ReviewReceptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs
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
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