LISOFYLLINE AS AN ADJUVANT TO HIGH-DOSE CYTOTOXIC THERAPY

Lisofylline, a dimethylxanthine derivative, has been shown to block th e induction of hematopoietic growth inhibitors produced in response to cytotoxic anticancer therapy. In the current study, mice bearing esta blished EMT-6 mammary carcinoma were treated with high dose cyclophosp hamide, melphalan, BCNU, 5-fluorouracil or with total body radiation a lone or with peripheral blood cells. The effect of lisofylline and/or G-CSF on leukocyte recovery was examined. Lisofylline was as effective as G-CSF in accelerating the recovery of white blood cells and granul ocytes after treatment with high dose chemotherapy or total body radia tion. Lisofylline alone or along with G-CSF was effective in protectin g animals from the weight loss caused by high dose melphalan but not f rom weight loss caused by other cytotoxic therapies. Administration of lisofylline did not alter the killing of bone marrow CFU-GM by single doses of cyclophosphamide, melphalan or BCNU. However, administration of lisofylline increased the killing of EMT-6 tumor cells taken from the same animals. Administration of lisofylline had no effect on EMT-6 tumor growth. However, treatment with lisofylline along with high dos e cyclophosphamide: melphalan, BCNU or 5-fluorouracil significantly in creased the tumor growth delay produced by these agents. Overall, in t he high dose therapy/EMT-6 mammary carcinoma model, lisofylline select ively enhanced hematopoietic recovery and increased tumor response to cytotoxic therapy.