Anticancer prodrugs for application in monotherapy: Targeting hypoxia, tumor-associated enzymes, and receptors

In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-speci fic delivery of cytotoxic anticancer agents. This review concentrates on re cent developments of antitumor prodrug monotherapy with prodrugs that are d esigned for direct recognition of tumor-associated factors, such as hypoxia , tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversio n of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta -glucuronidase leaks from necrotic areas within tumo rs, while tumor cells for invasive and metastatic activities need several t umor-associated proteases, like plasmin. These enzymes form an attractive t arget for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low mo lecular weight binding motifs for these receptors can be coupled to cytotox ic drugs in order to obtain tumor-homing conjugates. At present, receptor-b inding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of litera ture, which describes the complex interplay not only between tumor-associat ed enzymes, but also between these enzymes and tumor-associated receptors i n the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This pap er reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.