Review
Drug-targeting strategies in cancer therapy

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Abstract

Genetic changes in cell-cycle, apoptotic, and survival pathways cause tumorigenesis, leading to significant phenotypic changes in transformed cells. These changes in the tumor environment — elevated expression of surface proteases, increased angiogenesis and glucuronidase activity — can be taken advantage of to improve the therapeutic index of exisiting cancer therapies. Targeting cytotoxics to tumor cells by enzymatic activation is a promising strategy for improving chemotherapeutics.

Introduction

The most frequently used cancer therapies (e.g. taxol, cisplatin, Doxorubicin) were discovered in the laboratory >20 years ago. These therapies were discovered empirically, that is, they were identified in functional tumor cell-kill assays with no pre-exisiting knowledge of or bias towards the biochemical mechanism of action. More recently, the rational approach to drug design has been applied to the development of cancer therapies. This approach, which focuses on molecular targets that are responsible for cell transformation, has still been relatively ineffective at curing most malignancies. Recent clinical successes with inhibitors of the rational molecular targets that underlie the pathogenesis of cancer are encouraging (e.g. Abl kinase inhibitors [1], HER-2/neu antibody [2], and EGF receptor kinase inhibitors [3]) but the identification of all the molecular targets that are responsible for the majority of cancers is at present incomplete.

Ideally, a molecular target for cancer should play a unique causal role in the cancer's pathogenesis and be regulated differently between tumor cells and normal cycling tissues. Furthermore, the target should be positioned in a biochemical pathway so that a biochemical antagonist of the target will induce growth-arrest or apoptosis of the tumor cells. Identification of such targets is complicated by the genetic instability of cancer cells. Although multiple genetic changes contribute to the generation of cancer, many irrelevant genetic differences are commonly observed and complicate the identification of the critical molecular targets.

An alternative approach to developing more effective cancer therapies is to take advantage of phenotypic rather than genetic differences between tumor and normal tissues. These phenotypic differences can include elevated cell-surface protease activities, or increased expression of receptors or cell-surface antigens that may contribute to the transformation phenotype. Protein expression level changes in these cell surface markers can be, but are not necessarily correlated with, genetic changes. Many of these ‘phenotypic’ targets fail to meet all of the criteria outlined above for a pharmaceutically attractive anticancer target, and attempts to make inhibitors for several of these processes (e.g. gelatinase inhibitors [4], integrin antagonists [5], and bombesin antagonists [6]) have met with only limited success in both pre-clinical and clinical studies. Nevertheless, the relative selectivity of these cell-surface markers on cancer cells makes them intriguing molecules for the local delivery of established cancer therapeutics.

This tumor-targeted approach for cancer therapy is not new. Physical targeting can be achieved by a variety of mechanisms and this strategy has been adopted by many researchers. These efforts range from the addition of specific chemical moieties to well-characterized cytotoxic agents in an effort to simply improve the physical properties of the cytotoxic agent (e.g. see [7], [8]), to a prodrug strategy where activation of these complexes to cytotoxic metabolites occurs predominately in tumor cells (e.g. see [9], [10], [11]). The most rational and successful prodrug approaches involve conjugating specific cancer cell surface ligands (e.g. monoclonal antibodies, peptide hormones, or small molecules) with cancer chemotherapeutics, radioactive isotopes, or biological toxins in the hope of promoting their localization in tumor cells.

Multiple targeting strategies for cancer therapy have been comprehensively reviewed in several recent publications [12, [13]. The purpose of our article is to focus on a specific subset of these approaches in which recent advances in peptide–synthetic organic conjugation chemistry have demonstrated substantial improvements in antitumor activity. The most promising of these advances have occurred in the area of conjugation of small ligands or substrates (<1000 MW to existing chemotherapeutics such as the anthracyclines or taxanes. Most of the conjugates described here exhibit the highly desirable property of increasing the therapeutic index of existing cytotoxic agents in preclinical tumor models.

Section snippets

Rationale

The use of many anti-tumor compounds is restricted because of their narrow therapeutic index. Anthracycline (e.g. Doxorubicin, Daunorubicin therapy is limited, as the commonly used therapeutic doses induce myelo-suppression and cumulative doses that exceed 550mg/m2 engender a substantial risk of cardiotoxicity [14]. Doxorubucin is a DNA-damaging agent and can induce cell death through both p53-dependent and -independent pathways (e.g. see [15]). The basis for Doxorubicin's cardiotoxicity is

Glucuronidase-activated Doxorubicin

Attempts to reduce the toxicity of anthracyclines by incorporating their pharmacologically active species into prodrugs have been undertaken for many years. Similar strategies have also been applied to paclitaxel. One anthracycline prodrug which can be converted to Doxorubicin in the tumor microenvironment is HMR1826, which is a β-glucuronidase-activated substrate [19] (see Fig. 1). This compound, (N-4-β-glucoronosyl-3-nitrobenzyloxycarbonyl–Doxorubicin) contains glucuronic acid conjugated

Peptide hormone conjugates

In addition to the finding of β-glucuronidase in tumor tissue, many cancers exhibit elevated levels of several peptide hormone receptors (e.g. bombesin, lutenizing hormone-releasing hormone [LH-RH], or somatostatin receptors). Conjugation of a bombesin peptide to paclitaxel or an anthracycline to form a cytotoxic agent for treating tumors that express the bombesin receptor have recently been reported [25] (see Fig. 2). A seven amino acid bombesin/gastrin releasing peptide hormone was conjugated

Protease-activated conjugates

Conjugation of amino acid sequences on an alternative site of doxorubucin, the primary amine, also creates prodrugs with improved safety profiles relative to free Doxorubicin [39]. The primary mechanism of prodrug activation at this site is lysis of the amino-peptidyl bond by intracellular lysosomal proteases, resulting in an intracellular conversion to free Doxorubicin. Unlike the ester linkages present in the compound series noted above, the amino-peptidyl bond is relatively stable in serum

Conclusions

Each of the drug-targeting strategies mentioned above share a common principle of action which relies upon the delivery of a higher concentration of cytotoxic compound to the tumor cells than could otherwise be obtained by the administration of a free drug. These targeting approaches for improving cancer therapy are conceptually simple, although their execution is complex. The prodrug must be concentrated at the tumor cell through a combination of ligand binding and/or enzymatic processing. The

Acknowledgements

We wish to thank Charles Albright for helpful discussion and Kathy Kelly for help in preparing this manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • radical dotof special interest

  • radical dotradical dotof outstanding interest

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