HEMATOPOIETIC RESCUE VIA T-CELL-DEPENDENT, ENDOGENOUS GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR-INDUCED BY THE PINEAL NEUROHORMONE MELATONIN IN TUMOR-BEARING MICE

We investigated whether melatonin can affect tumor growth and/or hemat opoiesis in mice transplanted with Lewis lung carcinoma and treated wi th cyclophosphamide or etoposide. These agents were injected i.p. for 5 days at two different cumulative doses (cyclophosphamide, 40 and 160 mg/kg body weight; etoposide, 20 and 40 mg/kg body weight) from day 8 through day 12 after tumor transplantation. Melatonin was injected s. c. at a dose of 1 mg/kg body weight/day, from day 8 throughout the exp eriments and from days 8 through 12 or from day 13 onwards. Melatonin did not influence tumor growth but selectively counteracted bone marro w toxicity when administered together with the cancer chemotherapy com pounds without interfering with their anticancer action. In vitro, mel atonin proved to counteract apoptosis in bone marrow cells incubated w ith etoposide. Such protection was reflected by an increased frequency of granulocyte/macrophage-colony forming units but not of the pluripo tent spleen-colony forming units. The effect of melatonin was neutrali zed by anti-granulocyte/macrophage-colony-stimulating factor monoclona l antibodies. When athymic, T-cell-deficient mice were used as bone ma rrow donors, melatonin did not exert any protective effect. This sugge sted that melatonin is able to stimulate the endogenous production of granulocyte/macrophage-colony-stimulating factor via bone marrow T-cel ls. Due to the well known lack of toxic and undesirable side effects o f melatonin, these findings might have a straightforward clinical appl ication.