Lisofylline, a dimethylxanthine derivative, has been shown to block the induction of hematopoietic
growth inhibitors produced in response to cytotoxic anticancer
therapy. In the current study, mice bearing established EMT-6 mammary
carcinoma were treated with high dose
cyclophosphamide,
melphalan,
BCNU,
5-fluorouracil or with total body radiation alone 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 granulocytes
after treatment with high dose
chemotherapy or total body radiation.
Lisofylline alone or along with
G-CSF was effective in protecting animals from the
weight loss caused by high dose
melphalan but not from
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 dose
cyclophosphamide:
melphalan,
BCNU or
5-fluorouracil significantly increased the
tumor growth delay produced by these agents. Overall, in the high dose
therapy/EMT-6 mammary
carcinoma model,
lisofylline selectively enhanced hematopoietic recovery and increased
tumor response to cytotoxic
therapy.