Preface [Hot topic: Tumour-Selective Drug Activation (Executive Editor : L.H. Patterson)]

The problems associated with conventional anticancer agents that exert their actions by cytotoxicity are well known and often are dose limiting with regard to the therapeutic opportunity. Identification of strategies that rely on tumour selective drug activation is a very attractive approach to minimising host tissue toxicity and in principle can allow drug dosing regimens that are ultimately curative. Prodrug activation is central to the concept of tumour selective drug activation. Prodrugs sometimes do not find favour in the design of new drugs because of the possible biological variability in target tissue activation and consequent predictability of response. However in the treatment of cancers, which are invariably life-threatening, the prodrug offers a major opportunity for selective treatment whether it exploits the presence of a naturally occurring metabolic system or is coupled to a platform technology e.g. antibodies, genes, viral vectors and synthetic polymers all of which facilitate tumour specific activation. Both of these approaches were first identified in a previous issue of Current Pharmaceutical Design [1-7]. The present issue further elaborates prodrug activation that exploits tumour environment and delivery systems. Richard Knox and colleagues describes the use of NQO1 (DT- diaphorase) and nitroreductases as target enzymes for bioreductive activation of cytotoxic prodrugs. A fascinating component of this work is the discovery of NQO2, a latent nitroreductase that is present in some human tumours including colorectal cancers and hepatomas NQO2 in combination with the non-biogenic compound dihydronicotinamide riboside will reductively activate an aziridinyldinitrobenzamide (CB 1954) to a potent cytotoxin in vitro and in vivo [8]. The second article is by Brian Marples and colleagues and highlights the value of harnessing radiation therapy to control of the expression of a suicide gene delivered to the tumour prior to prodrug administration. Marples also discusses the treatment of tumours refractive to radiotherapy by employing oxygen-dependent promoters to produce selective therapeutic gene expression and prodrug activation in hypoxic cells [9]. A relatively new area, reviewed by Yoshisuke Nishi, is the use of catalytic antibodies (abzymes) that are genetically engineered to possess minimal immunogenicity and to selectively activate prodrugs that are not substrates for endogenous enzymes [10]. Adam Patterson and co-workers further elaborate on the theme of improving radiation therapy through GDEPT mediated prodrug activation and address the need for an effective bystander effect in which the cytotoxic prodrug metabolites redistribute efficiently into radiation responsive areas to enable radio sensitisation [11]. Lutz Tietze and T. Feuerstein elaborate further on enzyme activated prodrugs; specifically antibody-enzyme conjugates targeted to tumour associated antigens. Furthermore they discuss proton catalysed hydrolysis of prodrugs by harnessing the increased concentration of hydronium ions in malignant tissue under hyperglycaemic conditions [12]. References [1] McNally VA, Patterson AV, Williams KJ, Cowen RL, Stratford IJ, Jaffar M. Antiangiogenic bioreductive and gene therapy approaches to the treatment of hypoxic tumours. Curr Pharm Design 2002; 8: 1319-1333. [2] Patterson LH, Murray GI. Tumour cytochrome P450 and drug activation. Curr Pharm Design 2002; 8: 1335-1347. [3] Denny WA. Nitroreductase-based GDEPT. Curr Pharm Design 2002; 8: 1349-1361. [4] Wardman P. Indole-3-acetic acids and horseradish peroxidase: A new prodrug / enzyme combination for targeted cancer therapy. Curr Pharm Design 2002; 8: 1363-1374. [5] Searcey M. Duocarmycins-natures prodrugs? Curr Pharm Design 2002; 8: 1375-1389. [6] de Graaf M, Boven E, Scheeren HW, Haisma HJ, Pinedo H.M. Beta-glucuronidase-mediated drug release. Curr Pharm Design 2002; 8: 1391-1403. [7] Chen L, Waxman DJ. Cytochrome P450 gene-directed enzyme prodrug therapy (GDEPT) for cancer. Curr Pharm Design 2002; 8: 1405-1416. [8] Knox RJ, Burke PJ, Chen S, Kerr DJ. CB 1954: From the Walker tumour to NQO2 and VDEPT. Curr Pharm Design 2003; 9(26): 2091-2104. [9] Marples B, Greco O, Joiner MC, Scott SD. Radiogenetic therapy: Strategies to overcome tumour resistance. Curr Pharm Design 2003; 9(26): 2105-2112. [10] Nishi Y. Enzyme / Abzyme prodrug activation systems: Potential use in clinical oncology. Curr Pharm Design 2003; 9(26): 2113-2130. [11] Patterson AV, Saunders MP, Greco O. Prodrugs in genetic chemoradiotherapy. Curr Pharm Design 2003; 9(26): 2131- 2154. [12] Tietze LF, Feuerstein T. Enzyme and proton activated prodrugs for a selective cancer therapy. Curr Pharm Design 2003; 9(26): 2155-2175.