Oxazaphosphorine effects in L 5222 rat leukemia.

During the past two decades a few clinical reports have suggested that the therapeutic efficacy of cyclophosphamide against malignant tumors was partly mediated by drug effects on host immune mechanisms. This action was strictly dose-dependent: immunostimulation was only evident in the low dose range, whereas immunosuppression became significant at intermediate or high doses. In search for an experimental model of the immunoaugmenting effects of oxazaphosphorines it was found that the transplantable leukemia L 5222 of BD IX inbred rats could be cured by low doses of oxazaphosphorines, whereas this therapeutic activity was gradually lost with increasing doses. Dose-response relationship studies with cyclophosphamide and its stabilized 4-hydroxy-derivative mafosfamide showed a bell-shaped pattern. When the two compounds were compared, the immunotherapeutic range of mafosfamide was considerably broader. Further experiments suggested that the oxazaphosphorine effect was T-cell mediated. Treated and surviving animals were immune to additional tumor challenges. It was shown that mafosfamide at low concentrations inhibited preferentially T-suppressor cell proliferation in vitro; in analogy, an elimination of suppressor mechanisms could also be responsible for the in vivo effects. In clinical phase I studies, the maximally tolerated dose of mafosfamide was around 3 g/m2. The presented animal data, however, indicated that the immunopharmacological dose was approximately 10 times lower. Studies for immunotherapy with mafosfamide are currently ongoing in patients with non-small cell lung cancer and other malignant diseases.