Combinations of cytotoxic agents that have less than expected toxicity on normal tissues in mice.

A pretreatment dose of cyclophosphamide reduced lethality caused by high doses of busulphan or cyclophosphamide. In the case of cyclophosphamide given prior to busulphan, increased survival could be attributed to greater regeneration of haemopoietic stem cells in animals that received the combined dose compared with those that received busulphan alone. The mechanism by which cyclophosphamide pretreatment increased the animals' tolerance to a large dose of cyclophosphamide has not yet been elucidated. However, the urothelium in mice given the combined treatment was much less damaged than the urothelium in mice given the large dose alone, and its a known that bladder damage is a major feature of toxicity in patients given high-dose cyclophosphamide. This sparing combination exerted its expected toxicity on Lewis lung tumours, however, and so provided a useful differential effect against tumour tissue.