In recent years, a series of new and highly cytotoxic analogues of CC-1065 and the duocarmycins have been developed that can be transformed into much less toxic prodrugs for the use in antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) and prodrug monotherapy (PMT) of cancer. In all these approaches, a relatively non-toxic prodrug is applied and subsequently converted selectively in the tumour tissue into a highly cytotoxic drug, thus reducing undesired side effects accompanying conventional chemotherapy. Here, the design and biological evaluation of prodrugs based on analogues of CC-1065 and the duocarmycins for the use in tumour selective cancer therapies is reviewed. The advantage of this approach is the excellent therapeutic index of some of the new prodrugs of over 5000 and the high cytotoxicity of the corresponding drugs with IC50 values of as low as 16 pM (IC50: concentration required for 50 % growth inhibition of target cells). In addition, a novel method for the correlation of the alkylation efficiency and the cytotoxicity based on mass spectrometry is described.
Keywords: ADEPT, anti-tumour agents, CC-1065, duocarmycins, targeted cancer therapy, PMT, prodrugs
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Published on: 01 March, 2012
Page: [304 - 325]