Review
Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs

https://doi.org/10.1016/S0163-7258(99)00018-2Get rights and content

Abstract

This review is a survey of various approaches to targeting cytotoxic anticancer drugs to tumors primarily through biomolecules expressed by cancer cells or associated vasculature and stroma. These include monoclonal antibody immunoconjugates; enzyme prodrug therapies, such as antibody-directed enzyme prodrug therapy, gene-directed enzyme prodrug therapy, and bacterial-directed enzyme prodrug therapy; and metabolism-based therapies that seek to exploit increased tumor expression of, e.g., proteases, low-density lipoprotein receptors, hormones, and adhesion molecules. Following a discussion of factors that positively and negatively affect drug delivery to solid tumors, we concentrate on a mechanistic understanding of selective drug release or generation at the tumor site.

Introduction

Despite several decades of intensive research in the laboratory and the clinic, the long-term outlook for cancer patients with aggressive disease remains discouraging Brun et al. 1997, Dunton 1997, Piccart 1996, Rahman et al. 1997. Unlike bacteria and viruses, cancer cells do not contain molecular targets that are completely foreign to the host. As a result, cytotoxic anticancer therapy has relied primarily on the enhanced proliferative rate of cancer cells, using drugs that act on DNA, tubulin, and enzymes such as the topoisomerases that are important in DNA replication. However, for patients with appreciable tumor burdens, clinically approved cytotoxics usually only cause remissions of limited duration and variable degree, followed by regrowth and spread of often more malignant and multidrug-resistant disease (Eltahir et al., 1998). Part of the reason for this is that hypoxic cells in the center of tumors can be essentially dormant and much less susceptible to traditional cancer drugs (Clarkson, 1974), not only because they are temporarily in a growth-arrested state, but also because of limited drug penetration (Erlanson et al., 1992) and induced cellular resistance mechanisms (Wartenberg et al., 1998). When these cells are revived by vascularization, following destruction of the tumor periphery, there is evidence that they often have a higher metastatic potential Young & Hill 1990, Young et al. 1988. In addition, aggressive micrometastases and minimal residual disease (Hirsch-Ginsberg, 1998), often beginning only as vanishingly small populations of cells that evade resection of the primary tumor or first-line chemotherapy, are often the cause of clinical relapse (Schott et al., 1998). These stray cells, which are difficult to detect, can also be present as contamination in autologous grafts after high-dose chemotherapy (Ross, 1998). Newer approaches to cancer chemotherapy that exploit angiogenesis, tumor suppressors, and other signal transduction pathways show promise, but have yet to make an impact in the clinic Alessandro et al. 1996, OReilly 1997, Schwartz 1996, Sebti & Hamilton 1997.

It can be argued that many of the shortcomings of currently approved cytotoxics are a result of dose-limiting toxic side effects, not only toward normally proliferative cell populations (Lowenthal & Eaton, 1996), but also, in the case of specific classes of chemotherapeutics, organ-specific toxicities such as the cardiotoxicity shown by most members of the widely used anthracycline family of anticancer agents Hortobagyi 1997, Shan et al. 1996. This effectively limits the amount of agent that can be given to below the threshold that exposes all the tumor tissue to a killing dose, resulting in induction of resistance mechanisms and metastasis. In the past several decades, various approaches toward targeting cytotoxic agents to cancer cells have been developed that use conjugated forms of these agents with carriers that selectively accumulate in tumors. The best of these approaches combine a protective mechanism for normal tissues that deactivates the agent until the tumor is reached, at which time, a tumor-specific mechanism releases the cytotoxic effect. Therefore, the goal of targeting is 2-fold: to actively deliver an effective dose of a cytotoxic agent to tumor tissue and to protect the rest of the body from its toxic effects.

This review will survey various approaches to targeting cytotoxic drugs to neoplastic tissue, using vehicles that show affinity for specific biomolecules expressed on the surface of cancer cells or in tumor-associated tissue, such as vasculature and stroma. It will emphasize the rational design of drug release mechanisms that take advantage of conditions at the tumor site or within cancer cells. It will not cover the following areas, for which the reader is directed to recent reviews or leading articles: delivery of protein toxins Ghetie & Vitetta 1994, Pastan 1997, radioimmunotherapy (Schott et al., 1994), boron-neutron capture therapy Chen et al. 1997, Mehta & Lu 1996, targeted photodynamic therapy Akhlynina et al. 1997, Peterson et al. 1996, electrochemotherapy (Jaroszeski et al., 1997), drug delivery using magnetic particles Devineni et al. 1995, Lubbe et al. 1996, T-lymphocyte targeting using bacterial superantigens Giantonio et al. 1997, Hansson et al. 1997 and bi-specific antibodies (Abs) Mokotoff et al. 1996, Renner & Pfreundschuh 1995, and passive targeting using liposomes Ceh et al. 1997, Sharma & Sharma 1997 and polymers Cummings 1998, Soyez et al. 1996, Zalipsky 1995.

Section snippets

Tumor-associated antigens

The delivery of immunoconjugates to tumor-associated antigens (Ags) has been the most commonly employed method of anticancer targeting in preclinical studies. Cancer cells overexpress many proteins in comparison with normal tissue, as a result of their transformed state. Modern hybridoma technology has allowed the large-scale production of monoclonal antibodies (mAbs) raised to numerous tumor-associated Ags Hellstrom & Hellstrom 1991, Hellstrom & Hellstrom 1997, Urban & Schreiber 1992, Wick &

Monoclonal antibodies

Most targeted mAbs fall into the immunoglobulin-γ (IgG) class, although IgMs have also been used (Ballou et al., 1992), especially for liposome (Ohta et al., 1993) and polymer Flanagan et al. 1993, Hoes et al. 1996 targeting. IgGs are symmetric glycoproteins (MW ca. 150,000) composed of identical pairs of heavy and light chains (Fig. 1). At the ends of the two arms are hypervariable regions containing identical Ag-binding domains. A variable-sized branched carbohydrate domain is attached to the

Cancer-associated proteases

Many cancer cells, especially those in fast-growing or aggressive neoplastic disease, express proteolytic enzymes, such as cathepsins B (EC 3.4.22.1) Elliott & Sloane 1996, Yan et al. 1998, D (EC 3.4.23.5) Matsuo et al. 1996, Ren & Sloane 1996, and L (EC 3.4.22.15) (Castiglioni et al., 1994), matrix metalloproteinases (Sato & Seiki, 1996), and plasminogen activators Devries et al. 1996, Lauck-Birkel et al. 1995, either membrane-bound or secreted extracellularly Scott 1997, Sloane 1996. These

Gene-directed enzyme prodrug therapy (virus-directed enzyme prodrug therapy)

The overall goal of gene-directed enzyme prodrug therapy (GDEPT), the delivery of an enzyme to the tumor to effect selective drug release, is similar to that of ADEPT. However, GDEPT differs from ADEPT in that the gene encoding the enzyme and not the protein itself is transferred to tumor cells. In addition, intracellular expression of the targeted protein places different requirements on the choice of enzyme and prodrug. The enzyme must be stably expressed inside the cell and exhibit

Conclusion

Clearly, major advances have been made in Ab-based anticancer drug targeting in the last 2 decades. Among the most important are those related to reducing the human immune response to the protein and increasing the tumor selectivity of drug release. Remarkable progress on these fronts has systematically reduced or eliminated side effects observed in the earliest clinical studies. However, the lack of significant antitumor activity in human patients, even in the most recent trials, must be

References (657)

  • R. Blaese et al.

    In situ delivery of suicide genes for cancer treatment

    Eur J Cancer

    (1994)
  • C. Boeckler et al.

    Immunogenicity of new heterobifunctional cross-linking reagents used in the conjugation of synthetic peptides to liposomes

    J Immunol Methods

    (1996)
  • M.P. Boland et al.

    The difference in kinetics of rat and human DT diaphorase result in differential sensitivity of derived cell lines to CB 1954

    Biochem Pharmacol

    (1991)
  • Z. Brich et al.

    Preparation and characterization of a water soluble dextran immunoconjugate of doxorubicin and the monoclonal antibody (ABL-364)

    J Controlled Release

    (1992)
  • J.A. Bridgewater et al.

    Expression of the bacterial nitroreductase enzyme in mammalian cells renders them selectively sensitive to killing by the prodrug CB1954

    Eur J Cancer

    (1995)
  • P. Carter et al.

    Engineering antibodies for imaging and therapy

    Curr Opin Biotechnol

    (1997)
  • T. Castiglioni et al.

    Immunohistochemical analysis of cathepsins D, B, and L in human breast cancer

    Hum Pathol

    (1994)
  • B. Ceh et al.

    Stealth liposomesfrom theory to product

    Adv Drug Del Rev

    (1997)
  • W. Chen et al.

    Selective boron drug delivery to brain tumors for boron neutron capture therapy

    Adv Drug Delivery Rev

    (1997)
  • E. Aboud-Pirak et al.

    Inhibition of human tumor growth in nude mice by a conjugate of doxorubicin with monoclonal antibodies to epidermal growth factor receptor

    Proc Natl Acad Sci USA

    (1989)
  • R. Abraham et al.

    Conjugates of COL-1 monoclonal antibody and beta-d-galactosidase can specifically kill tumor cells by generation of 5-fluorouridine from the prodrug beta-d-galactosyl-5-fluorouridine

    Cell Biophys

    (1994)
  • J.R. Adair

    Engineering antibodies for therapy

    Immunol Rev

    (1992)
  • K. Affleck et al.

    Monoclonal antibody targeting of methotrexate (MTX) against MTX-resistant tumour cell lines

    Br J Cancer

    (1992)
  • H. Ahmad et al.

    Daunorubicin coupled to monoclonal antibodies via a cis-aconitic anhydride linkerbiochemical and cytotoxic properties revisited

    Anticancer Res

    (1990)
  • S.K. Akiyama et al.

    Fibronectin and integrins in invasion and metastasis

    Cancer Metastasis Rev

    (1995)
  • R. Alessandro et al.

    Signal transduction as a therapeutic target

    Curr Top Microbiol Immunol

    (1996)
  • T.M. Allen et al.

    Antibody-targeted stealth liposomes

  • A. Anichini et al.

    The role of cytokines in the modulation of cell surface antigens of human melanoma

    Int J Biol Markers

    (1993)
  • L.D. Apelgren et al.

    Antitumor activity of the monoclonal antibody-Vinca alkaloid immunoconjugate LY203725 (KS1/4-4-desacetylvinblastine-3-carbohydrazide) in a nude mouse model of human ovarian cancer

    Cancer Res

    (1990)
  • W. Arap et al.

    Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model

    Science

    (1998)
  • R. Arnon et al.

    In vitro and in vivo efficacy of conjugates of daunomycin with anti-tumor antibodies

    Immunol Rev

    (1982)
  • G.J. Atwell et al.

    Synthesis and evaluation of 4-substituted analogues of 5-[N,N-bis(2-chloroethyl)amino]-2-nitrobenzamide as bioreductively activated prodrugs using an Escherichia coli nitroreductase

    Anticancer Drug Des

    (1996)
  • K.D. Bagshawe

    Antibody directed enzymes revive anti-cancer prodrugs concept

    Br J Cancer

    (1987)
  • K.D. Bagshawe et al.

    Cyclosporin delays host immune response to antibody enzyme conjugate in ADEPT

    Transplant Proc

    (1996)
  • K.D. Bagshawe et al.

    A cytotoxic agent can be generated selectively at cancer sites

    Br J Cancer

    (1988)
  • K.D. Bagshawe et al.

    Antibody directed enzyme prodrug therapy (ADEPT)—clinical report

    Dis Marker

    (1991)
  • K.D. Bagshawe et al.

    Antibody directed enzyme prodrug therapya pilot scale clinical trial

    Tumor Target

    (1995)
  • S. Bailey et al.

    Nitroreductase activation of CB1954—an alternative ‘suicide’ gene system

    Gene Ther

    (1997)
  • S. Bailey et al.

    Investigation of alternative prodrugs for use with E. coli nitroreductase in ‘suicide gene’ approaches to cancer therapy

    Gene Ther

    (1996)
  • C.T. Baillie et al.

    Tumour vasculature—a potential therapeutic target

    Br J Cancer

    (1995)
  • S. Bajusz et al.

    Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone

    Proc Natl Acad Sci USA

    (1989)
  • S. Bajusz et al.

    Highly potent analogues of luteinizing hormone-releasing hormone containing d-phenylalanine nitrogen mustard in position 6

    Proc Natl Acad Sci USA

    (1989)
  • A.M. Ballesta et al.

    Carcinoembryonic antigen in staging and follow-up of patients with solid tumors

    Tumour Biol

    (1995)
  • B. Ballou et al.

    Tissue localization of methotrexate-monoclonal-IgM immunoconjugatesanti-SSEA-1 and MOPC 104E in mouse teratocarcinomas and normal tissues

    Cancer Immunol Immunother

    (1992)
  • R.B. Bankert et al.

    Immunospecific targeting of cytosine arabinonucleoside-containing liposomes to the idiotype on the surface of a murine B-cell tumor in vitro and in vivo

    Cancer Res

    (1989)
  • D. Barba et al.

    Thymidine kinase-mediated killing of rat brain tumors

    J Neurosurg

    (1993)
  • S. Baroni et al.

    Prognostic relevance of lipoprotein cholesterol levels in acute lymphocytic and nonlymphocytic leukemia

    Acta Haematol

    (1996)
  • A.J. Barrett

    Cathepsin B, cathepsin H, and cathepsin L

    Methods Enzymol

    (1981)
  • R.C. Bast et al.

    Selected molecular targets for diagnosis and therapy of epithelial ovarian cancer

    Cancer Mol Biol

    (1994)
  • R. Batchelder et al.

    Oxygen dependence of the cytotoxicity of the enediyne anti-tumor antibiotic esperamicin A1

    Br J Cancer

    (1996)
  • Cited by (261)

    • smProdrugs: A repository of small molecule prodrugs

      2023, European Journal of Medicinal Chemistry
    • Role of nanocarriers in photodynamic therapy

      2020, Photodiagnosis and Photodynamic Therapy
      Citation Excerpt :

      The treatment of cancer has still not achieved optimal outcome for various reasons including current therapies lack of tumor selectivity, toxicity, and marked collateral damaged to healthy cells. Therefore, among newly designed strategies for the treatment of cancer are those which deliver the drug directly to the tumor site, thereby enhancing the tumor selectivity via coupling to tumor-specific antibodies, use of carrier adapted system or the targeting of proteases expressed, abundantly in tumor environment [1]. Photodynamic therapy (PDT) received great attention t due to its tumor selectivity [2].

    • Antibody-drug conjugates: Current status and future perspectives

      2016, Pharmacology and Therapeutics
      Citation Excerpt :

      BR96-doxorubicin is an example of a first generation ADC (Trail et al., 1993), in which a chimeric mAb (BR96), directed against the LewisY tetrasaccharide (LeY) antigen commonly expressed on human carcinomas, was linked to eight molecules of doxorubicin, a clinically approved DNA intercalator. The drug was coupled to the hinge cysteine residues of BR96 by an acid-labile hydrazone linker (Dubowchik & Walker, 1999). Upon binding to cell surface antigens and internalization, the acidic environment (approx.

    View all citing articles on Scopus
    View full text