Cyclophosphamide, an orally active alkylating agent, is widely used to treat a variety of malignant and nonmalignant disorders. Although it has some tumour selectivity, it also possesses a wide spectrum of toxicities. The requirement of metabolic activation before cyclophosphamide exerts either its therapeutic or toxic effects is well established, but has not led to effective counter-measures. Clinically, damage to the bladder (haemorrhagic cystitis), immunosuppression (when not desired) and alopecia are the most significant toxicities associated with cyclophosphamide. Cardiotoxicity is also a possibility when very high doses are given. Preventing these toxicities has focused on modifications of the treatment regimens and, in the case of haemorrhagic cystitis, the administration of a drug which is excreted in the urine where it inactivates the bladder-toxic species. As treatment regimens for cancer become more effective in prolonging a patient's life, and as cyclophosphamide receives increasing use for nonmalignant disorders, the potential for cyclophosphamide-induced cancers, particularly in the bladder, must be recognised. Although the toxicities associated with cyclophosphamide are serious, this agent remains a highly effective drug in many situations. Research on the pathways which play an important role in activating this drug may improve our ability to target particular diseases and decrease unwanted side effects.

Reactive O2 species appear to be generated both during hypoxia and at reoxygenation, but it has not been established whether these species interact with heart tissue and cause injury. Oxidative changes were evaluated in isolated rat heart perfused with Krebs-Henseleit medium containing 10 mM glucose and 2.5 mM calcium. After 5-10 min hypoxia, tissue glutathione (GSH) decreased while glutathione disulfide (GSSG), protein carbonyls, and thiobarbituric acid reactive substances (TBARS) increased compared with controls. Similarly, sarcolemmal and sarcoplasmic reticular Ca-ATPase activity (an enzyme susceptible to oxidative inactivation) decreased in response to 10 min hypoxia. These changes were more pronounced after 60 min of hypoxia when protein-GSH mixed disulfides were also increased. There were no further oxidative changes after 4 min reoxygenation when the release of lactate dehydrogenase (LDH) was maximal. Myocardial protein thiol and alpha-tocopherol contents were not significantly changed by either hypoxia or reoxygenation. Mitochondria also exhibited oxidative changes but with more pronounced increases in GSSG and mixed disulfides. There was no change in GSH or GSSG efflux into the coronary effluent during hypoxia, although, in parallel with LDH release, both increased after reoxygenation. Diamide (200 microM), t-butylhydroperoxide (20 microM), or purine (2.3 mM) + xanthine oxidase (0.01 U/ml) were infused for 10 min. Except for large diamide-induced changes in protein thiols and mixed disulfides, the magnitude of the changes produced by these oxidants was similar to those produced by hypoxia. These data show that changes consistent with oxidative processes occur in whole heart and mitochondria in response to hypoxia. The absence of marked signs of oxidation at reoxygenation suggest that enzyme release at this time is unrelated to oxidative stress.

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In the human pancreatic cancer xenografts, i.t. administration of 5-FU/epi injectable gel provided significantly higher drug and/or metabolite concentrations for extended periods than was possible with either i.t. or i.p administration of drug solution. This i.t. drug delivery system could potentially be used to treat patients with pancreatic cancer to increase tumor exposure to drug and improve the therapeutic index in comparison to systemic drug administration.

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