 40 20 * * 12.7 Effic
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TNFα ng/ml 1.5 1 0.5 0 * Human (n=
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References 329 [33] Ikejima K, Enom
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References 331 [109] Dutt A, Priebe
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334 13 Pharmacokinetic/Pharmacodyna
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372 14 Drug Targeting Strategy: Scr
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374 14 Drug Targeting Strategy: Scr
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