Constitutive production of colony-stimulating factor by mouse lymphoma cell lines is correlated with granulocytosis in vivo.

The mouse lymphoma cell line Eb, its highly metastasizing variant ESb, and an unrelated metastasizing tumor MDAY-D2, were shown to produce colony-stimulating factor (CSF) constitutively both in vitro and in vivo in ascites. For each tumor, the amounts of CSF produced on a per-cell basis in vitro and in vivo were similar. The findings were substantiated using two different methods for CSF determination, a colony assay and an isotope incorporation test. Elevated levels of CSF in serum of mice with tumors were also found. Examination of blood from tumor-bearing mice revealed that whereas total leukocyte counts remained within the normal range, all three tumors caused a reversal of the normal neutrophil-lymphocyte ratio. The severity of the reversal correlated with the propensity of the tumor to elevate serum CSF rather than with in vitro CSF-producing capacity. Thus, whereas production of CSF in vivo was not related to the ability of the tumors to metastasize, it could be causative in creating an imbalance in normal hematopoiesis.

Effect of uracil arabinoside on metabolism and cytotoxicity of cytosine arabinoside in L5178Y murine leukemia.

Pretreatment of L5178Y murine leukemia cells with uracil arabinoside (ara-U) enhances the cytotoxicity of cytosine arabinoside (ara-C). This effect is mediated by the cytostatic effect of ara-U, which causes a delay of cell progression through S-phase. Consequently, the specific activity of enzymes that peak during S-phase increases, and deoxycytidine kinase increases 3.6-fold over untreated controls. This allows enhanced anabolism of ara-C to nucleotides, as well as increased incorporation into DNA with ultimate synergistic cytotoxicity. It is postulated that the systemic metabolism of high-dose ara-C to sustained high levels of ara-U in patients with acute leukemia may enhance the activity of subsequent doses of ara-C, and thus contribute to a means for pharmacologic self-potentiation, contributing to the unique therapeutic activity of high-dose ara-C.