Oxazaphosphorines: new therapeutic strategies for an old class of drugs.

IMPORTANCE OF THE FIELD: The oxazaphosphorines (cyclophosphamide, ifosfamide and trofosfamide) are widely used in clinical practice for their antitumor and immunomodulatory activities. However, their use is associated with toxicities. The metabolism of oxazaphosphorines involves cytochrome P450 biotransformations, leading to highly reactive metabolites such as acrolein and chloroacetaldehyde responsible for urotoxicity, neurotoxicity and nephrotoxicity. While the mechanisms behind these toxicities remain under investigation, some advances have been made, as exemplified by the use of mesna to limit acrolein related urotoxicity. AREAS COVERED IN THIS REVIEW: This review highlights potential strategies for limiting side effects commonly associated with the oxazaphosphorine drugs, through pharmacological or medicinal chemistry-based approaches. WHAT THE READER WILL GAIN: The readers will gain a comprehensive review of these approaches to treatment in terms of: i) pharmacology: use of antidotes and modification of metabolism through inhibition/induction of CYP enzymes or use of gene therapy; and ii) medicinal chemistry: the design of new drugs to target cancer cells and avoid CYP biotransformation with pre-activated prodrugs or with side-chain substituted analogues. TAKE HOME MESSAGE: An increased knowledge of oxazaphosphorines' metabolism and toxicity may allow the development of new anticancer drugs combined with drug delivery systems to circumvent drug toxicity, providing increased tumoral specificity and greater anticancer activity.