Current Pharmaceutical Design - Volume 8, Issue 15, 2002

Quinone based bioreductive drugs have, potentially, a very versatile use in cancer chemotherapy. They can be activated by DT-diaphorase and hence can be used to target tumour types rich in this O2- independent reductase enzyme. Small molecular modifications can substantially reduce specificity for DTdiaphorase and under these circumstances the quinones become much less toxic in air but retain their potent cytotoxic Read More

The expression of drug metabolising cytochrome P450s (CYPs) notably 1A, 1B, 2C, 3A, 2D subfamily members have been identified in a wide range of human cancers. Individual tumour types have distinct P450 profiles as studied by detection of P450 activity, identification of immunoreactive CYP protein and detection of CYP mRNA. Selected P450s, especially CYP1B1, are overexpressed in tumours including cancers of the lung, br Read More

Nitroreductases that metabolise aromatic nitro groups to hydroxylamines are attractive as enzymes for GDEPT because of the very large electronic change that this metabolism generates, providing an efficient “switch”that can be exploited to generate potent cytotoxins. While nitroreductase enzymes are widespread, nearly all the work using these in GDEPT has been with the nfsB gene product of Escherichia coli, an oxygen-in Read More

The duocarmycins and (+)-CC-1065 are amongst the most potent antitumour antibiotics discovered to date and yet have not progressed into the clinic. The natural products are extremely stable to nucleophilic attack until bound to their DNA target and are not substrates for any other biological nucleophile. The mechanism for this target activation of the duocarmycins is discussed with relation to both an acid-catalyzed Read More

The selective activation of a relatively non-toxic prodrug by an enzyme present only in the tumour should enhance the drug concentration at the tumour site and result in a better anti-tumour effect and a reduction in systemic toxicity as compared to conventional chemotherapy. β-Glucuronidase is such an enzyme. It is normally expressed in the lysosomes of cells. In larger tumours, however, high levels of the enzy Read More

Several commonly used cancer chemotherapeutic prodrugs, including cyclophosphamide and ifosfamide, are metabolized in the liver by a cytochrome P450 (CYP)-catalyzed prodrug activation reaction that is required for therapeutic activity. Preclinical studies have shown that the chemosensitivity of tumors to these prodrugs can be dramatically increased by P450 gene transfer, which confers the capability to activ Read More