LEUKOCYTE-INDUCED ANGIOGENESIS AND SUBCUTANEOUS GROWTH OF B16 MELANOMA

We investigated the mechanism(s) by which systemic administration of d oxorubicin (DXR) produced growth retardation of B16 melanomas in the s ubcutis of syngeneic mice. DXR or saline was injected intravenously (i .v.) into C57BL/6 mice, and B16-BL6 cells were implanted subcutaneousl y (s.c.) on day 3, 7, or 21 after DXR treatment. In the DXR-pretreated mice, the tumors grew at a slower rate than in control (saline-treate d) mice. The experiments were repeated with a B16 variant resistant to DXR with similar results. Tumor growth retardation correlated with ex tent of myelosuppression monitored by counting bone marrow cells, circ ulating leukocytes and peritoneal macrophages. In DXR-pretreated mice reconstituted with 1 x 10(7) viable syngeneic spleen cells, the sc. tu mors grew at a rate similar to that in control mice. DXR treatment and spleen cell reconstitution experiments were repeated in BALB/c athymi c nude mice. The results were very similar. The growth of s.c. tumors was directly correlated with the degree of peritumoral vascularity. Th ese data indicate that in addition to its well-documented direct antit umor effects, DXR may produce retardation of tumor growth by producing myelosuppression and, hence, inhibition of host cell-induced tumor an giogenesis.